http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Mon, 13 May 2013 10:57:27 +0000 http://www.hindawi.com/journals/jdd/2013/604293/ Giuseppe De Rosa, Michele Caraglia, Stefano Salmaso, and Tamer Elbayoumi Copyright © 2013 Giuseppe De Rosa et al. All rights reserved. Sun, 12 May 2013 10:21:06 +0000 http://www.hindawi.com/journals/jdd/2013/616197/ Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to “activate” nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery. M. Thanou and W. Gedroyc Copyright © 2013 M. Thanou and W. Gedroyc. All rights reserved. Thu, 02 May 2013 15:30:37 +0000 http://www.hindawi.com/journals/jdd/2013/905091/ Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab-paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms. Iole Cucinotto, Lucia Fiorillo, Simona Gualtieri, Mariamena Arbitrio, Domenico Ciliberto, Nicoletta Staropoli, Anna Grimaldi, Amalia Luce, Pierfrancesco Tassone, Michele Caraglia, and Pierosandro Tagliaferri Copyright © 2013 Iole Cucinotto et al. All rights reserved. Thu, 11 Apr 2013 16:07:26 +0000 http://www.hindawi.com/journals/jdd/2013/456248/ The antioxidant gallic acid (GA) has been incorporated into cotton (CO) and polyamide (PA) through two different vehicles, that is, liposomes and mixed micelles, and their respective absorption/desorption processes have been studied. Moreover, in vitro percutaneous absorption tests of different cosmetotextiles have been performed to demonstrate antioxidant penetration within the layers of the skin. When GA was embedded into the cosmetotextiles, it always promoted a reservoir effect that was much more marked than that observed for polyamide. Similar penetration was observed in the textiles treated with GA in mixed micelles or liposomes in such compartments of the skin as the stratum corneum, epidermis, and even the dermis. GA was detected in receptor fluid only when CO was treated with MM. This methodology may be useful in verifying how encapsulated substances incorporated into textile materials penetrate human skin. Indeed, such materials can be considered strategic delivery systems that release a given active compound into the skin at specific doses. Meritxell Martí, Cristina Alonso, Vanessa Martínez, Manel Lis, Alfons de la Maza, José L. Parra, and Luisa Coderch Copyright © 2013 Meritxell Martí et al. All rights reserved. Mon, 25 Mar 2013 08:47:59 +0000 http://www.hindawi.com/journals/jdd/2013/456409/ Drug delivery systems can provide enhanced efficacy and/or reduced toxicity for anticancer agents. Liposome drug delivery systems are able to modify the pharmacokinetics and biodistribution of cytostatic agents, increasing the concentration of the drug released to neoplastic tissue and reducing the exposure of normal tissue. Anthracyclines are a key drug in the treatment of both metastatic and early breast cancer, but one of their major limitations is cardiotoxicity. One of the strategies designed to minimize this side effect is liposome encapsulation. Liposomal anthracyclines have achieved highly efficient drug encapsulation and they have proven to be effective and with reduced cardiotoxicity, as a single agent or in combination with other drugs for the treatment of either anthracyclines-treated or naïve metastatic breast cancer patients. Of particular interest is the use of the combination of liposomal anthracyclines and trastuzumab in patients with HER2-overexpressing breast cancer. In this paper, we discuss the different studies on liposomal doxorubicin in metastatic and early breast cancer therapy. Juan Lao, Julia Madani, Teresa Puértolas, María Álvarez, Alba Hernández, Roberto Pazo-Cid, Ángel Artal, and Antonio Antón Torres Copyright © 2013 Juan Lao et al. All rights reserved. Mon, 25 Mar 2013 08:21:31 +0000 http://www.hindawi.com/journals/jdd/2013/897348/ Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed. Joana R. Viola, Diana F. Rafael, Ernst Wagner, Robert Besch, and Manfred Ogris Copyright © 2013 Joana R. Viola et al. All rights reserved. Thu, 14 Mar 2013 09:22:52 +0000 http://www.hindawi.com/journals/jdd/2013/898146/ Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD) in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent. Carmela Pisano, Sabrina Chiara Cecere, Marilena Di Napoli, Carla Cavaliere, Rosa Tambaro, Gaetano Facchini, Cono Scaffa, Simona Losito, Antonio Pizzolorusso, and Sandro Pignata Copyright © 2013 Carmela Pisano et al. All rights reserved. Thu, 07 Mar 2013 14:45:20 +0000 http://www.hindawi.com/journals/jdd/2013/860780/ Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan that exists in living systems, and it is a major component of the extracellular matrix. The hyaluronic acid receptor CD44 is found at low levels on the surface of epithelial, haematopoietic, and neuronal cells and is overexpressed in many cancer cells particularly in tumour initiating cells. HA has been therefore used as ligand attached to HA-lipid-based nanovectors for the active targeting of small or large active molecules for the treatment of cancer. This paper describes the different approaches employed for the preparation, characterization, and evaluation of these potent delivery systems. Silvia Arpicco, Giuseppe De Rosa, and Elias Fattal Copyright © 2013 Silvia Arpicco et al. All rights reserved. Thu, 07 Mar 2013 11:11:32 +0000 http://www.hindawi.com/journals/jdd/2013/705265/ Liposomes are delivery systems that have been used to formulate a vast variety of therapeutic and imaging agents for the past several decades. They have significant advantages over their free forms in terms of pharmacokinetics, sensitivity for cancer diagnosis and therapeutic efficacy. The multifactorial nature of cancer and the complex physiology of the tumor microenvironment require the development of multifunctional nanocarriers. Multifunctional liposomal nanocarriers should combine long blood circulation to improve pharmacokinetics of the loaded agent and selective distribution to the tumor lesion relative to healthy tissues, remote-controlled or tumor stimuli-sensitive extravasation from blood at the tumor’s vicinity, internalization motifs to move from tumor bounds and/or tumor intercellular space to the cytoplasm of cancer cells for effective tumor cell killing. This review will focus on current strategies used for cancer detection and therapy using liposomes with special attention to combination therapies. Federico Perche and Vladimir P. Torchilin Copyright © 2013 Federico Perche and Vladimir P. Torchilin. All rights reserved. Thu, 07 Mar 2013 08:42:09 +0000 http://www.hindawi.com/journals/jdd/2013/374252/ Over the last few decades, nanocarriers for drug delivery have emerged as powerful tools with unquestionable potential to improve the therapeutic efficacy of anticancer drugs. Many colloidal drug delivery systems are underdevelopment to ameliorate the site specificity of drug action and reduce the systemic side effects. By virtue of their small size they can be injected intravenously and disposed into the target tissues where they release the drug. Nanocarriers interact massively with the surrounding environment, namely, endothelium vessels as well as cells and blood proteins. Consequently, they are rapidly removed from the circulation mostly by the mononuclear phagocyte system. In order to endow nanosystems with long circulation properties, new technologies aimed at the surface modification of their physicochemical features have been developed. In particular, stealth nanocarriers can be obtained by polymeric coating. In this paper, the basic concept underlining the “stealth” properties of drug nanocarriers, the parameters influencing the polymer coating performance in terms of opsonins/macrophages interaction with the colloid surface, the most commonly used materials for the coating process and the outcomes of this peculiar procedure are thoroughly discussed. Stefano Salmaso and Paolo Caliceti Copyright © 2013 Stefano Salmaso and Paolo Caliceti. All rights reserved. Mon, 04 Mar 2013 13:58:15 +0000 http://www.hindawi.com/journals/jdd/2013/637976/ Bisphosphonates (BPs) are synthetic analogues of naturally occurring pyrophosphate compounds. They are used in clinical practice to inhibit bone resorption in bone metastases, osteoporosis, and Paget's disease. BPs induce apoptosis because they can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate. In addition, the nitrogen-containing BPs (N-BPs), second-generation BPs, act by inhibiting farnesyl diphosphate (FPP) synthase, a key enzyme of the mevalonate pathway. These molecules are able to induce apoptosis of a number of cancer cells in vitro. Moreover, antiangiogenic effect of BPs has also been reported. However, despite these promising properties, BPs rapidly accumulate into the bone, thus hampering their use to treat extraskeletal tumors. Nanotechnologies can represent an opportunity to limit BP accumulation into the bone, thus increasing drug level in extraskeletal sites of the body. Thus, nanocarriers encapsulating BPs can be used to target macrophages, to reduce angiogenesis, and to directly kill cancer cell. Moreover, nanocarriers can be conjugated with BPs to specifically deliver anticancer agent to bone tumors. This paper describes, in the first part, the state-of-art on the BPs, and, in the following part, the main studies in which nanotechnologies have been proposed to investigate new indications for BPs in cancer therapy. Giuseppe De Rosa, Gabriella Misso, Giuseppina Salzano, and Michele Caraglia Copyright © 2013 Giuseppe De Rosa et al. All rights reserved. Tue, 26 Feb 2013 16:03:58 +0000 http://www.hindawi.com/journals/jdd/2013/529312/ Cancer is nowadays considered to be both a genetic and an epigenetic disease. The most well studied epigenetic modification in humans is DNA methylation; however it becomes increasingly acknowledged that DNA methylation does not work alone, but rather is linked to other modifications, such as histone modifications. Epigenetic abnormalities are reversible and as a result novel therapies that work by reversing epigenetic effects are being increasingly explored. The biggest clinical impact of epigenetic modifying agents in neoplastic disorders thus far has been in haematological malignancies, and the efficacy of DNMT inhibitors and HDAC inhibitors in blood cancers clearly attests to the principle that therapeutic modification of the cancer cell epigenome can produce clinical benefit. This paper will discuss the most well studied epigenetic modifications and how these are linked to cancer, will give a brief overview of the clinical use of epigenetics as biomarkers, and will focus in more detail on epigenetic drugs and their use in solid and blood cancers. Eleftheria Hatzimichael and Tim Crook Copyright © 2013 Eleftheria Hatzimichael and Tim Crook. All rights reserved. Thu, 14 Feb 2013 13:21:23 +0000 http://www.hindawi.com/journals/jdd/2013/107573/ Recent improvements in the understanding of glioblastoma (GBM) have allowed for increased ability to develop specific, targeted therapies. In parallel, however, there is a need for effective methods of delivery to circumvent the therapeutic obstacles presented by the blood-brain barrier and systemic side effects. The ideal delivery system should allow for adequate targeting of the tumor while minimizing systemic exposure, applicability across a wide range of potential therapies, and have existing safe and efficacious systems that allow for widespread application. Though many alternatives to systemic delivery have been developed, this paper will focus on our experience with convection-enhanced delivery (CED) and our focus on translating this technology from pre-clinical studies to the treatment of human GBM. Jonathan Yun, Robert J. Rothrock, Peter Canoll, and Jeffrey N. Bruce Copyright © 2013 Jonathan Yun et al. All rights reserved. Wed, 13 Feb 2013 09:14:28 +0000 http://www.hindawi.com/journals/jdd/2013/957605/ The extragonadal synthesis of biological active steroid hormones from their inactive precursors in target tissues is named “intracrinology.” Of particular importance for the progression of estrogen-dependent cancers is the in situ formation of the biological most active estrogen, 17beta-estradiol (E2). In cancer cells, conversion of inactive steroid hormone precursors to E2 is accomplished from inactive, sulfated estrogens in the “sulfatase pathway” and from androgens in the “aromatase pathway.” Here, we provide an overview about expression and function of enzymes of the “sulfatase pathway,” particularly steroid sulfatase (STS) that activates estrogens and estrogen sulfotransferase (SULT1E1) that converts active estrone (E1) and other estrogens to their inactive sulfates. High expression of STS and low expression of SULT1E1 will increase levels of active estrogens in malignant tumor cells leading to the stimulation of cell proliferation and cancer progression. Therefore, blocking the “sulfatase pathway” by STS inhibitors may offer an attractive strategy to reduce levels of active estrogens. STS inhibitors either applied in combination with aromatase inhibitors or as novel, dual aromatase-steroid sulfatase inhibiting drugs are currently under investigation. Furthermore, STS inhibitors are also suitable as enzyme–based cancer imaging agents applied in the biomedical imaging technique positron emission tomography (PET) for cancer diagnosis. Lena Secky, Martin Svoboda, Lukas Klameth, Erika Bajna, Gerhard Hamilton, Robert Zeillinger, Walter Jäger, and Theresia Thalhammer Copyright © 2013 Lena Secky et al. All rights reserved. Sun, 03 Feb 2013 11:55:32 +0000 http://www.hindawi.com/journals/jdd/2013/863539/ Members of the organic anion transporter family (OATP) mediate the transmembrane uptake of clinical important drugs and hormones thereby affecting drug disposition and tissue penetration. Particularly OATP subfamily 1 is known to mediate the cellular uptake of anticancer drugs (e.g., methotrexate, derivatives of taxol and camptothecin, flavopiridol, and imatinib). Tissue-specific expression was shown for OATP1B1/OATP1B3 in liver, OATP4C1 in kidney, and OATP6A1 in testis, while other OATPs, for example, OATP4A1, are expressed in multiple cells and organs. Many different tumor entities show an altered expression of OATPs. OATP1B1/OATP1B3 are downregulated in liver tumors, but highly expressed in cancers in the gastrointestinal tract, breast, prostate, and lung. Similarly, testis-specific OATP6A1 is expressed in cancers in the lung, brain, and bladder. Due to their presence in various cancer tissues and their limited expression in normal tissues, OATP1B1, OATP1B3, and OATP6A1 could be a target for tumor immunotherapy. Otherwise, high levels of ubiquitous expressed OATP4A1 are found in colorectal cancers and their metastases. Therefore, this OATP might serve as biomarkers for these tumors. Expression of OATP is regulated by nuclear receptors, inflammatory cytokines, tissue factors, and also posttranslational modifications of the proteins. Through these processes, the distribution of the transporter in the tissue will be altered, and a shift from the plasma membrane to cytoplasmic compartments is possible. It will modify OATP uptake properties and, subsequently, change intracellular concentrations of drugs, hormones, and various other OATP substrates. Therefore, screening tumors for OATP expression before therapy should lead to an OATP-targeted therapy with higher efficacy and decreased side effects. Veronika Buxhofer-Ausch, Lena Secky, Katrin Wlcek, Martin Svoboda, Valentinos Kounnis, Evangelos Briasoulis, Andreas G. Tzakos, Walter Jaeger, and Theresia Thalhammer Copyright © 2013 Veronika Buxhofer-Ausch et al. All rights reserved. Thu, 17 Jan 2013 14:07:35 +0000 http://www.hindawi.com/journals/jdd/2013/172529/ The effectiveness of anticancer treatments is often hampered by the serious side effects owing to toxicity of anticancer drugs and their undesirable uptake by healthy cells in vivo. Thermosensitive liposome-mediated drug delivery has been developed as part of research efforts aimed at improving therapeutic efficacy while reducing the associated side effect. Since multiple steps are involved in the transport of drug-loaded liposomes, drug release, and its uptake, mathematical models become an indispensible tool to analyse the transport processes and predict the outcome of anticancer treatment. In this study, a computational model is developed which incorporates the key physical and biochemical processes involved in drug delivery and cellular uptake. The model has been applied to idealized tumour geometry, and comparisons are made between continuous infusion of doxorubicin and thermosensitive liposome-mediated delivery. Results show that thermosensitive liposome-mediated delivery performs better in reducing drug concentration in normal tissues, which may help lower the risk of associated side effects. Compared with direct infusion over a 2-hour period, thermosensitive liposome delivery leads to a much higher peak intracellular concentration of doxorubicin, which may increase cell killing in tumour thereby enhancing the therapeutic effect of the drug. Wenbo Zhan and Xiao Yun Xu Copyright © 2013 Wenbo Zhan and Xiao Yun Xu. All rights reserved. Wed, 16 Jan 2013 18:25:47 +0000 http://www.hindawi.com/journals/jdd/2013/147325/ Neoplastic dissemination to the leptomeninges is an increasingly common occurrence in patients with both haematological and solid tumors arising outside the central nervous system. Both refinement of diagnostic techniques (Magnetic resonance imaging) and increased survival in patients treated with targeted therapies for systemic tumors account for this increased frequency. Cerebrospinal fluid cytological analysis and MRI confirm clinical diagnosis based on multifocal central nervous system signs/symptoms in a patient with known malignancy. Overall survival in patients with leptomeningeal neoplastic dissemination from solid tumors is short, rarely exceeding 3-4 months. However, selected patients may benefit from aggressive therapies, Apart from symptomatic treatment, intrathecal chemotherapy is used, with both free (methotrexate, Thiotepa, AraC) and liposomal antitumor agents (liposomal AraC). Palliative radiotherapy is indicated only in cases of symptomatic bulky disease, surgery is limited to positioning of Ommaya recervoirs or C5F shunting. We report clinical data on a cohort of 26 prospectively followed patients with neoplastic leptomeningitis followed in Lombardia, Italy, in 2011. Prognostic factors and pattern of care are reported. A. Silvani, M. Caroli, P. Gaviani, V. Fetoni, R. Merli, M. Riva, M. De Rossi, F. Imbesi, and A. Salmaggi Copyright © 2013 A. Silvani et al. All rights reserved. Thu, 27 Dec 2012 18:41:33 +0000 http://www.hindawi.com/journals/jdd/2012/920764/ New approaches to improve the traditional gene carriers are still required. Here we explore Fe3O4 modified with degradable polymers that enhances gene delivery and target delivery using permanent magnetic field. Two magnetic Fe3O4 nanoparticles coated with chitosan (CTS) and polyethylene glycol (PEG) were synthesized by means of controlled chemical coprecipitation. Plasmid pEGFP was encapsulated as a reported gene. The ferriferous oxide complexes were approximately spherical; surface charge of CTS-Fe3O4 and PEG-Fe3O4 was about 20 mv and 0 mv, respectively. The controlled release of DNA from the CTS-Fe3O4 nanoparticles was observed. Concurrently, a desired Fe3O4 concentration of less than 2 mM was verified as safe by means of a cytotoxicity test in vitro. Presence of the permanent magnetic field significantly increased the transfection efficiency. Furthermore, the passive target property and safety of magnetic nanoparticles were also demonstrated in an in vivo test. The novel gene delivery system was proved to be an effective tool required for future target expression and gene therapy in vivo. Yu Kuang, Tun Yuan, Zhongwei Zhang, Mingyuan Li, and Yuan Yang Copyright © 2012 Yu Kuang et al. All rights reserved. Thu, 27 Dec 2012 15:10:02 +0000 http://www.hindawi.com/journals/jdd/2012/842785/ Previously, we demonstrated that the novel lectin Eucheuma serra agglutinin from a marine red alga (ESA) induces apoptotic cell death in carcinoma. We now find that ESA induces apoptosis also in the case of sarcoma cells. First, propidium iodide assays with OST cells and LM8 cells showed a decrease in cell viability after addition of ESA. With 50 g/ml ESA, the viabilities after 24 hours decreased to 54.7 ± 11.4% in the case of OST cells and to 41.7 ± 12.3% for LM8 cells. Second, using fluorescently labeled ESA and flow cytometric and fluorescence microscopic measurements, it could be shown that ESA does not bind to cells that were treated with glycosidases, indicating importance of the carbohydrate chains on the surface of the cells for efficient ESA-cell interactions. Third, Span 80 vesicles with surface-bound ESA as active targeting ligand were shown to display sarcoma cell binding activity, leading to apoptosis and complete OST cell death after 48 hours at 2 g/ml ESA. The findings indicate that Span 80 vesicles with surface-bound ESA are a potentially useful drug delivery system not only for the treatment of carcinoma but also for the treatment of osteosarcoma. Keita Hayashi, Peter Walde, Tatsuhiko Miyazaki, Kenshi Sakayama, Atsushi Nakamura, Kenji Kameda, Seizo Masuda, Hiroshi Umakoshi, and Keiichi Kato Copyright © 2012 Keita Hayashi et al. All rights reserved. Wed, 05 Dec 2012 17:52:47 +0000 http://www.hindawi.com/journals/jdd/2012/975763/ Chlorotoxin is a 36-amino acid peptide derived from Leiurus quinquestriatus (scorpion) venom, which has been shown to inhibit low-conductance chloride channels in colonic epithelial cells. Chlorotoxin also binds to matrix metalloproteinase-2 and other proteins on glioma cell surfaces. Glioma cells are considered to require the activation of matrix metalloproteinase-2 during invasion and migration. In this study, for targeting glioma, we designed two types of recombinant chlorotoxin fused to human IgG-Fcs with/without a hinge region. Chlorotoxin fused to IgG-Fcs was designed as a dimer of 60 kDa with a hinge region and a monomer of 30 kDa without a hinge region. The monomeric and dimeric forms of chlorotoxin inhibited cell proliferation at 300 nM and induced internalization in human glioma A172 cells. The monomer had a greater inhibitory effect than the dimer; therefore, monomeric chlorotoxin fused to IgG-Fc was multivalently displayed on the surface of bionanocapsules to develop a drug delivery system that targeted matrix metalloproteinase-2. The target-dependent internalization of bionanocapsules in A172 cells was observed when chlorotoxin was displayed on the bionanocapsules. This study indicates that chlorotoxin fused to IgG-Fcs could be useful for the active targeting of glioblastoma cells. Tomonari Kasai, Keisuke Nakamura, Arun Vaidyanath, Ling Chen, Sreeja Sekhar, Samah El-Ghlban, Masashi Okada, Akifumi Mizutani, Takayuki Kudoh, Hiroshi Murakami, and Masaharu Seno Copyright © 2012 Tomonari Kasai et al. All rights reserved. Wed, 05 Dec 2012 09:29:05 +0000 http://www.hindawi.com/journals/jdd/2012/167896/ In the last decade, the nanotechnology advancement has developed a plethora of novel and intriguing nanomaterial application in many sectors, including research and medicine. However, many risks have been highlighted in their use, particularly related to their unexpected toxicity in vitro and in vivo experimental models. This paper proposes an overview concerning the cell death modalities induced by the major nanomaterials. Daniela De Stefano, Rosa Carnuccio, and Maria Chiara Maiuri Copyright © 2012 Daniela De Stefano et al. All rights reserved. Wed, 14 Nov 2012 15:23:43 +0000 http://www.hindawi.com/journals/jdd/2012/592602/ Cancer treatment by chemotherapy is typically accompanied by deleterious side effects, attributed to the toxic action of chemotherapeutics on proliferating cells from nontumor tissues. The cell surface proteoglycan CD44 has been recognized as a cancer stem cell marker. The present study has examined CD44 targeting as a way to selectively deliver therapeutic agents encapsulated inside colloidal delivery systems. CD44/chondroitin sulfate proteoglycan binds to a triple-helical sequence derived from type IV collagen, α1(IV)1263–1277. We have assembled a peptide-amphiphile (PA) in which α1(IV)1263–1277 was sandwiched between 4 repeats of Gly-Pro-4-hydroxyproline and conjugated to palmitic acid. The PA was incorporated into liposomes composed of DSPG, DSPC, cholesterol, and DSPE-PEG-2000 (1 : 4 : 5 : 0.5). Doxorubicin-(DOX-)loaded liposomes with and without 10% α1(IV)1263–1277 PA were found to exhibit similar stability profiles. Incubation of DOX-loaded targeted liposomes with metastatic melanoma M14#5 and M15#11 cells and BJ fibroblasts resulted in IC50 values of 9.8, 9.3, and >100 μM, respectively. Nontargeted liposomes were considerably less efficacious for M14#5 cells. In the CD44+ B16F10 mouse melanoma model, CD44-targeted liposomes reduced the tumor size to 60% of that of the untreated control, whereas nontargeted liposomes were ineffective. These results suggest that PA targeted liposomes may represent a new class of nanotechnology-based drug delivery systems. Margaret W. Ndinguri, Alexander Zheleznyak, Janelle L. Lauer, Carolyn J. Anderson, and Gregg B. Fields Copyright © 2012 Margaret W. Ndinguri et al. All rights reserved. Wed, 14 Nov 2012 14:20:48 +0000 http://www.hindawi.com/journals/jdd/2012/265691/ The implementation of cytotoxic chemotherapeutic drugs in the fight against cancer has played an invariably essential role for minimizing the extent of tumour progression and/or metastases in the patient and thus allowing for longer event free survival periods following chemotherapy. However, such therapeutics are nonspecific and bring with them dose-dependent cumulative adverse effects which can severely exacerbate patient suffering. In addition, the emergence of innate and/or acquired chemoresistance to the exposed cytotoxic agents undoubtedly serves to thwart effective clinical efficacy of chemotherapy in the cancer patient. The advent of nanotechnology has led to the development of a myriad of nanoparticle-based strategies with the specific goal to overcome such therapeutic hurdles in multiple cancer conditions. This paper aims to provide a brief overview and recollection of all the latest advances in the last few years concerning the application of nanoparticle technology to enhance the safe and effective delivery of chemotherapeutic agents to the tumour site, together with providing possible solutions to circumvent cancer chemoresistance in the clinical setting. Duncan Ayers and Alessandro Nasti Copyright © 2012 Duncan Ayers and Alessandro Nasti. All rights reserved. Thu, 30 Aug 2012 09:45:01 +0000 http://www.hindawi.com/journals/jdd/2012/218940/ The siRNA transfection efficiency of nanoparticles (NPs), composed of a superparamagnetic iron oxide core modified with polycationic polymers (poly(hexamethylene biguanide) or branched polyethyleneimine), were studied in CHO-K1 and HeLa cell lines. Both NPs demonstrated to be good siRNA transfection vehicles, but unmodified branched polyethyleneimine (25 kD) was superior on both cell lines. However, application of an external magnetic field during transfection (magnetofection) increased the efficiency of the superparamagnetic NPs. Furthermore, our results reveal that these NPs are less toxic towards CHO-K1 cell lines than the unmodified polycationic-branched polyethyleneimine (PEI). In general, the external magnetic field did not alter the cell’s viability nor it disrupted the cell membranes, except for the poly(hexamethylene biguanide)-modified NP, where it was observed that in CHO-K1 cells application of the external magnetic field promoted membrane damage. This paper presents new polycationic superparamagnetic NPs as promising transfection vehicles for siRNA and demonstrates the advantages of magnetofection. Betzaida Castillo, Lev Bromberg, Xaira López, Valerie Badillo, Jose A. González Feliciano, Carlos I. González, T. Alan Hatton, and Gabriel Barletta Copyright © 2012 Betzaida Castillo et al. All rights reserved. Thu, 19 Jul 2012 13:20:40 +0000 http://www.hindawi.com/journals/jdd/2012/436710/ A terbinafine impregnated subcutaneous implant was evaluated to determine if drug was released into isotonic saline over the course of 6 months at two different temperatures, 37°C and 4°C. These temperatures were chosen to simulate the nonhibernating (37°C) and hibernating body (4°C) temperatures of little brown bats (Myotis lucifugus). Insectivorous bats of North America, including little brown bats, have been devastated by white nose syndrome, a fungal infection caused by Geomyces destructans. No treatments exist for bats infected with G. destructans. Implants were placed into isotonic saline; samples were collected once per week and analyzed with HPLC to determine terbinafine concentrations. The mean amount of terbinafine released weekly across the 28 weeks was approximately 1.7 μg at 4°C and 4.3 μg at 37°C. Although significant differences in the amount released did occur at some time points, these differences were not consistently greater or less at either of the temperatures. This study showed that terbinafine was released from an impregnated implant over the course of 6 months at concentrations ranging from 0.02 to 0.06 μg/mL depending on temperature, which may be appropriate for little brown bats (Myotis lucifugus) infected with Geomyces destructans, the etiologic agent of white nose syndrome. M. J. Souza, T. Cairns, J. Yarbrogh, and S. K. Cox Copyright © 2012 M. J. Souza et al. All rights reserved. Wed, 18 Jul 2012 15:41:29 +0000 http://www.hindawi.com/journals/jdd/2012/527516/ Ocular diseases, such as, glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa require drug management in order to prevent blindness and affecting million of adults in USA and worldwide. There is an increasing need to develop devices for drug delivery to address ocular diseases. This study focuses on the design, simulation, and development of an implantable ocular drug delivery device consisting of micro-/nanochannels embedded between top and bottom covers with a drug reservoir made from polydimethylsiloxane (PDMS) which is silicon-based organic and biodegradable polymer. Several simulations were carried out with six different micro-channel configurations in order to see the feasibility for ocular drug delivery applications. Based on the results obtained, channel design of osmotic I and osmotic II satisfied the diffusion rates required for ocular drug delivery. Finally, a prototype illustrating the three components of the drug delivery design is presented. In the future, the device will be tested for its functionality and diffusion characteristics. Jae-Hwan Lee, Ramana M. Pidaparti, Gary M. Atkinson, and Ramana S. Moorthy Copyright © 2012 Jae-Hwan Lee et al. All rights reserved. Thu, 05 Jul 2012 17:54:46 +0000 http://www.hindawi.com/journals/jdd/2012/579629/ The purpose of this study was to develop poly(lactic acid)-methacrylic acid copolymeric nanoparticles with the potential to serve as nanocarrier systems for methotrexate (MTX) used in the chemotherapy of primary central nervous system lymphoma (PCNSL). Nanoparticles were prepared by a double emulsion solvent evaporation technique employing a 3-Factor Box-Behnken experimental design strategy. Analysis of particle size, absolute zeta potential, polydispersity (Pdl), morphology, drug-loading capacity (DLC), structural transitions through FTIR spectroscopy, and drug release kinetics was undertaken. Molecular modelling elucidated the mechanisms of the experimental findings. Nanoparticles with particle sizes ranging from 211.0 to 378.3 nm and a recovery range of 36.8–86.2 mg (Pdl≤0.5) were synthesized. DLC values were initially low (12±0.5%) but were finally optimized to 98±0.3%. FTIR studies elucidated the comixing of MTX within the nanoparticles. An initial burst release (50% of MTX released in 24 hours) was obtained which was followed by a prolonged release phase of MTX over 84 hours. SEM images revealed near-spherical nanoparticles, while TEM micrographs revealed the presence of MTX within the nanoparticles. Stable nanoparticles were formed as corroborated by the chemometric modelling studies undertaken. Bongani Sibeko, Yahya E. Choonara, Lisa C. du Toit, Girish Modi, Dinesh Naidoo, Riaz A. Khan, Pradeep Kumar, Valence M. K. Ndesendo, Sunny E. Iyuke, and Viness Pillay Copyright © 2012 Bongani Sibeko et al. All rights reserved. Thu, 05 Jul 2012 10:22:16 +0000 http://www.hindawi.com/journals/jdd/2012/528123/ Rassoul Dinarvand, Paulo Cesar de Morais, and Antony D'Emanuele Copyright © 2012 Rassoul Dinarvand et al. All rights reserved. Tue, 19 Jun 2012 11:09:16 +0000 http://www.hindawi.com/journals/jdd/2012/291219/ Effective gene delivery tools offer the possibility of addressing multiple diseases; current strategies rely on viruses or polyplexes. Encapsulation of DNA within nanoparticles is an attractive alternative method for gene delivery. We investigated the use of our recently developed Logic Gate Nanoparticle for gene delivery. The nanoparticles, composed of a dual pH response random copolymer (poly-β-aminoester ketal-2), can undergo a two-step “in series” response to endosomal pH. The first sep is a hydrophobic-hydrophilic switch, which is followed immediately by rapid degradation. Rapid fragmentation is known to increase cytoplasmic delivery from nanoparticles. Therefore, we hypothesized that our Logic Gate Nanoparticles would enable increased gene delivery and expression relative to nanoparticles that degrade more slowly such as PLGA-based nanoparticles. Passive nanoparticle entry into cells was demonstrated by delivering Cy5-labeled pDNA encoding EGFP into HCT116, a colon carcinoma cell line. Flow cytometry analysis showed that cells are positive for Cy5-DNA-nanoparticles and produced EGFP expression superior to PLGA nanoparticles. Inhibition of V-ATPases using bafilomycin A1 demonstrates that expression of EGFP is dependent on low endosomal pH. The advanced Logic Gate Nanoparticles offer new therapeutic possibilities in gene delivery and other applications where rapid release is important. José M. Morachis, Enas A. Mahmoud, Jagadis Sankaranarayanan, and Adah Almutairi Copyright © 2012 José M. Morachis et al. All rights reserved. Fri, 15 Jun 2012 15:34:20 +0000 http://www.hindawi.com/journals/jdd/2012/626417/ Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons. Insulin-like growth factor 1 (IGF-1) is important in embryonic development and is considered as a potential therapeutic agent for several disorders of peripheral and central nervous systems. In circulation IGF-1 is mainly bound to its carrier protein IGFBP-3. As a therapeutic agent IGF-1 has shown to be more active as free than complexed form. However, this may cause side effects during the prolonged treatment. In addition to IGFBP-3 the bioavailability of IGF-1 can be modulated by using mesoporous silicon nanoparticles (NPs) which are optimal carriers for sustained release of unstable peptide hormones like IGF-1. In this study we compared biodistribution, pharmacokinetics, and bioavailability of radiolabeled free IGF-1, IGF-1/IGFBP-3, and IGF-1/NP complexes in a Cln1-/- knockout mouse model. IGF-1/NP was mainly accumulated in liver and spleen in all studied time points, whereas minor and more constant amounts were measured in other organs compared to free IGF-1 or IGF-1/IGFBP-3. Also concentration of IGF-1/NP in blood was relatively high and stable during studied time points suggesting continuous release of IGF-1 from the particles. Tuulia Huhtala, Jussi Rytkönen, Anu Jalanko, Martti Kaasalainen, Jarno Salonen, Raili Riikonen, and Ale Närvänen Copyright © 2012 Tuulia Huhtala et al. All rights reserved.