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Review Article | Open Access
Blood Brain Barrier: A Challenge for Effectual Therapy of Brain Tumors
Brain tumors are one of the most formidable diseases of mankind. They have only a fair to poor prognosis and high relapse rate. One of the major causes of extreme difficulty in brain tumor treatment is the presence of blood brain barrier (BBB). BBB comprises different molecular components and transport systems, which in turn create efflux machinery or hindrance for the entry of several drugs in brain. Thus, along with the conventional techniques, successful modification of drug delivery and novel therapeutic strategies are needed to overcome this obstacle for treatment of brain tumors. In this review, we have elucidated some critical insights into the composition and function of BBB and along with it we have discussed the effective methods for delivery of drugs to the brain and therapeutic strategies overcoming the barrier.
Brain is the most delicate organ of human body. Several diseases like encephalitis, neurological disorders, multiple sclerosis, stroke, and tumor induce deterioration of brain function. The development of new therapeutic approaches for these diseases is a difficult challenge, and there is no effective treatment for almost all the brain diseases. In most of the cases, the major cause of the failure in the development of drugs to treat brain diseases is the presence of BBB. Out of the several brain disorders, brain tumors commonly have poor prognosis, which varies according to the type and grade of the tumor. Due to the presence of BBB, drug delivery to brain tumors has long been a problematic issue. Some group of researchers like Vick et al. and Donelli et al. mentioned BBB as a controversial problem for brain tumor chemotherapy [1, 2]. They indicated that BBB is not the only factor responsible for impeding the success of brain tumor chemotherapy, but later, studies revealed the involvement of BBB in drug restriction to different brain neoplasias [3–6].
Brain tumors can be classified into two major classes, namely, primary brain tumors that start in the brain and secondary brain tumors that are generated by the cancer cells that migrated from tumors developed in other parts of the body. Primary brain tumors can arise from different type of brain cells or even from the membranes around the brain (meninges), nerves, or glands. The most common type of primary tumors in the brain is glioma, which arises from the glial tissue of the brain. Gliomas comprise several types, namely, astrocytoma, oligodendroglioma, and ependymomas. Astrocytomas are further classified as grade I (pilocytic), grade II (fibrillary), grade III (anaplastic), and grade IV (glioblastoma multiforme or GBM). BBB is poorly developed in these types of brain tumors causing an increased vascular permeability .
It has been shown earlier that leaky interendothelial tight junction is present in human glioma  due to the fact that poorly differentiated neoplastic astrocytes do not release factors essential for BBB function [9–11]. This tight junction opening causes increased chances of cerebral edema occurrence . It is also observed that BBB stability in lower grade gliomas is better than that in GBM. As the degree of BBB disruption differs from the malignancy of the tumor, treatment of low grade brain tumors is still a challenging task, because of the presence of almost intact BBB. On the contrary, recent studies have suggested that although the BBB may be disrupted at or near the core of the high grade brain tumors, most certainly it seems to be intact near the growing edge of the tumor where the invasive tumor cells may reside. The presence of the intact BBB in such regions of the tumors can considerably impede drug delivery to these regions [13–15]. On the other hand, lack of BBB has been observed in other primary brain tumors like meningiomas, schwannomas, or pineocytomas [16–18]. Disrupted BBB also exists in metastatic secondary brain tumors, but the disruption is negligible in smaller aggregates of metastatic tumor cells. Therefore, the drug delivery to these micrometastatic regions is not optimum; consequently, the tumor keeps growing and ultimately reaches to clinically significant size. Thus, along with the existing therapeutic modalities, new approaches of therapy are needed to combat against the BBB of different brain tumors (see Table 1).
BBB protects neural tissues in the brain and works as a diffusion barrier that impedes the influx of toxins and other compounds from blood to the brain. BBB was discovered in 1880s. It took almost 70 years to successfully prove the existence of BBB by electron microscopic cytochemical studies [19, 20]. Later, in 1981 Stewart and Wiley explained the initial understanding about the uniqueness of BBB tight junction and its physiology .
Molecular character of BBB shows the presence of two types of cellular junctions, the intercellular adherens junction and the paracellular tight junction. The functional integrity of BBB is maintained by adherens junction that is composed of vascular endothelium (VE), cadherin, actinin, and catenin . But the major functionality of BBB is maintained by tight junctions, as they are primarily responsible for permeability through BBB [23, 24]. The BBB in adult is comprised of a complex cellular network. The main components of this system are brain endothelial cells, highly specialized basal membrane, a plenty of pericytes embedded in the basal membrane, and astrocytic end-feet (see Figure 1).
Brain Endothelial Cells. These cells are required for proper barrier formation and interaction with the adjacent cells. They are also known as brain microvascular endothelial cells (BMECs). The BMECs differ from the endothelial cells present in the other organs in the following ways: (i) paracellular movement of molecules is prevented by continuous tight junctions present between brain endothelial cells, (ii) BMECs have few cytoplasmic vesicles and more mitochondria, and (iii) detectable transendothelial path like intracellular vesicular transport is not present in BMECs [22, 25]. Complex intercellular tight junctions restrict the passive diffusion of molecules into the brain and therefore the blood vessels showing extremely high transendothelial electrical resistance (TEER) in vivo . BMECs are also endowed with the ability to shuttle essential nutrients and metabolites across the BBB, which include molecules, like efflux transporters (p-glycoprotein). These transporters contribute to the BBB properties by efflux of small lipophilic molecules that are able to diffuse into BMECs, back to the blood stream.
Basal Membrane. It consists of type IV collagen, fibronectin, and laminin that completely covers the capillary endothelial cell layers. Pericytes are embedded in this membrane and surrounded by astrocytic end-feet. The potential function of this membrane is to restrict the movement of the solutes [27, 28].
Pericytes. The contractile cells which are wrapped around the endothelial cells are called pericytes. These cells play an essential role in the formation of BBB in several ways such as by regulating the expressions of BBB-specific genes in endothelial cells by inducing polarization of astrocytic end-feet surrounding CNS blood vessels, and also they inhibit CNS immune cells from damaging the proper formation of BBB. Besides, these cells also help in reduction of the expression of molecules that increase vascular permeability .
Astrocytic End-Feet. It is assumed earlier that the astrocytic end-feet encircling endothelial cells do not play substantial role in maintenance of BBB . But recent study by Nuriya et al., 2013, indicated the heterogeneity of diffusion patterns around astrocytic end-feet . They proved the existence of some astrocytic end-feet which can form tight networks that are able to block free diffusion of molecules across them. The types of blood vessels and morphological differences in the gliovascular interface like the space between the endothelial cells and astrocytic end-feet determine the heterogeneity of diffusion patterns. Thus, these networks cover the blood vessels tightly which suggests the potential functional roles of astrocytic end-feet .
2.1. Molecular Composition of BBB
The tight junction of BBB mainly consists of three main integral membrane proteins, namely, occludin, claudin, and junction adhesion molecules. Other than that, cytoplasmic accessory proteins like zonula occludens (ZO 1, ZO 2, ZO 3, etc.), cingulin, and others are also present in BBB (see Figure 1).
Occludin. It is the first transmembrane protein of the tight junction to be discovered. Occludin was first identified in 1993 by immunogold freeze fracture microscopy in chicken  and then in mammals . It is formed by four transmembrane domains: a long carboxy-terminal cytoplasmic domain, a short amino-terminal cytoplasmic domain, and two extracellular loops. The ZO proteins are directly associated with cytoplasmic domain of occludin. Phosphorylation of specific Ser/Thr/Tyr residues of occludin regulates its interaction with ZO proteins which in turn plays a regulatory role in tight junction formation .
Claudins. These are a multigene family of at least 24 members. They form tight junctions through homophilic “claudin-claudin” interactions mediated by their extracellular loops . Carboxy terminal of claudins binds to the cytoplasmic proteins including ZO family members . Occludins and claudins can also assemble into heteropolymers to form intramembranous strands. It has been proposed that these strands contain fluctuating channels, which allow the selective diffusion of ions and hydrophilic molecules . Claudins-1, -3, -5, and -12 have been shown to participate in the formation of tight junctions between BMECs [9, 10, 39, 40]. Each claudin regulates the diffusion of a group of molecules of specific size.
Junction Adhesion Molecules (JAM). These proteins belong to the immunoglobulin superfamily. Three JAM-related proteins, JAM-A, JAM-B, and JAM-C, have been investigated in rodent brain sections. In human, it is observed that JAM-A and JAM-C are expressed in the tight junctions of BBB but not JAM-B . JAM-B can be found in seminiferous epithelial cells . All JAM proteins comprise a single transmembrane domain; the extracellular portion has two immunoglobulin like loops. They regulate the formation of tight junctions during the acquisition of cell polarity .
Cytoplasmic Accessory Proteins. Cytoplasmic proteins like zonula occludens proteins (ZO 1, ZO 2, and ZO 3), cingulin, 7H6, and several others are also involved in tight junction formation. Zonula occludens are proteins belonging to the family of membrane associated guanylate kinase (MAGUK) . They provide the cytoskeletal anchorage for the transmembrane tight junction and control spatial distribution of claudins . Cingulins are actomyosin-associated proteins with large globular N-terminal “head” domain, coiled-coil “rod” domain, and small globular C-terminal “tail.” Cingulin helps in BBB formation by interacting with ZO proteins and junction adhesion molecules.
2.2. Transporters of BBB
Endogenous compounds and drugs may cross BBB by different mechanisms such as passive diffusion, carrier-mediated transport (like GLUT1 mediated transport), endocytosis, and active transport [45–52]. Participation of various transport proteins is there in most of these transport systems. These different transport proteins of brain mediate the uptake and extrusion of various metabolites and compounds. The efflux and influx transporter systems of BBB comprise transporters like ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporters.
2.2.1. ABC Transporters
ABC (ATP-binding cassette) transporters are ATP-driven drug efflux pumps present in the BBB which include P-glycoprotein, breast cancer resistance protein, and members of the multidrug resistance related proteins . These proteins form a key characteristic of the BBB by localizing at the luminal side of brain capillaries. They collectively impede brain uptake of a large variety of lipophilic molecules, xenobiotics, potentially toxic metabolites, and drugs. ABC transporters show broad substrate specificity and have been characterized by one or two cytoplasmically located nucleotide binding domains acting as a catalytic domain for nucleotide hydrolysis. There are 48 genes encoding ABC transporter superfamily of proteins, which are subdivided into 7 distinct subfamilies (ABCA to ABCG) . All ABC transporters have three highly conserved motifs known as Walker A, Walker B motifs and the ABC signature C motif (i.e., ALSGGQ) . It has been suggested that this domain may be involved in substrate recognition and ATP hydrolysis .
(1) P-glycoprotein (P-gp). It is a 170-kDa efflux transporter discovered in Chinese hamster ovary cells . P-gp is encoded by multidrug resistant (MDR) genes . Two MDR isoforms have been identified in human tissues, MDR-1 and MDR-2 [59, 60]. MDR1 encoded P-gp is a major efflux transporter of BBB, the expression of which is likely evolved to protect the brain from exposure to potentially neurotoxic xenobiotics. Thus, it is considered that P-gp has a key role in the maintenance of accurate homeostatic environment required for proper neuronal function . The MDR1 gene product is 1280 amino acids in length and has two homologous halves; each consists of six transmembrane domains and ATP- binding site. On the first extracellular loop, two to four glycosylation sites are present . In the brain, P-gp is localized to both the luminal and abluminal sides of BBB endothelium  and to the apical plasma membrane of choroid plexus epithelial cells . Substrates of P-gp are usually nonpolar, weakly amphipathic compounds which significantly vary in molecular size. The different types of endogenous substrates of P-gp include cytokines, lipids, steroid hormones, and peptides . P-gp has a vast endogenous and exogenous substrate profile that renders difficulty in drug delivery across the BBB.
(2) Breast Cancer Resistance Protein (BCRP). It was first identified in the MCF-7/AdrVp breast cancer cell line . It is also known as a “half-transporter.” Its molecular weight is approximately 72 kDa and it is composed of 655 amino acids. It has six transmembrane domains and both the C- and N-terminus regions are located on the intracellular side of the plasma membrane .
Furthermore, the extracellular loops of the protein contain two to three sites for N-linked glycosylation. According to the earlier reports, the functional capabilities of the transporter and its cellular localization are not dependent on these glycosylation sites [67, 68]. It is also known that BCRP forms functional homo- or heterodimers to maintain the efflux activity . BCRP is expressed at the luminal side of capillary endothelial cells, in astrocytes and microglia [70–72]. The substrate specificity of BCRP not only is limited to the physiological substrates, such as glutathione, steroid hormones, and folic acid , but also transports many structurally diverse therapeutic compounds. Significantly, the specificity of BCRP to the substrates overlaps with the substrate specificity of P-gp . It is also known that high expression of these BCRP proteins causes significant resistance to different cancer chemotherapeutic drugs [75, 76].
(3) Multidrug Resistance Proteins (MRPs). It is well established that MRP family has 9 homologues, designated as MRP1–9, and these isoforms have overlapping substrate profiles. Out of these, expression of MRP1–6 has been observed in human brain , whereas multiple MRPs like MRP1, 4, and 5 have been detected in the human BBB [72, 78, 79]. Existence of other MRPs, namely, MRP2, 3, and 6 and along with these MRP1, 4, and 5, has also been noticed in other vertebrates like rat, cow, pig, and fish. But presence of them in human BBB is still questionable. Structural similarity can be observed in MRP1, 2, 3, and 6, as each of them possesses 3 transmembrane domains (TMD) designated as TMD0, TMD1, and TMD2, respectively. TMD1 and TMD2 contain 6 alpha helices, whereas TMD0 contains only 5 alpha helices [80, 81]. It is believed that TMDs are assembled in the plasma membrane pore through which the transport of substrates occurs . On the contrary, MRP4 and MRP5 have structural similarity with P-gp that lack TMD0 [80, 82], but in all the MRP homologues, the conserved cytoplasmic linker (L0) portion is essential for transport function. MRP1, 4, and 5 are restricted to the luminal membrane of human brain capillary endothelial cells . The localization of MRPs suggests that they play a crucial role in drug efflux transport through BBB.
2.2.2. Solute Carrier (SLC) Transporters
SLC transporters belong to SLC superfamily which comprises 43 known subfamilies of SLC transporters (SLC1–SLC43). At the BBB, SLC15A1, SLC16, SLC21, SLC22, SLC28, and SLC29 are expressed . The major SLC transporters include proton coupled oligopeptide transporters, monocarboxylate transporters, organic anion polypeptide transporters, organic ion (anion and cation) transporters, and nucleoside transporters (see Figure 2) [84, 85]. Most of these transporters of BBB regulate the transport of brain tumor drugs by hindering their entry into the tumor regions. Generally, these SLC transporters do not require ATP to translocate substrates across BBB; however, the electrochemical or concentration gradients of solute are essentially required for this type of transportation.
(1) Proton Coupled Oligopeptide Transporters (POT). POT belongs to SLC15A family solute carrier transporters. Names of the subfamilies of POT are peptide transporters (PEPT) and peptide/histidine transporter (PHT). Peptide transporter-1 (PEPT1; SLC15A1) and peptide transporter-2 (PEPT2; SLC15A2) are the members of PEPT subfamily, whereas PHT comprises peptide/histidine transporter-1 (PHT1; SLC15A4) and peptide/histidine transporter-2 (PHT2; SLC15A3) [86, 87]. These oligopeptide transporters are able to transport small peptides across the BBB by an electrochemical proton gradient . Structural similarity can be observed in POT family members due to the presence of 12 α-helical transmembrane domains with intracellularly located C- and N-terminal regions. Two to seven glycosylation sites exist in the extracellular loops, while intracellular loops have protein kinase A and C phosphorylation sites [86, 89]. Other than the above-mentioned peptide transporters, peptide uptake and distribution in brain are also determined by peptide transport system (PTS) expressed endogenously at the BBB endothelium . In the BBB, seven transport systems have been found for transport of peptides, which includes PTS1–PTS7. PTSs, PTS2, PTS4, and PTS6, are bidirectional, whereas the rest are unidirectional. The unidirectional PTSs, PTS1 and PTS5, facilitate brain-to-blood peptide transport, whereas PTS3 and PTS7 are known for reverse process .
(2) Monocarboxylate Transporters (MCTs). Generally, the MCTs facilitate the rapid transport of monocarboxylates across the biological membranes. In brain, MCTs not only assist the transport of the monocarboxylates for uptake into the neurons but also mediate the transport of some drugs across the BBB . These MCTs are members of solute carrier family 16 (SLC16). SLC16 has 14 members, out of which only six have been functionally characterized and those MCTs are MCT1–4, MCT8, and the T-type amino acid transporter-1 (TAT-1/MCT10) (326, 327). MCT1, MCT2, and MCT4 are the most important BBB transporters, whereas active MCT8 expression has also been detected in BBB [92–94]. The MCT1 protein is present in the membrane of the capillary endothelium and astrocytes, while MCT2 and MCT4 are found on neurons and astrocytes, respectively [95, 96].
(3) Organic Anion Transporters Polypeptides (OATPs). These membrane influx transporters are present in BBB to regulate cellular uptake of a number of endogenous compounds and clinically important drugs . The human OATP comprises 11 members: OATP1A2, 1B1, 1B3, 1C1, 2A1, 2B1, 3A1, 4A1, 4C1, 5A1, and 6A1 [98–100], where OATP1A2 is the first discovered human member of the OATP family . The OATP genes are classified within the SLCO (formerly SLC21A) family. Members of the same OATPs family share ~40% , whereas members of individual subfamilies possess ~60% amino acid sequence similarity. This group of transporters has broad substrate specificity. The OATP dependent transport of the substrates does not require ATP as energy source, yet it is conducted by electrochemical gradients that utilize an inorganic or organic solute as a driving force. The OATPs family members OATP1A2, 1C1, 2A1, 2B1, 3A1, and 4A1 are present in human brain . OATP1A2 is the only human OATP isoform whose expression and function are widely established at BBB. The localization of OATP1A2 can be observed at both the luminal and abluminal membranes of human BBB endothelial cells . The endogenous substrates of OATP1A2 are bilirubin, bromosulfophthalein, cholate, deltorphin-II, estradiol-17β-glucuronide, estrone-3-sulfate, glycocholate, hydroxyurea, PGE2, reverse-T3, taurocholate, taurochenodeoxycholate, tauroursodeoxycholate, T4, T3, and so forth , whereas a broad exogenous therapeutic substrate specificity can be noticed for this kind of OATPs. OATP1C1 and OATP3A1 are known to be present in both apical and basal sides of the brain endothelial cells and blood cerebrospinal fluid barrier, respectively, while the exact role of other OATPs is yet to be determined [104, 105].
(4) Organic Ion Transporters. These transporters can be classified into two specific types: (i) organic anion transporters (OATs) and (ii) organic cation transporters (OCTs). These transporters are the members of SLC transporter 22 superfamily (SLC22A) [83, 106].
(i) Organic Anion Transporters (OATs). The OAT family comprises OAT 1–6 and the renal specific transporter (RST) [107–111]. This classification is based on ATP-dependent energy requirements and involvement of Na+ ion. . Movement of the organic anions across biological membranes is determined by these OATs. Various endogenous molecules like anionic metabolites of neurotransmitters, hormones, prostaglandins, and exogenous molecules such as different drugs are known to cross the biological membrane by these OATs . The general structure of OATs comprises 12 membrane-spanning α-helices and several glycosylation and PKC sites, which can be found on extracellular loops connecting helices 6 and 7 . In brain, OAT3 is the most highly expressed isoform. It is reported earlier that OAT3 is present in the abluminal (brain side) and brush-border membrane (CSF side) of brain capillary endothelial cells and choroid plexus epithelial cells, respectively [114, 115]. Other than this, OAT1, OAT2, and OAT4–6 are also expressed in brain [78, 105, 109, 114–117]. But the proper localization and function of these OATs are yet to be known.
(ii) Organic Cation Transporters (OCTs). OCTs regulate the transport mechanisms to facilitate the passage of organic cations through biological membranes . According to their transport capabilities, OCTs are categorized into two subgroups, namely, oligospecific organic cation transporters and polyspecific organic cation transporters. Apart from this, organic cation transporters can also be classified as chemical potential sensitive organic cation transporters (OCTs) and H+ gradient-dependent novel organic transporters (OCTNs). OCTs comprise OCT1–3, whereas OCTN transport system includes OCTN1 and OCTN2 . Cellular influx and efflux of various cationic substrates are maintained by OCTs and OCTNs, respectively [120, 121]. All OCT family members generally contain 12 α-helical transmembrane domains with intracellular N- and C-termini. Furthermore, large extracellular loop between TMD1 and TMD2 and small intercellular loop connecting TMD6 and TMD7 are also present in OCT family members. In brain, OCT1–3 are localized to the basolateral membrane of BMECs and choroid plexus epithelial cells [122–124], and OCTN2 is reported to be localized to the luminal side of the BBB [125–127], whereas OCTN1 is reportedly absent in human CNS tissue . Other than the transport of endogenous organic cations, OCT family members may also play crucial role in drug penetration through BBB .
(5) Nucleoside Transporters. The nucleosides play a major role as second messengers in many signal transduction pathways. Thus, their regulation of them is crucial for proper neuronal function . The recycling pathways for nucleosides transportation into CNS tissue are needed, as brain cannot synthesize nucleosides de novo. Depending on the Na+ dependence nucleoside, the membrane transporters are again classified into two subcategories: equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs). ENTs are the members of the SLC29A transporter family and are Na+-independent, whereas CNTs are the members of the SLC28A transporter family and are Na+-dependent [131, 132]. In humans four isoforms of ENTs have been discovered, which are ENT1–4 [133–135]. All of them possess 11 α-helical transmembrane domains with intracellular N-terminus and extracellular C-terminus regions. Each and every isoform of ENTs also possesses a large cytoplasmic loop and an extracellular loop [136, 137]. ENT1, ENT2, and ENT4 are ubiquitously expressed in brain tissue and are localized to cellular membranes [138–140]. CNTs also have three isoforms: CNT1–3. They are integral membrane proteins with 13 transmembrane α-helices and a large extracellular C-terminal region, present in various regions of brain  and work as antiporters. CNT1 and CNT2 transport nucleosides into the cell in exchange for sodium ions, while CNT3 transports nucleosides in exchange for either sodium ions or protons . But prominent expression of CNT2 protein has been observed at the luminal side of the BBB endothelium. Other than the endogenous nucleoside transporters, CNTs are also responsible for the cellular uptake of a number of nucleoside-derived drugs .
2.3. Aberrant Expression of BBB Components in Brain Tumors
BBB components claudins and occludins are either downregulated or not at all expressed in brain tumors. Loss of claudin-1 and downregulation of claudin-3 and claudin-5 expressions in high grade glioma are reported earlier [9, 142]. This variation of expression of claudins causes loosening of BBB tight junctions, but the involvement of claudins in the mechanism for the compromised tight junction function in BBB is not very clear. Claudin-1 proteins are known to regulate different signaling pathways, which in turn alter the expression and function of different cell-cell adhesion molecules . It is also reported that claudin-5 regulates BBB permeability during the metastasis of brain tumors . Loss of expression of another transmembrane protein occludin in microvessels is also observed in astrocytomas and metastatic adenocarcinomas. The probability of their contribution to endothelial tight junction opening is also very high . High grade astrocytomas secrete vascular endothelial growth factor (VEGF), which downregulates the expression of occludins and increases endothelial cell permeability . However, besides VEGF, cytokines and scatter factor or hepatocyte growth factor are also secreted by astrocytoma and other brain tumors. These factors are believed to be involved in the downregulation of tight junction molecules leading to its leakage [146, 147].
3. Drug Delivery Approaches and Current Advances in Brain Tumor Therapy
Most of the brain tumor drugs are ineffective due to their limited entry through BBB. Nowadays scientific communities are interested in providing solutions to this problem, and it is not surprising that most of the brain tumor patients could benefit from the improved drug delivery approaches. Few established approaches are intra-arterial drug delivery, intrathecal and intraventricular drug administration, intratumoral delivery, receptor-mediated transport, disruption of BBB, inhibition of drug efflux by BBB, and the use of intranasal drug delivery route.
The clinical trials of intra-arterial delivery in brain tumor drugs show minimal improvement in survival of brain tumor patients [148–154], but recently the neurosurgeons of New York Presbyterian Hospital/Weill Cornell Medical Center for the first time showed the successful intra-arterial delivery of monoclonal antibody like bevacizumab to the tumor region by means of transient blood brain barrier disruption . In case of intrathecal drug administration, the drugs possess limited ability to enter the extracellular space of brain from the CSF [156–159]. The convection enhanced diffusion (CED) technique is used in transcranial brain drug delivery approaches to evade the BBB for forceful delivery of fluid into the brain and to increase the effective infiltration of drug into tumor region . Application of microdialysis in neurooncology is also well established since it has been proposed as an efficient method of intratumoral drug delivery. This method employs the passive diffusion of a drug across the BBB [161, 162] and distributes drugs away from the dialysis catheter . On the other hand, the receptor-mediated endocytosis and exocytosis facilitate the entry of the therapeutic compounds across the BBB of brain tumors. Receptor targeted monoclonal antibody-based drugs are delivered across the BBB by the help of receptor-mediated transport systems [164, 165]. Another traditional approach to solve the problem of drug delivery into the brain is BBB disruption. Osmotic disruption technique, bradykinin-analogue or alkylglycerol mediated disruption technique, MRI-guided focused ultrasound BBB disruption technique, and so forth are used to disrupt the BBB [166–169]. Though, bradykinin analogue mediated delivery of drug is abandoned due to its ineffectiveness when administered in combination with carboplatin. Recently, MRI-guided focused ultrasound BBB disruption technique is used to disrupt BBB for effective drug delivery .
P-glycoproteins (P-gp) of the ABC drug efflux transporters are present not only in low grade brain tumors but also in different malignant glioma cells . Modulation of P-gp may cause effective delivery of drugs to the tumor niche. The poor in vivo efficacy of the first generation P-gp modulators (verapamil, cyclosporine A, tamoxifen, and several calmodulin antagonists) is due to their low binding affinities, which necessitated the use of high doses, resulting in intolerable toxicity . The coadministration of the second-generation P-gp modulators (dexverapamil, dexniguldipine, valspodar (PSC 833), and biricodar (VX-710)) [173, 174] and chemotherapy agents in clinical trials has provided limited success; hence, third-generation P-gp modulators come in the scenario. These modulators include anthranilamide derivative tariquidar (XR9576), cyclopropyldibenzosuberane zosuquidar (LY335979), laniquidar (R101933), and elacridar (GF120918) [175–178]. Kemper et al. showed 5-fold increase in brain uptake of paclitaxel by combinatorial treatment with elacridar (GF120918) . Other than P-gp inhibitors, MRP inhibitors (like sulfinpyrazone, probenecid, etc.) and BCRP inhibitors (fumitremorgin C and its analogues) are also reported as transporter inhibitors [172, 179]. Ongoing clinical trials with these new P-gp inhibitors should prove whether this approach will result in increased survival of brain tumor patients.
A promising drug delivery technique that can bypass the BBB is the usage of intranasal drug delivery route. This technique eliminates the risk of surgery and the nonspecific spillover effect of drug to normal tissue. Intranasal delivery provides successful drug targeting mechanism which utilizes the unique anatomic connections of olfactory and trigeminal nerves of nasal mucosa and the central nervous system [180, 181]. The drugs administered through this path reach the cerebrospinal fluid (CSF), spinal cord, and brain parenchyma very rapidly. This delivery system has been proven to be successful in delivering anticancer agents to the brain, like raltitrexed, 5-fluorouracil, GRN163, and methotrexate [182–185]. Further studies about intranasal therapeutic agents are needed and it could be a major candidate for clinical trials in brain tumor patients.
Current techniques and new approaches in drug delivery across the BBB can be classified as follows.
3.1. Modification of Existing Drugs
The ability of drug to cross the BBB depends on few factors like molecular size (should be less than 500 Da), charge (should have low hydrogen bonding capabilities), and lipophilicity (should have high lipophilicity) . Thus, chemical modification of brain tumor drugs refers to the process of making an existing drug smaller in size, more perfectly charged, and more lipid soluble  (Table 2). Existing brain tumor drugs may also be modified to make analogue of the ligand to the particular receptor present in the BBB or the ligand or a peptide can be linked to a drug against the cellular receptors of BBB. The drug melphalan has been modified by using this approach where melphalan nitrogen mustard (mechlorethamine) was linked to phenylalanine . Another approach of drug modification is the use of lipid carriers for efficient transport through BBB. One example of such modification is incorporation of small drugs in fatty acids like N-docosahexaenoic acid (DHA) [189, 190]. Drugs are also modified in such a way that they acquire increased capillary permeability, but after crossing the BBB they undergo an enzymatic reaction and return to their active state. This approach is also known as prodrug therapy [191, 192].
3.2. Nanosystem Based Delivery
Nanosystems are colloidal carriers that mainly consist of liposomes and polymeric nanoparticles while other systems, including solid lipid nanoparticles, polymeric micelles, and dendrimers, have also been studied recently. Sizes of these nanosystems vary within 1–1000 nm. These kinds of functionalized drug colloidal carriers can act as a vehicle to deliver antitumor drugs to brain tumor tissues. These nanosystems generally use passive diffusion mechanism as they rely on increased vascular permeability of brain tumor location, but usage of active chemically modified drugs with nanoparticles and receptor-mediated or adsorptive endocytosis processes of nanoparticle delivery have also been reported [219–221]. Conjugation of ligands targeting BBB on the surface of the nanosystem increases their specificity for brain tumors. One of the important features of these nanosystems is that they can circulate in the bloodstream for a prolonged time period. But the interaction of the nanosystems with the reticuloendothelial system (RES) causes its rapid removal from systemic circulation . Therefore, to minimize the interactions of nanosystems with the RES, polyethylene glycol (PEG) coating or direct chemical linking of PEG to the particle surface is a widely accepted approach. These colloidal nanosystems comprise liposomes and nanoparticles, which have shown potential to target brain tumors as drug carriers. Furthermore, studies are going on for the development of novel transport-enhancing nanocarriers for brain tumor treatment.
Liposome is a good carrier system for the delivery of therapeutic agents for brain tumors. They are easy to prepare, biocompatible, less toxic, and commercially available. Along with PEGylation, the liposomes can also be modified with monoclonal antibodies against transferrin receptors (OX-26), glial fibrillary acidic proteins (GFAP), or human insulin receptors . Effective delivery of drugs like 5-fluorouracil (5-FU) and sodium borocaptate (Na210B12H11SH, BSH) to high grade brain tumors has been achieved by liposome mediated delivery [224, 225]. Modified liposomes like p-aminophenyl-α-D-mannopyranoside (MAN) and transferrin conjugated daunorubicin liposomes and trans-activating transcriptional peptide (TATp) modified liposomes have also been used in vitro and in vivo for targeting brain tumors [226, 227].
Polymeric nanoparticles (NP) are colloidal particles which can be found in the form of nanocapsules or nanospheres. The drugs are dissolved, entrapped, encapsulated, adsorbed, or chemically linked to the surface of the NPs. The polymer structure and the drug trapping method determine the drug characteristics and its release kinetics from the nanoparticles . One example of nanoparticle drug delivery approach is the usage of nanoparticles coated choline derivative that is reported to be transported across brain-derived endothelial cells by the cation transporter system . Other remarkable systems are polysorbate-coated doxorubicin nanoparticles and doxorubicin-loaded folic acid-decorated nanoparticles, which cause effective penetration of drugs through BBB [230, 231]. Brain tumors can also be selectively targeted by bionanocapsules conjugated with anti-human EGFR antibody that recognizes EGFRvIII known to be overexpressed in high grade brain tumors like glioblastoma multiforme . Those bionanocapsules may also contain virus, active proteins, vaccines, genes, or small interference RNA for targeted therapy of brain tumors. Solid lipid nanoparticles (SLNs), which are the dispersions of solid lipid stabilized with emulsifier or emulsifier/coemulsifier complex in water, are also known for delivering brain tumor drugs like camptothecin, doxorubicin, and paclitaxel to brain effectively . Furthermore, gold nanoparticles and carbon nanoparticles (like carbon nanotubes, graphene, and carbon dots) are also able to deliver drugs (like doxorubicin) successfully [234–237]. Thus, nanoparticles may be considered as one of the most promising tools to deliver therapeutic drugs across the BBB to treat brain tumors .
Other nanosystems like polymeric micelles and dendrimers are also effective for targeted delivery of drugs to the tumors in the brain. Formation of polymeric micelles occurs spontaneously in aqueous solutions of amphiphilic block copolymers, whereas dendrimers are highly branched polymer molecules formed by a central core. These types of nanopreparations loaded with anticancer drugs should be considered as highly potential antitumor nanomedicines as they have the ability to cross the BBB by modulating BBB transporters like P-gp or glucose transporters [239–241].
3.3. Delivery Systems Used in Gene Therapy
Effective treatment of brain tumor can be obtained from intracerebral implantation of a therapeutic gene, inserted into a viral vector. It is a specifically targeted therapy where volume of the implantation is very low (<1 mm3). Thus, the expression of exogenous gene is highly localized. But gene reformulation may cause the generalised expression of exogenous gene in the total brain tumor niche. Few examples of carriers in this type of therapeutic systems are viral vectors like adenovirus, herpes simplex virus (HSV), and nonviral gene delivery system like cationic liposome-DNA complexes [242–244]. The O6-methylguanine-DNA methyltransferase (MGMT) upregulation in GBM makes it resistant to Temozolomide (TMZ), a well-known drug for glioma. Therefore, upregulation of wild-type (wt) p53 expression is needed which downmodulates MGMT. Since p53 therapy for GBM is not very efficient due to the presence of the blood brain barrier (BBB), a systemic nanodelivery platform (scL) for tumor-specific targeting (primary and metastatic) has been developed by Kim et al. It has been observed that the combination of scL-p53 and TMZ increased the antibrain tumor efficacy of TMZ . Another report shows the efficacy of CMV-specific T cell therapy, as it is reported that the expression of human cytomegalovirus (CMV) antigens in GBM tissues is pretty high. Distinct gene expression correlated with the better clinical response is recorded for the high grade brain tumor patients, who availed themselves of CMV-specific T cell therapy .
3.4. Effective Delivery of Therapeutic Peptides
Towards fulfilling the goal of effective therapy, recently selective peptides have been developed against brain cancer. Discovery of novel peptide as novel specific chemical entity is encouraged by the identification of several protein/peptide receptors and tumor-related peptides/proteins, those expressed in brain cancer cells. Small sized, less toxic peptides are advantageous over the monoclonal antibodies (mAbs) and large proteins that have large size and high toxicity have poor rate of BBB crossing. Other major advantages of peptides are their BBB penetrating ability in brain tumors, ease of synthesis and modification, and good biocompatibility . Chlorotoxin is such a peptide which selectively binds to glioma cells . Somatostatin analogues, which can be defined as peptide receptor radionuclide therapeutic agents, are the only approved cancer therapeutic peptides in the market  and there are reports of their binding to the cellular receptors in brain tumors in vivo . Another new approach of brain tumor therapy is developing vaccines consisting of peptides derived from the protein sequence of brain tumor-associated or specific antigens . Autologous DC vaccine against CD133 (a marker of GBM), survivin peptide vaccine, rindopepimut (also known as CDX-110) against EGFRVIII, and so forth are the examples of peptide vaccines for high grade brain tumors and these are now under clinical trials [252–254].
3.5. Molecular Trojan Horses (MTH)
Recently a new technique is used to ferry drug molecules across the BBB, which is called Molecular Trojan Horse (MTH) mediated drug delivery. Delivery of particular substances to the brain after attaching them to a protein, which can cross BBB, is the main focus of this type of delivery system. One of the recent progresses of MTH is “Trojan horse liposome” (THL) technology [255–257]. The application of this technology to transvascular nonviral gene therapy of brain represents a potential way out of the transvascular brain gene delivery problem. The THL is constructed with PEG-conjugated lipids which encapsulate plasmid DNA encoding proteins or shRNA/siRNA. Marked decrease in expression of EGFR protein in the tumor region was noticed after using THL mediated RNAi gene therapy. This resulted in a 90% increase in survival time of brain tumor patients .
3.6. Drug Delivery Targeting Brain Cancer Stem Cells
Cancer stem cells (CSCs) are the tumor initiating cells present in the tumor niche. These cells cause drug resistance, metastasis, and relapse of cancer. Most of the current chemotherapeutic molecules are able to destroy the cancer cells but not the CSCs. Thus, to kill these CSCs in brain tumors, effective treatment modalities are needed, which should also have the ability to cross the BBB; for example, curcumin encapsulated in nanoparticles caused a dose-dependent growth inhibition of brain tumor CSCs and neurospheres . Other than this, targeting active genes like MGMT in brain CSCs by liposomes with anti-MGMT siRNA for oral Temozolomide therapy and destruction of brain CSCs niche by mAb-vectorized SWNT (single-walled carbon nanotubes) for hypothermic treatment also resulted in destruction of CSCs [260, 261]. The efficacy of the CSC targeting drugs can be improved by optimisation of chemo- and nanotherapies, novel gene-silencing techniques, and drug efflux inhibition techniques which may increase survivability of the brain tumor patients.
4. Concluding Remarks
Modern era of brain cancer therapy is characterized by novel target specific drugs with efficient delivery strategies. However, the prognosis and median survival of the brain tumor patients are not satisfactory till date. This is due to molecular heterogeneity of the brain tumors, presence of CSCs, and lack of effective drug delivery because of the presence of BBB. Rapid progress is needed in the sector of brain tumor characterization and BBB research. Till now, most effective drugs for brain tumor therapies are Temozolomide, Procarbazine, Carmustine (BCNU), Lomustine (CCNU), and Vincristine. Better modification of these drugs or identification of new chemical entities with enhanced efficacy and low side effect is always commendable. Alternatively, identification of drugs which can modulate BBB components or transporter systems could be an effective future strategy. Another potential future approach is combinatorial therapy, where through BBB destruction/modification, tumor cells/CSCs could be targeted easily. Modern techniques like nanotherapy may facilitate this kind of approach. Therefore, future research is needed to focus on the development of more specific targeting strategies to cure brain cancer, overcoming the above-mentioned difficulties arising due to the presence of the BBB.
|BBB:||Blood brain barrier|
|BMEC:||Brain macrovascular endothelial cells|
|CNS:||Central nervous system|
|JAM:||Junction adhesion molecules|
|GLUT1:||Glucose transporter 1|
|BCRP:||Breast cancer resistance protein|
|MRP:||Multidrug resistance proteins|
|POT:||Proton coupled oligopeptide transporters|
|PTS:||Peptide transport system|
|TAT:||T-type amino acid transporter|
|OATP:||Organic anion transporters polypeptides|
|OAT:||Organic anion transporters|
|OCT:||Organic cation transporters|
|OCTN:||Organic cation transporter novel|
|ENT:||Equilibrative nucleoside transporters|
|CNT:||Concentrative nucleoside transporters|
|VEGF:||Vascular endothelial growth factor|
|CED:||Convection enhanced diffusion|
|LDL:||Low density lipoprotein|
|MRI:||Magnetic resonance imaging|
|GFAP:||Glial fibrillary acidic proteins|
|EGFR:||Epidermal growth factor receptor|
|EGFRvIII:||Epidermal growth factor receptor variant III|
|SLN:||Solid lipid nanoparticle|
|HSV:||Herpes simplex virus|
|MTH:||Molecular Trojan Horse|
|THL:||Trojan horse liposome|
|shRNA:||Short hairpin RNA|
|siRNA:||Small interfering RNA|
|CSC:||Cancer stem cell|
|SWNT:||Single-walled carbon nanotubes.|
Conflict of Interests
The authors declare no conflict of interests.
Mrinal Kanti Ghosh, Arijit Bhowmik, and Rajni Khan wrote and analyzed the paper.
This work was supported by grants from Council of Scientific and Industrial Research (CSIR) (EMPOWER: OLP-002, MEDCHEM: BSC-0108, and miND: BSC-0115).
- N. A. Vick, J. D. Khandekar, and D. D. Bigner, “Chemotherapy of brain tumors: the “blood-brain barrier” is not a factor,” Archives of Neurology, vol. 34, no. 9, pp. 523–526, 1977.
- M. G. Donelli, M. Zucchetti, and M. D'Incalci, “Do anticancer agents reach the tumor target in the human brain?” Cancer Chemotherapy and Pharmacology, vol. 30, no. 4, pp. 251–260, 1992.
- W. M. Pardridge, “CNS drug design based on principles of blood-brain barrier transport,” Journal of Neurochemistry, vol. 70, no. 5, pp. 1781–1792, 1998.
- S. I. Rapoport, “Modulation of blood-brain barrier permeability,” Journal of Drug Targeting, vol. 3, no. 6, pp. 417–425, 1996.
- A. Tsuji and I. Tamai, “Sodium- and chloride-dependent transport of taurine at the blood-brain barrier,” Advances in Experimental Medicine and Biology, vol. 403, pp. 385–391, 1996.
- D. R. Groothuis, “The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery,” Neuro-Oncology, vol. 2, no. 1, pp. 45–49, 2000.
- D. R. Groothuis, F. J. Vriesendorp, B. Kupfer et al., “Quantitative measurements of capillary transport in human brain tumors by computed tomography,” Annals of Neurology, vol. 30, no. 4, pp. 581–588, 1991.
- D. M. Long, “Capillary ultrastructure and the blood-brain barrier in human malignant brain tumors,” Journal of Neurosurgery, vol. 32, no. 2, pp. 127–144, 1970.
- S. Liebner, A. Fischmann, G. Rascher et al., “Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme,” Acta Neuropathologica, vol. 100, no. 3, pp. 323–331, 2000.
- S. Liebner, U. Kniesel, H. Kalbacher, and H. Wolburg, “Correlation of tight junction morphology with the expression of tight junction proteins in blood-brain barrier endothelial cells,” European Journal of Cell Biology, vol. 79, no. 10, pp. 707–717, 2000.
- M. C. Papadopoulos, S. Saadoun, C. J. Woodrow et al., “Occludin expression in microvessels of neoplastic and non-neoplastic human brain,” Neuropathology and Applied Neurobiology, vol. 27, no. 5, pp. 384–395, 2001.
- K. Lamszus, J. Laterra, M. Westphal, and E. M. Rosen, “Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas,” International Journal of Developmental Neuroscience, vol. 17, no. 5-6, pp. 517–530, 1999.
- M. W. Pitz, A. Desai, S. A. Grossman, and J. O. Blakeley, “Tissue concentration of systemically administered antineoplastic agents in human brain tumors,” Journal of Neuro-Oncology, vol. 104, no. 3, pp. 629–638, 2011.
- L. Rosso, C. S. Brock, J. M. Gallo et al., “A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients,” Cancer Research, vol. 69, no. 1, pp. 120–127, 2009.
- R. L. Fine, J. Chen, C. Balmaceda et al., “Randomized study of paclitaxel and tamoxifen deposition into human brain tumors: implications for the treatment of metastatic brain tumors,” Clinical Cancer Research, vol. 12, no. 19, pp. 5770–5776, 2006.
- C. Meewes, K. H. Bohuslavizki, B. Krisch, J. Held-Feindt, E. Henze, and M. Clausen, “Molecular biologic and scintigraphic analyses of somatostatin receptor-negative meningiomas,” Journal of Nuclear Medicine, vol. 42, no. 9, pp. 1338–1345, 2001.
- S. Ammoun and C. O. Hanemann, “Emerging therapeutic targets in schwannomas and other merlin-deficient tumors,” Nature Reviews Neurology, vol. 7, no. 7, pp. 392–399, 2011.
- S. Fakhran and E. J. Escott, “Pineocytoma mimicking a pineal cyst on imaging: true diagnostic dilemma or a case of incomplete imaging?” The American Journal of Neuroradiology, vol. 29, no. 1, pp. 159–163, 2008.
- T. S. Reese and M. J. Karnovsky, “Fine structural localization of a blood-brain barrier to exogenous peroxidase,” The Journal of Cell Biology, vol. 34, no. 1, pp. 207–217, 1967.
- M. W. Brightman and T. S. Reese, “Junctions between intimately apposed cell membranes in the vertebrate brain,” Journal of Cell Biology, vol. 40, no. 3, pp. 648–677, 1969.
- P. A. Stewart and M. J. Wiley, “Structural and histochemical features of the avian blood-brain barrier,” Journal of Comparative Neurology, vol. 202, no. 2, pp. 157–167, 1981.
- A. W. Vorbrodt and D. H. Dobrogowska, “Molecular anatomy of intercellular junctions in brain endothelial and epithelial barriers: electron microscopist's view,” Brain Research Reviews, vol. 42, no. 3, pp. 221–242, 2003.
- B. V. Zlokovic, “The blood-brain barrier in health and chronic neurodegenerative disorders,” Neuron, vol. 57, no. 2, pp. 178–201, 2008.
- B. T. Hawkins and T. P. Davis, “The blood-brain barrier/neurovascular unit in health and disease,” Pharmacological Reviews, vol. 57, no. 2, pp. 173–185, 2005.
- R. A. Hawkins, R. L. O'Kane, I. A. Simpson, and J. R. Viña, “Structure of the blood-brain barrier and its role in the transport of amino acids,” Journal of Nutrition, vol. 136, supplement 1, pp. 218S–226S, 2006.
- A. M. Butt, H. C. Jones, and N. J. Abbott, “Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study,” Journal of Physiology, vol. 429, pp. 47–62, 1990.
- P. T. Ronaldson and T. P. Davis, “Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke,” Current Pharmaceutical Design, vol. 18, no. 25, pp. 3624–3644, 2012.
- N. J. Abbott, L. Rönnbäck, and E. Hansson, “Astrocyte-endothelial interactions at the blood-brain barrier,” Nature Reviews Neuroscience, vol. 7, no. 1, pp. 41–53, 2006.
- A. Armulik, G. Genové, M. Mäe et al., “Pericytes regulate the blood-brain barrier,” Nature, vol. 468, no. 7323, pp. 557–561, 2010.
- H. Kimelberg, T. Jalonen, and W. Walz, “Regulation of brain microenvironment: transmitters and ions,” in Astrocytes: Pharmacology and Function, S. Murphy, Ed., pp. 193–222, Academic Press, San Diego, Calif, USA, 1993.
- M. Nuriya, T. Shinotsuka, and M. Yasui, “Diffusion properties of molecules at the blood-brain interface: potential contributions of astrocyte endfeet to diffusion barrier functions,” Cerebral Cortex, vol. 23, no. 9, pp. 2118–2126, 2013.
- T. M. Mathiisen, K. P. Lehre, N. C. Danbolt, and O. P. Ottersen, “The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction,” Glia, vol. 58, no. 9, pp. 1094–1103, 2010.
- M. Furuse, T. Hirase, M. Itoh, A. Nagafuchi, S. Yonemura, and S. Tsukita, “Occludin: a novel integral membrane protein localizing at tight junctions,” Journal of Cell Biology, vol. 123, no. 6, pp. 1777–1788, 1993.
- Y. Ando-Akatsuka, M. Saitou, T. Hirase et al., “Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse, dog, and rat-kangaroo homologues,” Journal of Cell Biology, vol. 133, no. 1, pp. 43–47, 1996.
- R. Rao, “Occludin phosphorylation in regulation of epithelial tight junctions,” Annals of the New York Academy of Sciences, vol. 1165, pp. 62–68, 2009.
- J. Piontek, L. Winkler, H. Wolburg et al., “Formation of tight junction: determinants of homophilic interaction between classic claudins,” The FASEB Journal, vol. 22, no. 1, pp. 146–158, 2008.
- M. Itoh, M. Furuse, K. Morita, K. Kubota, M. Saitou, and S. Tsukita, “Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins,” The Journal of Cell Biology, vol. 147, no. 6, pp. 1351–1363, 1999.
- K. Matter and M. S. Balda, “Holey barrier: claudins and the regulation of brain endothelial permeability,” The Journal of Cell Biology, vol. 161, no. 3, pp. 459–460, 2003.
- T. Nitta, M. Hata, S. Gotoh et al., “Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice,” Journal of Cell Biology, vol. 161, no. 3, pp. 653–660, 2003.
- A. Schrade, H. Sade, P.-O. Couraud, I. A. Romero, B. B. Weksler, and J. Niewoehner, “Expression and localization of claudins-3 and -12 in transformed human brain endothelium,” Fluids and Barriers of the CNS, vol. 9, no. 1, article 6, 2012.
- M. Aurrand-Lions, C. Johnson-Leger, C. Wong, L. Du Pasquier, and B. A. Imhof, “Heterogeneity of endothelial junctions is reflected by differential expression and specific subcellular localization of the three JAM family members,” Blood, vol. 98, no. 13, pp. 3699–3707, 2001.
- G. Gliki, K. Ebnet, M. Aurrand-Lions, B. A. Imhof, and R. H. Adams, “Spermatid differentiation requires the assembly of a cell polarity complex downstream of junctional adhesion molecule-C,” Nature, vol. 431, no. 7006, pp. 320–324, 2004.
- K. Ebnet, A. Suzuki, S. Ohno, and D. Vestweber, “Junctional adhesion molecules (JAMs): more molecules with dual functions?” Journal of Cell Science, vol. 117, part 1, pp. 19–29, 2004.
- J. Haskins, L. Gu, E. S. Wittchen, J. Hibbard, and B. R. Stevenson, “ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin,” The Journal of Cell Biology, vol. 141, no. 1, pp. 199–208, 1998.
- H. Fischer, R. Gottschlich, and A. Seelig, “Blood-brain barrier permeation: molecular parameters governing passive diffusion,” Journal of Membrane Biology, vol. 165, no. 3, pp. 201–211, 1998.
- L. M. Roberts, D. S. Black, C. Raman et al., “Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation,” Neuroscience, vol. 155, no. 2, pp. 423–438, 2008.
- M. Uldry and B. Thorens, “The SLC2 family of facilitated hexose and polyol transporters,” Pflügers Archiv, vol. 447, no. 5, pp. 480–489, 2004.
- M. Simionescu, A. Gafencu, and F. Antohe, “Transcytosis of plasma macromolecules in endothelial cells: a cell biological survey,” Microscopy Research and Technique, vol. 57, no. 5, pp. 269–288, 2002.
- A. M. Wolka, J. D. Huber, and T. P. Davis, “Pain and the blood-brain barrier: obstacles to drug delivery,” Advanced Drug Delivery Reviews, vol. 55, no. 8, pp. 987–1006, 2003.
- L. B. Thomsen, J. Lichota, T. N. Eskehave et al., “Brain delivery systems via mechanism independent of receptor-mediated endocytosis and adsorptive-mediated endocytosis,” Current Pharmaceutical Biotechnology, vol. 13, no. 12, pp. 2349–2354, 2012.
- N. J. Abbott and I. A. Romero, “Transporting therapeutics across the blood-brain barrier,” Molecular Medicine Today, vol. 2, no. 3, pp. 106–113, 1996.
- G. Lee, S. Dallas, M. Hong, and R. Bendayan, “Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations,” Pharmacological Reviews, vol. 53, no. 4, pp. 569–596, 2001.
- D. J. Begley, “ABC transporters and the blood-brain barrier,” Current Pharmaceutical Design, vol. 10, no. 12, pp. 1295–1312, 2004.
- K. Moitra, “ABC transporters in human disease,” Colloquium Series on The Genetic Basis of Human Disease, vol. 1, no. 1, pp. 1–84, 2012.
- F. J. Sharom, “ABC multidrug transporters: structure, function and role in chemoresistance,” Pharmacogenomics, vol. 9, no. 1, pp. 105–127, 2008.
- K. Hollenstein, R. J. Dawson, and K. P. Locher, “Structure and mechanism of ABC transporter proteins,” Current Opinion in Structural Biology, vol. 17, no. 4, pp. 412–418, 2007.
- V. Ling and L. H. Thompson, “Reduced permeability in CHO cells as a mechanism of resistance to colchicine,” Journal of Cellular Physiology, vol. 83, no. 1, pp. 103–116, 1974.
- M. M. Gottesman, C. A. Hrycyna, P. V. Schoenlein, U. A. Germann, and I. Pastan, “Genetic analysis of the multidrug transporter,” Annual Review of Genetics, vol. 29, pp. 607–649, 1995.
- C.-J. Chen, J. E. Chin, K. Ueda et al., “Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells,” Cell, vol. 47, no. 3, pp. 381–389, 1986.
- I. B. Roninson, J. E. Chin, K. Choi et al., “Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 12, pp. 4538–4542, 1986.
- L. Sanchez-Covarrubias, L. M. Slosky, B. J. Thompson et al., “P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac,” PLoS ONE, vol. 9, no. 2, Article ID e88516, 2014.
- T. W. Loo and D. M. Clarke, “P-glycoprotein: Associations between domains and between domains and molecular chaperones,” Journal of Biological Chemistry, vol. 270, no. 37, pp. 21839–21844, 1995.
- R. Bendayan, P. T. Ronaldson, D. Gingras, and M. Bendayan, “In situ localization of P-glycoprotein (ABCB1) in human and rat brain,” Journal of Histochemistry and Cytochemistry, vol. 54, no. 10, pp. 1159–1167, 2006.
- V. V. Rao, J. L. Dahlheimer, M. E. Bardgett et al., “Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood- cerebrospinal-fluid drug-permeability barrier,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 7, pp. 3900–3905, 1999.
- T. Litman, T. Zeuthen, T. Skovsgaard, and W. D. Stein, “Competitive, non-competitive and cooperative interactions between substrates of P-glycoproteins as measured by ATPase activity,” Biochimica et Biophysica Acta: Molecular Basis of Disease, vol. 1361, no. 2, pp. 169–176, 1997.
- Y.-N. Chen, L. A. Mickley, A. M. Schwartz, E. M. Acton, J. Hwang, and A. T. Fojo, “Characterization of adriamycin-resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein,” The Journal of Biological Chemistry, vol. 265, no. 17, pp. 10073–10080, 1990.
- L. A. Doyle, W. Yang, L. V. Abruzzo et al., “A multidrug resistance transporter from human MCF-7 breast cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 26, pp. 15665–15670, 1998.
- K. Mohrmann, M. A. J. van Eijndhoven, A. H. Schinkel, and J. H. M. Schellens, “Absence of N-linked glycosylation does not affect plasma membrane localization of breast cancer resistance protein (BCRP/ABCG2),” Cancer Chemotherapy and Pharmacology, vol. 56, no. 4, pp. 344–350, 2005.
- T. Nakanishi, L. A. Doyle, B. Hassel et al., “Functional Characterization of Human Breast Cancer Resistance Protein (BCRP, ABCG2) Expressed in the Oocytes of Xenopus laevis,” Molecular Pharmacology, vol. 64, no. 6, pp. 1452–1462, 2003.
- G. Lee, K. Babakhanian, M. Ramaswamy, A. Prat, K. Wosik, and R. Bendayan, “Expression of the ATP-binding cassette membrane transporter, ABCG2, in human and rodent brain microvessel endothelial and glial cell culture systems,” Pharmaceutical Research, vol. 24, no. 7, pp. 1262–1274, 2007.
- T. Eisenblätter, S. Hüwel, and H.-J. Galla, “Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood-brain barrier,” Brain Research, vol. 971, no. 2, pp. 221–231, 2003.
- W. Zhang, J. Mojsilovic-Petrovic, M. F. Andrade, H. Zhang, M. Ball, and D. B. Stanimirovic, “The expression and functional characterization of ABCG2 in brain endothelial cells and vessels,” The FASEB Journal, vol. 17, no. 14, pp. 2085–2087, 2003.
- Q. Mao and J. D. Unadkat, “Role of the breast cancer resistance protein (ABCG2) in drug transport,” The AAPS Journal, vol. 7, no. 1, pp. E118–E133, 2005.
- F. Staud and P. Pavek, “Breast cancer resistance protein (BCRP/ABCG2),” The International Journal of Biochemistry & Cell Biology, vol. 37, no. 4, pp. 720–725, 2005.
- D. D. Ross, W. Yang, L. V. Abruzzo et al., “Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines,” Journal of the National Cancer Institute, vol. 91, no. 5, pp. 429–433, 1999.
- K. Miyake, L. Mickley, T. Litman et al., “Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes,” Cancer Research, vol. 59, no. 1, pp. 8–13, 1999.
- A. T. Nies, G. Jedlitschky, J. König et al., “Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain,” Neuroscience, vol. 129, no. 2, pp. 349–360, 2004.
- H. Bronger, J. König, K. Kopplow et al., “ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier,” Cancer Research, vol. 65, no. 24, pp. 11419–11428, 2005.
- D. S. Miller, S. N. Nobmann, H. Gutmann, M. Toeroek, J. Drewe, and G. Fricker, “Xenobiotic transport across isolated brain microvessels studied by confocal microscopy,” Molecular Pharmacology, vol. 58, no. 6, pp. 1357–1367, 2000.
- P. Borst, R. Evers, M. Kool, and J. Wijnholds, “A family of drug transporters: the multidrug resistance-associated proteins,” Journal of the National Cancer Institute, vol. 92, no. 16, pp. 1295–1302, 2000.
- S. Dallas, D. S. Miller, and R. Bendayan, “Multidrug resistance-associated proteins: expression and function in the central nervous system,” Pharmacological Reviews, vol. 58, no. 2, pp. 140–161, 2006.
- Y.-J. Lee, H. Kusuhara, and Y. Sugiyama, “Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17 -glucuronide and 2 ,4-dinitrophenyl-S-glutathione across the blood-cerebrospinal fluid barrier?” Journal of Pharmaceutical Sciences, vol. 93, no. 1, pp. 99–107, 2004.
- H. Kusuhara and Y. Sugiyama, “Active efflux across the blood-brain barrier: role of the solute carrier family,” NeuroRx, vol. 2, no. 1, pp. 73–85, 2005.
- M. A. Hediger, M. F. Romero, J.-B. Peng, A. Rolfs, H. Takanaga, and E. A. Bruford, “The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins,” Pflugers Archiv European Journal of Physiology, vol. 447, no. 5, pp. 465–468, 2004.
- M. Molina-Arcas, F. J. Casado, and M. Pastor-Anglada, “Nucleoside transporter proteins,” Current Vascular Pharmacology, vol. 7, no. 4, pp. 426–434, 2009.
- H. Daniel and G. Kottra, “The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology,” Pflügers Archiv, vol. 447, no. 5, pp. 610–618, 2004.
- D. Herrera-Ruiz and G. T. Knipp, “Current perspectives on established and putative mammalian oligopeptide transporters,” Journal of Pharmaceutical Sciences, vol. 92, no. 4, pp. 691–714, 2003.
- S. M. Carl, D. J. Lindley, D. Das et al., “ABC and SLC transporter expression and proton oligopeptide transporter (POT) mediated permeation across the human blood–brain barrier cell line, hCMEC/D3 [corrected],” Molecular Pharmaceutics, vol. 7, no. 4, pp. 1057–1068, 2010.
- D. E. Smith, C. E. Johanson, and R. F. Keep, “Peptide and peptide analog transport systems at the blood-CSF barrier,” Advanced Drug Delivery Reviews, vol. 56, no. 12, pp. 1765–1791, 2004.
- W. A. Banks and A. J. Kastin, “Brain-to-blood transport of peptides and the alcohol withdrawal syndrome,” Annals of the New York Academy of Sciences, vol. 739, pp. 108–118, 1994.
- A. P. Halestrap and M. C. Wilson, “The monocarboxylate transporter family—role and regulation,” IUBMB Life, vol. 64, no. 2, pp. 109–119, 2012.
- B. E. Enerson and L. R. Drewes, “Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery,” Journal of Pharmaceutical Sciences, vol. 92, no. 8, pp. 1531–1544, 2003.
- K. Pierre and L. Pellerin, “Monocarboxylate transporters in the central nervous system: distribution, regulation and function,” Journal of Neurochemistry, vol. 94, no. 1, pp. 1–14, 2005.
- A. Ceballos, M. M. Belinchon, E. Sanchez-Mendoza et al., “Importance of monocarboxylate transporter 8 for the blood-brain barrier-dependent availability of 3,5,3′-triiodo-L-thyronine,” Endocrinology, vol. 150, no. 5, pp. 2491–2496, 2009.
- S. Bröer, B. Rahman, G. Pellegri et al., “Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons,” Journal of Biological Chemistry, vol. 272, no. 48, pp. 30096–30102, 1997.
- L. Pellerin, A. P. Halestrap, and K. Pierre, “Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain,” Journal of Neuroscience Research, vol. 79, no. 1-2, pp. 55–64, 2005.
- M. Niemi, “Role of OATP transporters in the disposition of drugs,” Pharmacogenomics, vol. 8, no. 7, pp. 787–802, 2007.
- T. Mikkaichi, T. Suzuki, M. Tanemoto, S. Ito, and T. Abe, “The organic anion transporter (OATP) family,” Drug Metabolism and Pharmacokinetics, vol. 19, no. 3, pp. 171–179, 2004.
- B. Hagenbuch and P. J. Meier, “Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO super-family, new nomenclature and molecular/functional properties,” Pflugers Archiv European Journal of Physiology, vol. 447, no. 5, pp. 653–665, 2004.
- J. König, A. Seithel, U. Gradhand, and M. F. Fromm, “Pharmacogenomics of human OATP transporters,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 372, no. 6, pp. 432–443, 2006.
- G. A. Kullak-Ublick, B. Hagenbuch, B. Stieger et al., “Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver,” Gastroenterology, vol. 109, no. 4, pp. 1274–1282, 1995.
- W. Lee, H. Glaeser, L. H. Smith et al., “Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry,” The Journal of Biological Chemistry, vol. 280, no. 10, pp. 9610–9617, 2005.
- M. Roth, A. Obaidat, and B. Hagenbuch, “OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies,” British Journal of Pharmacology, vol. 165, no. 5, pp. 1260–1287, 2012.
- R. D. Huber, B. Gao, M.-A. S. Pfändler et al., “Characterization of two splice variants of human organic anion transporting polypeptide 3A1 isolated from human brain,” American Journal of Physiology: Cell Physiology, vol. 292, no. 2, pp. C795–C806, 2007.
- G. A. Baldeshwiler, A Structure Function Study of Organic Anion Transporting Polypeptide 1c1 (Oatp1c1), 2011.
- J. W. Jonker and A. H. Schinkel, “Pharmacological and physiological functions of the polyspecific organic cation transporters: oct1, 2, and 3 (SLC22A1-3),” Journal of Pharmacology and Experimental Therapeutics, vol. 308, no. 1, pp. 2–9, 2004.
- H. Kusuhara, T. Sekine, N. Utsunomiya-Tate et al., “Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain,” The Journal of Biological Chemistry, vol. 274, no. 19, pp. 13675–13680, 1999.
- S. H. Cha, T. Sekine, H. Kusuhara et al., “Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta,” Journal of Biological Chemistry, vol. 275, no. 6, pp. 4507–4512, 2000.
- T. Sekine, N. Watanabe, M. Hosoyamada, Y. Kanai, and H. Endou, “Expression cloning and characterization of a novel multispecific organic anion transporter,” The Journal of Biological Chemistry, vol. 272, no. 30, pp. 18526–18529, 1997.
- D. H. Sweet and J. B. Pritchard, “The molecular biology of renal organic anion and organic cation transporters,” Cell Biochemistry and Biophysics, vol. 31, no. 1, pp. 89–118, 1999.
- J. C. Monte, M. A. Nagle, S. A. Eraly, and S. K. Nigam, “Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa,” Biochemical and Biophysical Research Communications, vol. 323, no. 2, pp. 429–436, 2004.
- T. Sekine, S. H. Cha, and H. Endou, “The multispecific organic anion transporter (OAT) family,” Pflügers Archiv, vol. 440, no. 3, pp. 337–350, 2000.
- A. E. Riedmaier, A. T. Nies, E. Schaeffeler, and M. Schwab, “Organic anion transporters and their implications in pharmacotherapy,” Pharmacological Reviews, vol. 64, no. 3, pp. 421–449, 2012.
- S. Mori, H. Takanaga, S. Ohtsuki et al., “Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells,” Journal of Cerebral Blood Flow and Metabolism, vol. 23, no. 4, pp. 432–440, 2003.
- D. H. Sweet, D. S. Miller, J. B. Pritchard, Y. Fujiwara, D. R. Beier, and S. K. Nigam, “Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice,” The Journal of Biological Chemistry, vol. 277, no. 30, pp. 26934–26943, 2002.
- T. Sekine, S. H. Cha, M. Tsuda et al., “Identification of multispecific organic anion transporter 2 expressed predominantly in the liver,” FEBS Letters, vol. 429, no. 2, pp. 179–182, 1998.
- G. L. Youngblood and D. H. Sweet, “Identification and functional assessment of the novel murine organic anion transporter Oat5 (Slc22a19) expressed in kidney,” The American Journal of Physiology—Renal Physiology, vol. 287, no. 2, pp. F236–F244, 2004.
- H. Koepsell, “Organic cation transporters in intestine, kidney, liver, and brain,” Annual Review of Physiology, vol. 60, pp. 243–266, 1998.
- H. Koepsell and H. Endou, “The SLC22 drug transporter family,” Pflügers Archiv, vol. 447, no. 5, pp. 666–676, 2004.
- D. Gründemann, J. Babin-Ebell, F. Martel, N. Örding, A. Schmidt, and E. Schömig, “Primary structure and functional expression of the apical organic cation transporter from kidney epithelial LLC-PK1 cells,” Journal of Biological Chemistry, vol. 272, no. 16, pp. 10408–10413, 1997.
- G. Ciarimboli and E. Schlatter, “Regulation of organic cation transport,” Pflügers Archiv, vol. 449, no. 5, pp. 423–441, 2005.
- C.-J. Lin, Y. Tai, M.-T. Huang et al., “Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents,” Journal of Neurochemistry, vol. 114, no. 3, pp. 717–727, 2010.
- D. Dickens, A. Owen, A. Alfirevic et al., “Lamotrigine is a substrate for OCT1 in brain endothelial cells,” Biochemical Pharmacology, vol. 83, no. 6, pp. 805–814, 2012.
- X. Wu, R. Kekuda, W. Huang et al., “Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain,” The Journal of Biological Chemistry, vol. 273, no. 49, pp. 32776–32786, 1998.
- X. Wu, R. L. George, W. Huang et al., “Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta,” Biochimica et Biophysica Acta: Biomembranes, vol. 1466, no. 1-2, pp. 315–327, 2000.
- A. Inano, Y. Sai, H. Nikaido et al., “Acetyl-L-carnitine permeability across the blood-brain barrier and involvement of carnitine transporter OCTN2,” Biopharmaceutics and Drug Disposition, vol. 24, no. 8, pp. 357–365, 2003.
- A.-M. Lamhonwah, C. A. Ackerley, A. Tilups, V. D. Edwards, R. J. Wanders, and I. Tein, “OCTN3 is a mammalian peroxisomal membrane carnitine transporter,” Biochemical and Biophysical Research Communications, vol. 338, no. 4, pp. 1966–1972, 2005.
- I. Tamai, H. Yabuuchi, J.-I. Nezu et al., “Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1,” The FEBS Letters, vol. 419, no. 1, pp. 107–111, 1997.
- R. Ohashi, I. Tamai, H. Yabuuchi et al., “Na+-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance,” Journal of Pharmacology and Experimental Therapeutics, vol. 291, no. 2, pp. 778–784, 1999.
- J. M. Lauder, “Neurotransmitters as growth regulatory signals: role of receptors and second messengers,” Trends in Neurosciences, vol. 16, no. 6, pp. 233–240, 1993.
- J. R. Mackey, R. S. Mani, M. Selner et al., “Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines,” Cancer Research, vol. 58, no. 19, pp. 4349–4357, 1998.
- J. H. Gray, R. P. Owen, and K. M. Giacomini, “The concentrative nucleoside transporter family, SLC28,” Pflügers Archiv, vol. 447, no. 5, pp. 728–734, 2004.
- M. A. Cabrita, S. A. Baldwin, J. D. Young, and C. E. Cass, “Molecular biology and regulation of nucleoside and nucleobase transporter proteins in eukaryotes and prokaryotes,” Biochemistry and Cell Biology, vol. 80, no. 5, pp. 623–638, 2002.
- S. A. Baldwin, S. Y. M. Yao, R. J. Hyde et al., “Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes,” The Journal of Biological Chemistry, vol. 280, no. 16, pp. 15880–15887, 2005.
- C. Wang, W. Lin, H. Playa, S. Sun, K. Cameron, and J. K. Buolamwini, “Dipyridamole analogs as pharmacological inhibitors of equilibrative nucleoside transporters. Identification of novel potent and selective inhibitors of the adenosine transporter function of human equilibrative nucleoside transporter 4 (hENT4),” Biochemical Pharmacology, vol. 86, no. 11, pp. 1531–1540, 2013.
- R. J. Hyde, C. E. Cass, J. D. Young, and S. A. Baldwin, “The ENT family of eukaryote nucleoside and nucleobase transporters: recent advances in the investigation of structure/function relationships and the identification of novel isoforms,” Molecular Membrane Biology, vol. 18, no. 1, pp. 53–63, 2001.
- M. Sundaram, S. Y. M. Yao, J. C. Ingram et al., “Topology of a human equilibrative, nitrobenzylthioinosine (NBMPR)-sensitive nucleoside transporter (hENT1) implicated in the cellular uptake of adenosine and anti-cancer drugs,” Journal of Biological Chemistry, vol. 276, no. 48, pp. 45270–45275, 2001.
- R. S. Mani, J. R. Hammond, J. M. J. Marjan et al., “Demonstration of equilibrative nucleoside transporters (hENT1 and hENT2) in nuclear envelopes of cultured human choriocarcinoma (BeWo) cells by functional reconstitution in proteoliposomes,” The Journal of Biological Chemistry, vol. 273, no. 46, pp. 30818–30825, 1998.
- C. R. Crawford, D. H. Patel, C. Naeve, and J. A. Belt, “Cloning of the human equilibrative, nitrobenzylmercaptopurine riboside (NBMPR)-insensitive nucleoside transporter ei by functional expression in a transport-deficient cell line,” The Journal of Biological Chemistry, vol. 273, no. 9, pp. 5288–5293, 1998.
- K. Engel, M. Zhou, and J. Wang, “Identification and characterization of a novel monoamine transporter in the human brain,” The Journal of Biological Chemistry, vol. 279, no. 48, pp. 50042–50049, 2004.
- K. M. Smith, S. K. Slugoski, A. M. L. Loewen et al., “The broadly selective human Na+/nucleoside cotransporter (hCNT3) exhibits novel cation-coupled nucleoside transport characteristics,” The Journal of Biological Chemistry, vol. 280, no. 27, pp. 25436–25449, 2005.
- H. Wolburg, K. Wolburg-Buchholz, J. Kraus et al., “Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme,” Acta Neuropathologica, vol. 105, no. 6, pp. 586–592, 2003.
- P. Dhawan, A. B. Singh, N. G. Deane et al., “Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer,” The Journal of Clinical Investigation, vol. 115, no. 7, pp. 1765–1776, 2005.
- W. Jia, R. Lu, T. A. Martin, and W. G. Jiang, “The role of claudin-5 in blood-brain barrier (BBB) and brain metastases (review),” Molecular Medicine Reports, vol. 9, no. 3, pp. 779–785, 2014.
- D. C. Davies, “Blood-brain barrier breakdown in septic encephalopathy and brain tumours,” Journal of Anatomy, vol. 200, no. 6, pp. 639–646, 2002.
- H. E. de Vries, M. C. M. Blom-Roosemalen, M. van Oosten et al., “The influence of cytokines on the integrity of the blood-brain barrier in vitro,” Journal of Neuroimmunology, vol. 64, no. 1, pp. 37–43, 1996.
- K. Lamszus, N. O. Schmidt, S. Ergün, and M. Westphal, “Isolation and culture of human neuromicrovascular endothelial cells for the study of angiogenesis in vitro,” Journal of Neuroscience Research, vol. 55, no. 3, pp. 370–381, 1999.
- A. L. Cowles and J. D. Fenstermacher, “Theoretical considerations in the chemotherapy of brain tumors,” in Antineoplastic and Immunosuppressive Agents Part I, A. C. Sartorelli and D. G. Johns, Eds., pp. 319–329, Springer, Berlin, Germany, 1974.
- J. D. Fenstermacher and A. L. Cowles, “Theoretic limitations of intracarotid infusions in brain tumor chemotherapy,” Cancer Treatment Reports, vol. 61, no. 4, pp. 519–526, 1977.
- W. W. Eckman, C. S. Patlak, and J. D. Fenstermacher, “A critical evaluation of the principles governing the advantages of intra arterial infusions,” Journal of Pharmacokinetics and Biopharmaceutics, vol. 2, no. 3, pp. 257–285, 1974.
- J. Fenstermacher and J. Gazendam, “Intra-arterial infusions of drugs and hyperosmotic solutions as ways of enhancing CNS chemotherapy,” Cancer Treatment Reports, vol. 65, supplement 2, pp. 27–37, 1981.
- Y. Hirano, K. Mineura, K. Mizoi, and N. Tomura, “Therapeutic results of intra-arterial chemotherapy in patients with malignant glioma,” International Journal of Oncology, vol. 13, no. 3, pp. 537–542, 1998.
- E. J. Dropcho, S. S. Rosenfeld, J. Vitek, B. L. Guthrie, and R. B. Morawetz, “Phase II study of intracarotid or selective intracerebral infusion of cisplatin for treatment of recurrent anaplastic gliomas,” Journal of Neuro-Oncology, vol. 36, no. 2, pp. 191–198, 1998.
- S. Gundersen, K. Lote, and K. Watne, “A retrospective study of the value of chemotherapy as adjuvant therapy to surgery and radiotherapy in grade 3 and 4 gliomas,” European Journal of Cancer, vol. 34, no. 10, pp. 1565–1569, 1998.
- H. A. Riina, J. F. Fraser, S. Fralin, J. Knopman, R. J. Scheff, and J. A. Boockvar, “Superselective intraarterial cerebral infusion of bevacizumab: a revival of interventional neuro-oncology for malignant glioma,” Journal of Experimental Therapeutics and Oncology, vol. 8, no. 2, pp. 145–150, 2009.
- R. G. Blasberg, C. S. Patlak, and W. R. Shapiro, “Distribution of methotrexate in the cerebrospinal fluid and brain after intraventricular administration,” Cancer Treatment Reports, vol. 61, no. 4, pp. 633–641, 1977.
- R. G. Blasberg, “Methotrexate, cytosine arabinoside, and BCNU concentration in brain after ventriculocisternal perfusion,” Cancer Treatment Reports, vol. 61, no. 4, pp. 625–631, 1977.
- R. G. Blasberg, “Pharmacodynamics and the blood-brain barrier,” National Cancer Institute monograph, vol. 46, pp. 19–27, 1977.
- D. R. Groothuis and R. M. Levy, “The entry of antiviral and antiretroviral drugs into the central nervous system,” Journal of NeuroVirology, vol. 3, no. 6, pp. 387–400, 1997.
- D. W. Laske, R. J. Youle, and E. H. Oldfield, “Tumor regression with regional distribution of the targeted toxin TF- CRM107 in patients with malignant brain tumors,” Nature Medicine, vol. 3, no. 12, pp. 1362–1368, 1997.
- L. H. Parsons and J. B. Justice Jr., “Quantitative approaches to in vivo brain microdialysis,” Critical Reviews in Neurobiology, vol. 8, no. 3, pp. 189–220, 1994.
- E. C. M. De Lange, B. A. G. De Boer, and D. D. Breimer, “Microdialysis for pharmacokinetic analysis of drug transport to the brain,” Advanced Drug Delivery Reviews, vol. 36, no. 2-3, pp. 211–227, 1999.
- K. H. Dykstra, J. K. Hsiao, P. F. Morrison et al., “Quantitative examination of tissue concentration profiles associated with microdialysis,” Journal of Neurochemistry, vol. 58, no. 3, pp. 931–940, 1992.
- W. M. Pardridge, “Blood-brain barrier drug targeting: the future of brain drug development,” Molecular Interventions, vol. 3, no. 2, pp. 90–51, 2003.
- V. Chandramohan, J. H. Sampson, I. Pastan, and D. D. Bigner, “Toxin-based targeted therapy for malignant brain tumors,” Clinical and Developmental Immunology, vol. 2012, Article ID 480429, 2012.
- D. Fortin, C. Gendron, M. Boudrias, and M.-P. Garant, “Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in the treatment of cerebral metastasis,” Cancer, vol. 109, no. 4, pp. 751–760, 2007.
- C. V. Borlongan and D. F. Emerich, “Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport,” Brain Research Bulletin, vol. 60, no. 3, pp. 297–306, 2003.
- K. Matsukado, T. Inamura, S. Nakano, M. Fukui, R. T. Bartus, and K. L. Black, “Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7,” Neurosurgery, vol. 39, no. 1, pp. 125–134, 1996.
- B. Erdlenbruch, V. Jendrossek, H. Eibl, and M. Lakomek, “Transient and controllable opening of the blood-brain barrier to cytostatic and antibiotic agents by alkylglycerols in rats,” Experimental Brain Research, vol. 135, no. 3, pp. 417–422, 2000.
- M. Kinoshita, N. McDannold, F. A. Jolesz, and K. Hynynen, “Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 31, pp. 11719–11723, 2006.
- F. Leweke, M. S. Damian, C. Schindler, and W. Schachenmayr, “Multidrug resistance in glioblastoma. Chemosensitivity testing and immunohistochemical demonstration of P-glycoprotein,” Pathology Research and Practice, vol. 194, no. 3, pp. 149–155, 1998.
- L. A. Doyle and D. D. Ross, “Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2),” Oncogene, vol. 22, no. 47, pp. 7340–7358, 2003.
- S. F. Bates, C. Chen, R. Robey, M. Kang, W. D. Figg, and T. Fojo, “Reversal of multidrug resistance: lessons from clinical oncology,” Novartis Foundation Symposia, vol. 243, pp. 83–185, 2002.
- H. Thomas and H. M. Coley, “Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein,” Cancer Control, vol. 10, no. 2, pp. 159–165, 2003.
- R. Michael, A. Folkes, P. Ashworth et al., “Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives,” Bioorganic & Medicinal Chemistry Letters, vol. 9, no. 4, pp. 595–600, 1999.
- A. H. Dantzig, R. L. Shepard, K. L. Law et al., “Selectivity of the multidrug resistance modulator, LY335979, for P- glycoprotein and effect on cytochrome P-450 activities,” Journal of Pharmacology and Experimental Therapeutics, vol. 290, no. 2, pp. 854–862, 1999.
- L. Van Zuylen, A. Sparreboom, A. Van Der Gaast et al., “The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel,” Clinical Cancer Research, vol. 6, no. 4, pp. 1365–1371, 2000.
- E. M. Kemper, A. E. van Zandbergen, C. Cleypool et al., “Increased penetration of paclitaxel into the brain by inhibition of P-glycoprotein,” Clinical Cancer Research, vol. 9, no. 7, pp. 2849–2855, 2003.
- G. Fricker and D. S. Miller, “Modulation of drug transporters at the blood-brain barrier,” Pharmacology, vol. 70, no. 4, pp. 169–176, 2004.
- R. G. Thorne, C. R. Emory, T. A. Ala, and W. H. Frey II, “Quantitative analysis of the olfactory pathway for drug delivery to the brain,” Brain Research, vol. 692, no. 1-2, pp. 278–282, 1995.
- D. Dhanda, W. Frey II, D. Leopold, and U. Kompella, “Approaches for drug deposition in the human olfactory epithelium,” Drug Development & Delivery, vol. 5, pp. 64–72, 2005.
- D. Wang, Y. Gao, and L. Yun, “Study on brain targeting of raltitrexed following intranasal administration in rats,” Cancer Chemotherapy and Pharmacology, vol. 57, no. 1, pp. 97–104, 2006.
- T. Sakane, S. Yamashita, N. Yata, and H. Sezaki, “Transnasal delivery of 5-fluorouracil to the brain in the rat,” Journal of Drug Targeting, vol. 7, no. 3, pp. 233–240, 1999.
- R. Hashizume, T. Ozawa, S. M. Gryaznov et al., “New therapeutic approach for brain tumors: intranasal delivery of telomerase inhibitor GRN163,” Neuro-Oncology, vol. 10, no. 2, pp. 112–120, 2008.
- F. Wang, X. Jiang, and W. Lu, “Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats,” International Journal of Pharmaceutics, vol. 263, no. 1-2, pp. 1–7, 2003.
- C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney, “Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings,” Advanced Drug Delivery Reviews, vol. 46, no. 1–3, pp. 3–26, 2001.
- W. M. Pardridge, “Transport of small molecules through the blood-brain barrier: biology and methodology,” Advanced Drug Delivery Reviews, vol. 15, no. 1–3, pp. 5–36, 1995.
- D. R. Groothuis, B. E. Lippitz, I. Fekete et al., “The effect of an amino acid-lowering diet on the rate of melphalan entry into brain and xenotransplanted glioma,” Cancer Research, vol. 52, no. 20, pp. 5590–5596, 1992.
- V. E. Shashoua and G. W. Hesse, “N-docosahexaenoyl, 3 hydroxytyramine: a dopaminergic compound that penetrates the blood-brain barrier and suppresses appetite,” Life Sciences, vol. 58, no. 16, pp. 1347–1357, 1996.
- M. O. Bradley, N. L. Webb, F. H. Anthony et al., “Tumor targeting by covalent conjugation of a natural fatty acid to paclitaxel,” Clinical Cancer Research, vol. 7, no. 10, pp. 3229–3238, 2001.
- M. E. Sherman, Y. S. Erozan, R. B. Mann et al., “Stereotactic brain biopsy in the diagnosis of malignant lymphoma,” The American Journal of Clinical Pathology, vol. 95, no. 6, pp. 878–883, 1991.
- T. Yoshikawa, T. Sakaeda, T. Sugawara, K. Hirano, and V. J. Stella, “A novel chemical delivery system for brain targeting,” Advanced Drug Delivery Reviews, vol. 36, no. 2-3, pp. 255–275, 1999.
- X.-H. Tian, X.-N. Lin, F. Wei et al., “Enhanced brain targeting of temozolomide in polysorbate-80 coated polybutylcyanoacrylate nanoparticles,” International Journal of Nanomedicine, vol. 6, pp. 445–452, 2011.
- A. Jain, G. Chasoo, S. K. Singh, A. K. Saxena, and S. K. Jain, “Transferrin-appended PEGylated nanoparticles for temozolomide delivery to brain: in vitro characterisation,” Journal of Microencapsulation, vol. 28, no. 1, pp. 21–28, 2011.
- G. Huang, N. Zhang, X. Bi, and M. Dou, “Solid lipid nanoparticles of temozolomide: potential reduction of cardial and nephric toxicity,” International Journal of Pharmaceutics, vol. 355, no. 1-2, pp. 314–320, 2008.
- Y. Ling, K. Wei, F. Zou, and S. Zhong, “Temozolomide loaded PLGA-based superparamagnetic nanoparticles for magnetic resonance imaging and treatment of malignant glioma,” International Journal of Pharmaceutics, vol. 430, no. 1-2, pp. 266–275, 2012.
- D. S. Jain, R. B. Athawale, A. N. Bajaj et al., “Unraveling the cytotoxic potential of Temozolomide loaded into PLGA nanoparticles,” DARU, Journal of Pharmaceutical Sciences, vol. 22, article 18, 2014.
- C. Abrudan, I. S. Florian, A. Baritchii et al., “Assessment of temozolomide action encapsulated in chitosan and polymer nanostructures on glioblastoma cell lines,” Romanian Neurosurgery, vol. 21, no. 1, pp. 18–29, 2014.
- J. Tao, P. Hua-Nan, Y. Jin-Na et al., “Preparation and brain delivery evaluation of temozolomide-loaded albumin nanoparticles,” Chinese Journal of Pharmaceuticals, vol. 44, no. 1, pp. 41–45, 2013.
- D. A. Bota, A. Desjardins, J. A. Quinn, M. L. Affronti, and H. S. Friedman, “Interstitial chemotherapy with biodegradable BCNU (Gliadel®) wafers in the treatment of malignant gliomas,” Therapeutics and Clinical Risk Management, vol. 3, no. 5, pp. 707–715, 2007.
- L. Qian, J. Zheng, K. Wang et al., “Cationic core-shell nanoparticles with carmustine contained within O6-benzylguanine shell for glioma therapy,” Biomaterials, vol. 34, no. 35, pp. 8968–8978, 2013.
- Y.-C. Kuo and C.-T. Liang, “Inhibition of human brain malignant glioblastoma cells using carmustine-loaded catanionic solid lipid nanoparticles with surface anti-epithelial growth factor receptor,” Biomaterials, vol. 32, no. 12, pp. 3340–3350, 2011.
- C. Kang, X. Yuan, Y. Zhong et al., “Growth inhibition against intracranial C6 glioma cells by stereotactic delivery of BCNU by controlled release from poly(D,L-lactic acid) nanoparticles,” Technology in Cancer Research and Treatment, vol. 8, no. 1, pp. 61–70, 2009.
- K. Fabel, J. Dietrich, P. Hau et al., “Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin,” Cancer, vol. 92, no. 7, pp. 1936–1942, 2001.
- Y.-C. Kuo and C.-T. Liang, “Catanionic solid lipid nanoparticles carrying doxorubicin for inhibiting the growth of U87MG cells,” Colloids and Surfaces B: Biointerfaces, vol. 85, no. 2, pp. 131–137, 2011.
- S. Wohlfart, A. S. Khalansky, S. Gelperina et al., “Efficient chemotherapy of rat glioblastoma using doxorubicin-loaded PLGA nanoparticles with different stabilizers,” PLoS ONE, vol. 6, no. 5, Article ID e19121, 2011.
- J. P. Wang, X. L. Zhu, Y. W. Xi, D. F. Wang, and G. H. Huang, “Preparation of lomustine loaded liposomes and studies of its pharmacokinetics and tissue distribution properties,” Journal of Chinese Pharmaceutical Sciences, vol. 19, no. 5, pp. 353–362, 2010.
- A. Y. Bedikian, N. E. Papadopoulos, K. B. Kim et al., “A pilot study with vincristine sulfate liposome infusion in patients with metastatic melanoma,” Melanoma Research, vol. 18, no. 6, pp. 400–404, 2008.
- R. Saito, J. R. Bringas, T. R. McKnight et al., “Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging,” Cancer Research, vol. 64, no. 7, pp. 2572–2579, 2004.
- Q. Lv, L.-M. Li, M. Han et al., “Characteristics of sequential targeting of brain glioma for transferrin-modified cisplatin liposome,” International Journal of Pharmaceutics, vol. 444, no. 1-2, pp. 1–9, 2013.
- A. Fiorillo, G. Maggi, N. Greco et al., “Second-line chemotherapy with the association of liposomal daunorubicin, carboplatin and etoposide in children with recurrent malignant brain tumors,” Journal of Neuro-Oncology, vol. 66, no. 1-2, pp. 179–185, 2004.
- M. Wankhede, A. Bouras, M. Kaluzova, and C. G. Hadjipanayis, “Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy,” Expert Review of Clinical Pharmacology, vol. 5, no. 2, pp. 173–186, 2012.
- Y.-C. Kuo and T.-Y. Hong, “Delivering etoposide to the brain using catanionic solid lipid nanoparticles with surface 5-HT-moduline,” International Journal of Pharmaceutics, vol. 465, no. 1-2, pp. 132–142, 2014.
- R. L. Juliano and D. Stamp, “Pharmacokinetics of liposome-encapsulated anti-tumor drugs: studies with vinblastine, actinomycin D, cytosine arabinoside, and daunomycin,” Biochemical Pharmacology, vol. 27, no. 1, pp. 21–27, 1978.
- P.-Y. Chen, T. Ozawa, D. C. Drummond et al., “Comparing routes of delivery for nanoliposomal irinotecan shows superior anti-tumor activity of local administration in treating intracranial glioblastoma xenografts,” Neuro-Oncology, vol. 15, no. 2, pp. 189–197, 2013.
- B. J. Turunen, H. Ge, J. Oyetunji et al., “Paclitaxel succinate analogs: anionic and amide introduction as a strategy to impart blood-brain barrier permeability,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 22, pp. 5971–5974, 2008.
- Y. Wang, C. Wang, C. Gong, G. Guo, F. Luo, and Z. Qian, “Polysorbate 80 coated poly (ε-caprolactone)-poly (ethylene glycol)-poly (ε-caprolactone) micelles for paclitaxel delivery,” International Journal of Pharmaceutics, vol. 434, no. 1-2, pp. 1–8, 2012.
- X.-Y. Li, Y. Zhao, M.-G. Sun et al., “Multifunctional liposomes loaded with paclitaxel and artemether for treatment of invasive brain glioma,” Biomaterials, vol. 35, no. 21, pp. 5591–5604, 2014.
- J. M. Provenzale, S. Mukundan, and M. Dewhirst, “The role of blood-brain barrier permeability in brain tumor imaging and therapeutics,” American Journal of Roentgenology, vol. 185, no. 3, pp. 763–767, 2005.
- J. Kreuter, “Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain,” Journal of Nanoscience and Nanotechnology, vol. 4, no. 5, pp. 484–488, 2004.
- Y. Jallouli, A. Paillard, J. Chang, E. Sevin, and D. Betbeder, “Influence of surface charge and inner composition of porous nanoparticles to cross blood-brain barrier in vitro,” International Journal of Pharmaceutics, vol. 344, no. 1-2, pp. 103–109, 2007.
- S. M. Moghimi, A. C. Hunter, and J. C. Murray, “Long-circulating and target-specific nanoparticles: theory to practice,” Pharmacological Reviews, vol. 53, no. 2, pp. 283–318, 2001.
- W. M. Pardridge, “Vector-mediated drug delivery to the brain,” Advanced Drug Delivery Reviews, vol. 36, no. 2-3, pp. 299–321, 1999.
- V. Soni, D. V. Kohli, and S. K. Jain, “Transferrin-conjugated liposomal system for improved delivery of 5-fluorouracil to brain,” Journal of Drug Targeting, vol. 16, no. 1, pp. 73–78, 2008.
- A. Doi, S. Kawabata, K. Iida et al., “Tumor-specific targeting of sodium borocaptate (BSH) to malignant glioma by transferrin-PEG liposomes: a modality for boron neutron capture therapy,” Journal of Neuro-oncology, vol. 87, no. 3, pp. 287–294, 2008.
- X. Ying, H. Wen, W.-L. Lu et al., “Dual-targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals,” Journal of Controlled Release, vol. 141, no. 2, pp. 183–192, 2010.
- B. Gupta, T. S. Levchenko, and V. P. Torchilin, “TAT peptide-modified liposomes provide enhanced gene delivery to intracranial human brain tumor xenografts in nude mice,” Oncology Research, vol. 16, no. 8, pp. 351–359, 2007.
- L. Juillerat-Jeanneret, “Critical analysis of cancer therapy using nanomaterials,” in Nanotechnologies for the Life Sciences, Wiley-VCH, 2007.
- L. Fenart, A. Casanova, B. Dehouck et al., “Evaluation of effect of charge and lipid coating on ability of 60-nm nanoparticles to cross an in vitro model of the blood-brain barrier,” Journal of Pharmacology and Experimental Therapeutics, vol. 291, no. 3, pp. 1017–1022, 1999.
- D. Wu and W. M. Pardridge, “Blood-brain barrier transport of reduced folic acid,” Pharmaceutical Research, vol. 16, no. 3, pp. 415–419, 1999.
- B. Petri, A. Bootz, A. Khalansky et al., “Chemotherapy of brain tumour using doxorubicin bound to surfactant-coated poly (butyl cyanoacrylate) nanoparticles: revisiting the role of surfactants,” Journal of Controlled Release, vol. 117, no. 1, pp. 51–58, 2007.
- Y. Tsutsui, K. Tomizawa, M. Nagita et al., “Development of bionanocapsules targeting brain tumors,” Journal of Controlled Release, vol. 122, no. 2, pp. 159–164, 2007.
- H. L. Wong, R. Bendayan, A. M. Rauth, Y. Li, and X. Y. Wu, “Chemotherapy with anticancer drugs encapsulated in solid lipid nanoparticles,” Advanced Drug Delivery Reviews, vol. 59, no. 6, pp. 491–504, 2007.
- H. Chen, X. Zhang, S. Dai et al., “Multifunctional gold nanostar conjugates for tumor imaging and combined photothermal and chemo-therapy,” Theranostics, vol. 3, no. 9, pp. 633–649, 2013.
- W.-H. Chen, X.-D. Xu, H.-Z. Jia et al., “Therapeutic nanomedicine based on dual-intelligent functionalized gold nanoparticles for cancer imaging and therapy in vivo,” Biomaterials, vol. 34, no. 34, pp. 8798–8807, 2013.
- Z. Liu and X.-J. Liang, “Nano-carbons as theranostics,” Theranostics, vol. 2, no. 3, pp. 235–237, 2012.
- S.-Y. Qin, J. Feng, L. Rong et al., “Theranostic GO-based nanohybrid for tumor induced imaging and potential combinational tumor therapy,” Small, vol. 10, no. 3, pp. 599–608, 2014.
- K. K. Jain, “Use of nanoparticles for drug delivery in glioblastoma multiforme,” Expert Review of Neurotherapeutics, vol. 7, no. 4, pp. 363–372, 2007.
- A. V. Kabanov, E. V. Batrakova, and D. W. Miller, “Pluronic block copolymers as modulators of drug efflux transporter activity in the blood-brain barrier,” Advanced Drug Delivery Reviews, vol. 55, no. 1, pp. 151–164, 2003.
- E. V. Batrakova and A. V. Kabanov, “Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers,” Journal of Controlled Release, vol. 130, no. 2, pp. 98–106, 2008.
- R. S. Dhanikula, A. Argaw, J.-F. Bouchard, and P. Hildgen, “Methotrexate loaded polyether-copolyester dendrimers for the treatment of gliomas: enhanced efficacy and intratumoral transport capability,” Molecular Pharmaceutics, vol. 5, no. 1, pp. 105–116, 2008.
- C. M. Kramm, N. G. Rainov, M. Sena-Esteves et al., “Herpes vector-mediated delivery of marker genes to disseminated central nervous system tumors,” Human Gene Therapy, vol. 7, no. 3, pp. 291–300, 1996.
- J. Chen, T. Bezdek, J. Chang et al., “A glial-specific, repressible, adenovirus vector for brain tumor gene therapy,” Cancer Research, vol. 58, no. 16, pp. 3504–3507, 1998.
- H. E. J. Hofland, D. Nagy, J.-J. Liu et al., “In vivo gene transfer by intravenous administration of stable cationic lipid/DNA complex,” Pharmaceutical Research, vol. 14, no. 6, pp. 742–749, 1997.
- S.-S. Kim, A. Rait, E. Kim et al., “Nanoparticle carrying the p53 gene targets tumors including cancer stem cells, sensitizes glioblastoma to chemotherapy and improves survival,” ACS Nano, vol. 8, no. 6, pp. 5494–5514, 2014.
- A. Schuessler, C. Smith, L. Beagley et al., “Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma,” Cancer Research, vol. 74, no. 13, pp. 3466–3476, 2014.
- A. M. Thayer, “Improving peptides,” Chemical & Engineering News Archive, vol. 89, no. 22, pp. 13–20, 2011.
- L. Soroceanu, Y. Gillespie, M. B. Khazaeli, and H. Sontheimer, “Use of chlorotoxin for targeting of primary brain tumors,” Cancer Research, vol. 58, no. 21, pp. 4871–4879, 1998.
- M. Z. Strowski and A. D. Blake, “Function and expression of somatostatin receptors of the endocrine pancreas,” Molecular and Cellular Endocrinology, vol. 286, no. 1-2, pp. 169–179, 2008.
- K. De, A. Bhowmik, A. Behera, I. Banerjee, M. K. Ghosh, and M. Misra, “Synthesis, radiolabeling, and preclinical evaluation of a new octreotide analog for somatostatin receptor-positive tumor scintigraphy,” Journal of Peptide Science, vol. 18, no. 12, pp. 720–730, 2012.
- R. A. Henderson, S. Mossman, N. Nairn, and M. A. Cheever, “Cancer vaccines and immunotherapies: emerging perspectives,” Vaccine, vol. 23, no. 17-18, pp. 2359–2362, 2005.
- R. A. Fenstermaker and M. J. Ciesielski, “Challenges in the development of a survivin vaccine (SurVaxM) for malignant glioma,” Expert Review of Vaccines, vol. 13, no. 3, pp. 377–385, 2014.
- J. H. Sampson, G. E. Archer, D. A. Mitchell et al., “An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme,” Molecular Cancer Therapeutics, vol. 8, no. 10, pp. 2773–2779, 2009.
- L. W. Xu, K. K. H. Chow, M. Lim, and G. Li, “Current vaccine trials in glioblastoma: a review,” Journal of Immunology Research, vol. 2014, Article ID 796856, 10 pages, 2014.
- R. J. Boado, “Blood-brain barrier transport of non-viral gene and RNAi therapeutics,” Pharmaceutical Research, vol. 24, no. 9, pp. 1772–1787, 2007.
- N. Shi and W. M. Pardridge, “Noninvasive gene targeting to the brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 13, pp. 7567–7572, 2000.
- W. M. Pardridge, “Gene targeting in vivo with pegylated immunoliposomes,” Methods in Enzymology, vol. 373, pp. 507–528, 2003.
- Y. Zhang, Y.-F. Zhang, J. Bryant, A. Charles, R. J. Boado, and W. M. Pardridge, “Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer,” Clinical Cancer Research, vol. 10, no. 11, pp. 3667–3677, 2004.
- K. J. Lim, S. Bisht, E. E. Bar, A. Maitra, and C. G. Eberhart, “A polymeric nanoparticle formulation of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain tumors,” Cancer Biology and Therapy, vol. 11, no. 5, pp. 464–473, 2011.
- T. Kato, A. Natsume, H. Toda et al., “Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells,” Gene Therapy, vol. 17, no. 11, pp. 1363–1371, 2010.
- C.-H. Wang, S.-H. Chiou, C.-P. Chou, Y.-C. Chen, Y.-J. Huang, and C.-A. Peng, “Photothermolysis of glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody,” Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 7, no. 1, pp. 69–79, 2011.
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