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Journal of Drug Delivery
Volume 2013 (2013), Article ID 905091, 10 pages
http://dx.doi.org/10.1155/2013/905091
Review Article

Nanoparticle Albumin Bound Paclitaxel in the Treatment of Human Cancer: Nanodelivery Reaches Prime-Time?

1Medical Oncology Unit, Department of Experimental and Clinical Medicine, University “Magna Graecia” of Catanzaro and “Tommaso Campanella” Cancer Center, Campus Salvatore Venuta, Viale Europa, 88100 Catanzaro, Italy
2Institute of Neurological Science (ISN-CNR), UOS of Pharmacology, Roccelletta di Borgia, 88021 Catanzaro, Italy
3Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, 80138 Naples, Italy

Received 31 January 2013; Accepted 5 March 2013

Academic Editor: Giuseppe De Rosa

Copyright © 2013 Iole Cucinotto et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.

1. Introduction

Current development of cancer treatment mainly relies on three avenues:(a)the identification of molecular targets for selective blockade of driver pathways in cancer cells or in tumour microenvironment,(b)immunemodulatory approaches which might enhance the antitumor specific immune response,(c)new delivery approaches in order to achieve higher bioavailability of anticancer agents.

The topic of the current review is the nanoparticle albumin bound paclitaxel (nab-paclitaxel) development, which has opened a novel scenario in cancer treatment by the enhancement of paclitaxel delivery by the use of nanotechnology.

2. Taxane (First) Revolution of Cancer Therapy

Taxanes are an important class of antitumor agents using solvent-based delivery vehicles. Paclitaxel (Bristol-Myers Squibb (New York, NY)) was identified in 1966, as an extract from Taxus brevifolia, obtained in a pure form in 1969 but its structure was published in 1971. Investigators faced several problems due to low concentration and structure complexities for low water solubility [1, 2] (Figure 1).

905091.fig.001
Figure 1: Structure of paclitaxel (5 ,20-epoxy-1,2 ,4,7 ,13 -hex-ahydroxytan-11-en-9-one-4,10-diacetate2-benzoate-13-ester with (2R.3S)-N-benzoyl-3-phenyllioserine).

In fact, only in 1979 Susan Horwitz discovered that paclitaxel has a unique mechanism of action and interest which was additionally stimulated when impressive activity was demonstrated in NCI tumor screening [3]. Paclitaxel is a diterpenoid pseudoalkaloid with formula C47H51NO14 (  Da) whose activity was demonstrated in different preclinical models. For antitumor activity the presence of the entire taxane molecule is required (Figure 2) for the inactivity of the ester and the tetraol formed by a low temperature cleavage of paclitaxel [4].

905091.fig.002
Figure 2: Taxane nucleus.

Although the development of paclitaxel was hampered by limited availability of its primary source and the difficulties inherent to large-scale isolation, extraction, and its poor aqueous solubility, interest was maintained after characterization of its novel mechanism of cytotoxic action. In order to afford new preclinical and clinical studies, it was necessary to find new and more abundant and renewable resources. These studies led to the development of docetaxel (Taxotere), a semisynthetic taxane analogue extracted from Taxus baccata, a European yew. Docetaxel differs from paclitaxel in two positions in its chemical structure and this small alteration makes it more watersoluble. Taxanes disrupt microtubule dynamics by stabilizing the microtubule against depolymerization, enhancing their polymerization, promoting the nucleation and elongation phases of the polymerization reaction, and reducing the critical tubulin subunit concentration required for microtubule assembly. Moreover they alter the tubulin dissociation rate at both ends of the microtubule. This leads to reduced dynamic instability, whereas the association rate is not affected. After the treatment with taxanes, the microtubules are highly stable and resistant to depolymerization by cold, calcium ions, dilution, and other antimicrotubule agents. The final result is the impairment of dynamics of microtubule depolymerization, which is a critical event in the mitotic process [5].

Paclitaxel is active against primary epithelial ovarian carcinoma, breast cancer, colon, non-small-cell lung cancer, and AIDS-related Kaposi’s sarcoma in preclinical models [3, 6, 7] and is presently of common use in the treatment of several important malignancies as lung cancer, breast cancer, Kaposi’s sarcoma, squamous cell carcinoma of the head and neck, gastric cancer, esophageal cancer, bladder cancer, and other carcinomas. Despite being clinically very active, paclitaxel and docetaxel are associated with many serious sideeffects which often preclude the prolonged use in patients. A number of these side effects have been associated with the vehicles used for the formulation: the cremophor EL (CrEL-polyethoxylated castor oil) [8] for paclitaxel and polysorbate 80 (Tween 80) for docetaxel, respectively, that altered also their pharmacokinetic profiles; CrEL is considered to be responsible for the hypersensitivity reactions seen in patients during paclitaxel therapy. In vitro, CrEL caused axonal swelling, demyelination, and axonal degeneration, and, thus, it may also contribute to the development of neuropathy in patients receiving paclitaxel. The use of CrEL requires premedication with antihistamines and corticosteroids to prevent hypersensitivity reactions and, despite these premedications, approximately 40% of all patients will have minor reactions (e.g., flushing and rash) and 3% will have life threatening reactions. CrEL also causes leaching of the plasticizers from polyvinyl chloride (PVC) bags and infusions sets; thus paclitaxel must be infused via the use of special non-PVC infusion systems and in-line filtration. Another effect induced by CrEL is the alteration of lipoprotein pattern and the consequent hyperlipidemia. Moreover, CrEL and polysorbate 80 interfere with efficacy by limiting tumor penetration through the formation of large polar micelles, which for CrEL-paclitaxel can lead to nonlinear pharmacokinetics and decreased unbound drug fraction [9].

To overcome the ideal dosage form and bypass all the present limitations, novel “carrier delivery systems,” including liposomes, micelles, and particulate drug delivery systems, were formulated as common practice for novel drugs like microRNAs [1015].

Some of them have already reached the clinical practice like liposomal doxorubicin or liposomal amphotericin B. Another example of nanotechnology applied to drug delivery is the preclinical development of stealth liposomes encapsulating zoledronic acid (LipoZOL) to reduce binding of ZOL to bone and increase its bioavailability in extraskeletal tumor sites [16]. Natural human protein based carrier can also be used to manufacture nanocarriers for drug delivery: this is the example of the paclitaxel albumin bound by which it is possible to selectively deliver larger amounts of drug to tumors, reducing the toxicities related to solvent-based formulations. Albumin is a natural carrier of hydrophobic endogenous molecules (such as vitamins, hormones, and other plasma constituents), in a noncovalent and reversible binding and allows for transport in the body and release at the cell surface [17].

Abraxane (nab-paclitaxel; ABI 007 or Abraxane; Celgene Inc, Odenton, MD,USA) was the first to receive FDA approval in 2005, for the treatment of breast cancer in patients who reported progressive disease after chemotherapy for metastatic cancer or relapse within 6 months of adjuvant chemotherapy.

Nab-paclitaxel is a colloidal suspension of 130 nanometer particles, solvent-free, homogenized with human serum albumin (3%-4%), by which it is possible to infuse higher doses of drug than the standard dose used in paclitaxel therapy, with fewer side effects, with less infusion time (30 minutes) and without premedication. The new formulation allows the delivery of paclitaxel to tumors with a 4.5-fold increase in its transport, coupled with albumin receptors, across endothelial cells [18] with an enhanced intracellular antitumor paclitaxel delivery and activity [19]. In the mechanism of drug delivery an albumin receptor (gp60) on endothelial cells seems to be involved which transports paclitaxel into the extravascular space with subsequent invagination of the cell membrane to form caveolae, transcytotic vesicles, and also tumor accumulation of nanoparticle bound to SPARC (secreted protein, acidic and rich in cysteine), which is overexpressed in many solid tumors, including bladder, prostate, and pancreas cancers [20]. Its intravenous infusion is more manageable and safe because it is performed by standard plastic intravenous infusion bags and can also be reconstituted in a much smaller volume of normal saline compared to paclitaxel. Preclinical studies have demonstrated that nab-paclitaxel achieved higher intratumor concentrations compared to CrEL-paclitaxel with a better bioavailability and showed an improved efficacy and therapeutic index in multiple animal models [21]. Other new technologies recently used to deliver paclitaxel have led to the development of innovative formulations such as Nanoxel and liposomal and polymeric paclitaxel.

Nanoxel-PM is efficacious and less toxic than free docetaxel formulation and was evaluated in comparison with Taxotere in preclinical studies. Nanoxel-PM can reduce sideeffects of hypersensitivity reactions and fluid retention while retaining antitumor efficacy in cancer patients [22].

Further studies led to the development of new formulations of liposomal paclitaxel. The special composition of the liposomal membrane which contains high doses of paclitaxel could reduce the aggregation giving the molecule higher stability and confers an increase of efficacy in animal models as in human tumors [23].

An hydrotropic polymer micelle system has also been developed for delivery of poorly water-soluble drugs as paclitaxel. This polymer showed not only higher loading capacity but also enhanced physical stability in aqueous media and provides an alternative approach for formulation of poorly soluble drugs [24, 25].

3. Nab-Paclitaxel in Breast Cancer Treatment

Breast cancer (BC) is the most common cancer in female patients and follows lung cancer as the most common cause of female cancer death. While only 5–7% of BC patients present metastatic disease (mBC) at diagnosis and more than 30% presenting localized disease will eventually recur, 5 year survival of advanced disease is less than 20% [33]. Current treatment of advanced breast cancer is mainly aimed to ameliorate quality of life and prolong survival. Treatment choice is not an easy task in terms of drug selection and combination. Chemotherapy plays an essential role for the treatment of mBC. Among anticancer drugs, taxanes are considered the most effective, while their use involves long infusion time, neurotoxicity, and high risk of hypersensitivity reactions [8, 34, 35]. These latter effects are due to allergic reactions induced by the use of solubilizing agents (as chromophores) and today are less common due to the use in the clinical practice of corticosteroids and antihistamines [36]. In order to overcome these important limitations, a major interest is devoted to novel drugs as nab-paclitaxel, eribulin, ixabepilone, PARP inhibitors, and new HER 2 inhibitors as lapatinib, pertuzumab, TDM1, and neratinib [3743].

Following phase I studies, by Ibrahim et al. in 2002 [19] and by Teng et al in 2004 [44], which led to MTD identification at 300 mg/m2 in the three weekly schedule with neurotoxicity as dose limiting toxicity, Nyman et al. in 2005 [45] identify in the weekly schedule the MTD at 100 mg/sqm for highly pretreated patients and 150 mg/m2 for nonhighly pretreated patients with grade 4 neutropenia and grade 3 neuropathy as DLT with earlier onset at higher dosages. The pivotal phase 3 study was published in 2005 where Gradishar et al. [30] compared nab-paclitaxel (260 mg/m2) at three week schedule with CrEL-paclitaxel 175 mg/m2 also at three week schedule. The study clearly demonstrated a survival advantage for nab-paclitaxel with an improved toxicity profile.

In 2009 a phase II randomized study [26] compared three week docetaxel 100 mg/m2 with three week nab-paclitaxel 300 mg/m2, weekly nab-paclitaxel 100 mg/sqm and weekly nab-paclitaxel 150 mg/sqm. The 150 nab-paclitaxel weekly schedule provided the best PFS (>5 months) which resulted to be statistically significant. An update of this study published by Gradishar et al. in 2012 demonstrated a median overall survival (OS) of 33.8 months which statistically overcame the other treatment arms.

All together these data demonstrated that nab-paclitaxel is superior to CrEL-paclitaxel in the three week schedule and that nab-paclitaxel at weekly 150 schedule provides an impressive long term survival [27]. Recently, nab-paclitaxel was administered in combination with biological agents in the treatment of mBC. In detail, a safety analysis of the first ten enrolled patients treated for at least one cycle of the initial doses of nab-paclitaxel (125 mg/m2 i.v. on days 1, 8, and 15 every 28 days) in combination with lapatinib (1,250 mg orally once daily on a continuous basis) in a 4-week cycle for a planned minimum of six cycles was performed. However, during the ongoing safety review of the first five patients, Grade 3 toxicities were observed in all five patients (four with neutropenia and one with neutropenic fever and diarrhea) and the decision was made to reduce the dose of both study drugs. All subsequent patients ( ) received nab-paclitaxel (100 mg/m2 i.v. on days 1, 8, and 15 every 28 days) in combination with lapatinib (1,000 mg orally once daily on a continuous basis) in a 4-week cycle for a minimum of six cycles. RR was 53% with the majority of patient responses demonstrating a partial response (PR) (47%). Four (7%) patient responses demonstrated a complete response (CR), and ten (17%) demonstrated a stable disease. The progression-free survival (PFS) and time to progression (TTP) were 39.7 weeks (95% CI 34.1–63.9) and 41 weeks (95% CI 39.1–64.6), respectively. Lapatinib 1,000 mg with nab-paclitaxel 100 mg/m2 i.v. is feasible with manageable and predictable toxicity and an RR of 53% comparing favorably with other HER2-based combinations in this setting [50].

Two important points under investigation are the comparison of weekly nab-paclitaxel with CrEL-paclitaxel both at weekly schedules and the potential advantage of combination with bevacizumab. Finally nab-paclitaxel has shown some activity also in CrEL-paclitaxel heavily pretreated and resistant patients [28] (Table 1).

tab1
Table 1: Randomized phase II and III trials with nab-paclitaxel in mBC.

4. Nab-Paclitaxel in Pancreatic Cancer Treatment

Pancreatic cancer (PC) is at present a big cancer killer, with an expected survival of 6 months in advanced stage PC (aPC). Till a recent report demonstrating good activity of oxaliplatin, irinotecan, and fluorofolate (FOLFIRINOX combination), gemcitabine is still the mainstay treatment. In a recent meta-analysis, Ciliberto et al. [51] described a statistically superiority in terms of survival and response rate for gemcitabine-based combination compared to gemcitabine alone. Moreover, this advantage was marginal and at the cost of an increased toxicity. The authors concluded that in the era of targeted therapy new approaches were possible only in presence of solid preclinical findings.

A report by von Hoff et al. [31] demonstrated in a phase I/II study an interesting activity of gemcitabine/nab-paclitaxel combination at gemcitabine 1000 mg/m2 and nab-paclitaxel at 125 mg/m2 doses weekly for three doses in a 4 week schedule. A 48% response rate was achieved at MTD. The authors additionally demonstrated that SPARC-expressing tumors appeared more sensitive to the drug combination.

An interesting finding from a preclinical study reported that nab-paclitaxel demonstrated the capacity of increasing the gemcitabine bioavailability inside the tumors. These findings led to the design of a phase III study where gemcitabine/nab-paclitaxel was compared to gemcitabine alone showing an advantage in OS, PFS, and RR. This study, presented to ASCO GI 2013 (American Society of Clinical Oncology, Gastrointestinal Cancer Symposium) by von Hoff, is clearly a changing practice study and the gemcitabine/nab-paclitaxel, which led to an almost two month longer OS should be now compared to FOLFIRINOX combination (Table 2). The biological bases of the synergistic interaction between nab-paclitaxel and gemcitabine have recently been elucidated by an in vivo study in animal models. In detail, the combination treatment was administered to KPC mice that develop advanced and metastatic pancreas ductal adenocarcinoma. The authors have demonstrated an increase of intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species-mediated degradation, resulting in the increased stabilization of gemcitabine. These findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PC [52]. This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer.

tab2
Table 2: Randomized phase I/II and III trials with nab-paclitaxel in aPC.

5. Other Areas of Nab-Paclitaxel Development

Melanoma represents 5% and 4% of all cancers in males in females, respectively. However, the rates of incidence of melanoma are steadily increasing in the USA as in most parts of Europe [53]. The survival rates of melanoma become worse with advancing stage. Therefore, early diagnosis in addition to surgical treatment before its spread is the most effective treatment.

Melanomas are a heterogeneous group of tumors characterized by specific genetic alterations, including mutations in kinase, such as BRAF or c-kit. Dacarbazine is commonly used as a treatment for metastatic melanoma and has been for long time the standard of care for this disease. Recently, new approaches have completely changed the diagnosis and treatment of melanoma. New medications like vemurafenib have been developed for the systemic therapy of advanced melanomas in subpopulations identified by BRAF mutation tests. Taxanes have been reported to have some limited activity in malignant melanoma [5458], due to the high toxicity attributed to their waterinsolubility. In a phase II clinical trial Hersh at al. in 2010 [46] demonstrated that nab-paclitaxel has activity not only in chemotherapy-naïve patients with metastatic melanoma administered at a dose of 150 mg/m2 but also in previously treated patients administered at a dose of 100 mg/m2 for 3 of 4 weeks. In this study, PFS and OS were longer than the previous results reported with conventional standard of care. In previously treated and chemotherapy-naïve patients, PFS was 4.5 months and 3.5 months, respectively, and similarly OS was 9.6 months and 12.1 months (in respect to 1.6 months of PFS reported in the literature for treatment with dacarbazine and temozolomide). In another phase II clinical trial, Kottschade et al. in 2011 [59] demonstrated that in patients with metastatic melanoma the combination of nab-paclitaxel 100 mg/m2 and carboplatin AUC2 administered in days 1, 8, and 15 every 28 days is moderately tolerated for the occurrence of adverse effects that were fatigue, myelodepression, and gastrointestinal toxicity. This study confirms that the efficacy and toxicity of nab-paclitaxel are similar to those of paclitaxel when combined with carboplatin for the treatment of patients with metastatic melanoma. Even if such regimens have not been formally compared in a randomized study, we can say that nab-paclitaxel is a good alternative for patients who cannot tolerate conventional therapy with paclitaxel. Last November at the Society of Melanoma Research a preliminary analysis of a Phase III study by Hersh was presented which shows benefit in terms of PFS in favor of nab-paclitaxel compared to dacarbazine (4.8 versus 2.5 months); the same trend was observed in the interim analysis that shows a trend for better OS (12.8 versus 10.7 months) (Table 3). Recently, nab-paclitaxel was efficiently combined with temozolomide and oblimersen in the treatment of melanoma patients. In detail, in a phase I trial, chemotherapy-naïve patients with metastatic melanoma and normal LDH levels were enrolled in 3 cohorts. The treatment regimen consisted of 56-day cycles of oblimersen (7 mg/kg/day continuous i.v. infusion on days 1–7 and 22–28 in cohort 1 and 2; 900 mg fixed dose, twice weekly in weeks 1-2, 4-5 for cohort 3), temozolomide (75 mg/m2, days 1–42), and nab-paclitaxel (175 mg/m2 in cohort 1 and 3, 260 mg/m2 in cohort 2 on days 7 and 28). The RR in the 32 treated patients was 40.6% (2 CR and 11 PR) and 11 patients had stable disease, for a disease control rate of 75%. Haematological, renal, and neurologic toxicity never exceeded grade 3 demonstrating a good tolerability of the schedule [60].

tab3
Table 3: Randomized phase II and III trials with nab-paclitaxel in melanoma.

Lung cancer (LC) is the first cause of cancer death all over the world, with a 5 year survival of 5% for metastatic disease. Treatment selection is based on different factors like the performance status, comorbidities, histology, and, in the last years, the molecular mutational profile, which is now mandatory to assess before deciding treatment. The most common chemotherapy approach is a platinum based doublet which is commonly combined with gemcitabine, vinorelbine, or pemetrexed [61] in Europe, while in the USA the most common combination is carboplatin paclitaxel doublet (RR 15–32%); this combination is effective and relatively well tolerated in the elderly [6265]. Bevacizumab addition to this combination led to improved survival [66]. Socinski et al. reported in 2012 a phase III trial enrolling 1052 IIIb aNSCLC (advanced non-small-cell lung cancer) patients in the first line of treatment which compared weekly nab-paclitaxel 100 mg/m2 and carboplatin AUC6 every three weeks with carboplatin AUC6 and CrEL-paclitaxel 200 mg/m2 every three weeks [49]. The nab-paclitaxel/carboplatin combination was more active in terms of RR with a trend in PFS and OS improvement and was also better tolerated (Table 4).

tab4
Table 4: Randomized phase III trials with nab-paclitaxel in aNSCLC.

6. Conclusions and Future Developments

Nab-paclitaxel has produced a paradigm change in the treatment of tumors like breast cancer, pancreatic cancer, and melanoma and a large use in these important diseases can be predicted. Also in lung cancer, nab-paclitaxel has produced a good safety profile and increase in RR.

We think that nab-paclitaxel has opened a new way to human cancer treatment and indeed reached the prime-time.

References

  1. M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon, and A. T. McPhail, “Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia,” Journal of the American Chemical Society, vol. 93, no. 9, pp. 2325–2327, 1971. View at Scopus
  2. A. K. Singla, A. Garg, and D. Aggarwal, “Paclitaxel and its formulations,” International Journal of Pharmaceutics, vol. 235, no. 1-2, pp. 179–192, 2002. View at Publisher · View at Google Scholar · View at Scopus
  3. S. B. Horwitz, “Mechanism of action of taxol,” Trends in Pharmacological Sciences, vol. 13, no. 4, pp. 134–136, 1992. View at Publisher · View at Google Scholar · View at Scopus
  4. M. E. Wall and M. C. Wani, “Camptothecin and taxol: from discovery to clinic,” Journal of Ethnopharmacology, vol. 51, no. 1–3, pp. 239–254, 1996. View at Publisher · View at Google Scholar · View at Scopus
  5. J. J. Correia and S. Lobert, “Physiochemical aspects of tubulin-interacting antimitotic drugs,” Current Pharmaceutical Design, vol. 7, no. 13, pp. 1213–1228, 2001. View at Publisher · View at Google Scholar · View at Scopus
  6. C. M. Spencer and D. Faulds, “Paclitaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of cancer,” Drugs, vol. 48, no. 5, pp. 794–847, 1994. View at Scopus
  7. E. K. Rowinsky and R. C. Donehower, “Paclitaxel (taxol),” The New England Journal of Medicine, vol. 332, no. 15, pp. 1004–1014, 1995. View at Publisher · View at Google Scholar · View at Scopus
  8. H. Gelderblom, J. Verweij, K. Nooter, and A. Sparreboom, “Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation,” European Journal of Cancer, vol. 37, no. 13, pp. 1590–1598, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Sparreboom, L. van Zuylen, E. Brouwer et al., “Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications,” Cancer Research, vol. 59, no. 7, pp. 1454–1457, 1999. View at Scopus
  10. M. Conti, V. Tazzari, C. Baccini, G. Pertici, L. P. Serino, and U. De Giorgi, “Anticancer drug delivery with nanoparticles,” In Vivo, vol. 20, no. 6, pp. 697–702, 2006. View at Scopus
  11. M. Rossi, M. R. Pitari, N. Amodio et al., “miR-29b negatively regulates human osteoclastic cell differentiation and function: implications for the treatment of multiple myeloma-related bone disease,” Journal of Cellular Physiology, 2012. View at Publisher · View at Google Scholar
  12. N. Amodio, M. T. Di Martino, U. Foresta et al., “miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1,” Cell Death and Disease, vol. 3, no. 11, p. e436, 2012.
  13. N. Amodio, M. Leotta, D. Bellizzi et al., “DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma,” Oncotarget, vol. 3, no. 10, pp. 1246–1258, 2012.
  14. M. T. Di Martino, E. Leone, N. Amodio et al., “Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence,” Clinical Cancer Research, vol. 18, pp. 6260–6270, 2012. View at Publisher · View at Google Scholar
  15. P. Tagliaferri, M. Rossi, M. T. Di Martino et al., “Promises and challenges of MicroRNA-based treatment of multiple myeloma,” Current Cancer Drug Targets, vol. 12, no. 7, pp. 838–846, 2012. View at Publisher · View at Google Scholar
  16. M. Marra, G. Salzano, C. Leonetti et al., “Nanotechnologies to use bisphosphonates as potent anticancer agents: the effects of zoledronic acid encapsulated into liposomes,” Nanomedicine, vol. 7, no. 6, pp. 955–964, 2011. View at Publisher · View at Google Scholar
  17. M. Purcell, J. F. Neault, and H. A. Tajmir-Riahi, “Interaction of taxol with human serum albumin,” Biochimica et Biophysica Acta, vol. 1478, no. 1, pp. 61–68, 2000. View at Publisher · View at Google Scholar · View at Scopus
  18. N. Authier, J. P. Gillet, J. Fialip, A. Eschalier, and F. Coudore, “Description of a short-term Taxol-induced nociceptive neuropathy in rats,” Brain Research, vol. 887, no. 2, pp. 239–249, 2000. View at Publisher · View at Google Scholar · View at Scopus
  19. N. K. Ibrahim, N. Desai, S. Legha et al., “Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel,” Clinical Cancer Research, vol. 8, no. 5, pp. 1038–1044, 2002. View at Scopus
  20. M. S. Surapaneni, S. K. Das, and N. G. Das, “Designing Paclitaxel drug delivery systems aimed at improved patient outcomes: current status and challenges,” ISRN Pharmacology, vol. 2012, Article ID 623139, 15 pages, 2012. View at Publisher · View at Google Scholar
  21. N. Desai, V. Trieu, Z. Yao et al., “Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel,” Clinical Cancer Research, vol. 12, no. 4, pp. 1317–1324, 2006. View at Publisher · View at Google Scholar · View at Scopus
  22. S. W. Lee, M. H. Yun, S. W. Jeong et al., “Development of docetaxel-loaded intravenous formulation, Nanoxel-PM using polymer-based delivery system,” Journal of Controlled Release, vol. 155, no. 2, pp. 262–271, 2011.
  23. P. Kan, C. W. Tsao, A. J. Wang, W. C. Su, and H. F. Liang, “A liposomal formulation able to incorporate a high content of Paclitaxel and exert promising anticancer effect,” Journal of Drug Delivery, vol. 2011, Article ID 629234, 9 pages, 2011. View at Publisher · View at Google Scholar
  24. Y. W. Cho, J. Lee, S. C. Lee, K. M. Huh, and K. Park, “Hydrotropic agents for study of in vitro paclitaxel release from polymeric micelles,” Journal of Controlled Release, vol. 97, no. 2, pp. 249–257, 2004. View at Publisher · View at Google Scholar · View at Scopus
  25. K. M. Huh, S. C. Lee, Y. W. Cho, J. Lee, J. H. Jeong, and K. Park, “Hydrotropic polymer micelle system for delivery of paclitaxel,” Journal of Controlled Release, vol. 101, no. 1-3, pp. 59–68, 2005. View at Publisher · View at Google Scholar · View at Scopus
  26. W. J. Gradishar, D. Krasnojon, S. Cheporov et al., “Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer,” Journal of Clinical Oncology, vol. 27, no. 22, pp. 3611–3619, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. W. J. Gradishar, D. Krasnojon, S. Cheporov et al., “Phase II trial of nab-paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast cancer: final analysis of overall survival,” Clinical Breast Cancer, vol. 12, no. 5, pp. 313–321, 2012. View at Publisher · View at Google Scholar
  28. J. L. Blum, M. A. Savin, G. Edelman et al., “Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes,” Clinical Breast Cancer, vol. 7, no. 11, pp. 850–856, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. V. Roy, B. R. LaPlant, G. G. Gross, C. L. Bane, and F. M. Palmieri, “North Central Cancer Treatment Group. Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531),” Annals of Oncology, vol. 20, no. 3, pp. 449–453, 2009.
  30. W. J. Gradishar, S. Tjulandin, N. Davidson et al., “Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer,” Journal of Clinical Oncology, vol. 23, no. 31, pp. 7794–7803, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. D. D. von Hoff, R. K. Ramanathan, M. J. Borad et al., “Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial,” Journal of Clinical Oncology, vol. 29, no. 34, pp. 4548–4554, 2011. View at Publisher · View at Google Scholar
  32. D. D. Von Hoff, R. K. Ramanathan, M. J. Borad, et al., “Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial,” Journal of Clinical Oncology, vol. 29, no. 34, pp. 4548–4554, 2011.
  33. E. L. Mayer and H. J. Burstein, “Chemotherapy for metastatic breast cancer,” Hematology/Oncology Clinics of North America, vol. 21, no. 2, pp. 257–272, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. G. Capri, E. Tarenzi, F. Fulfaro, and L. Gianni, “The role of taxanes in the treatment of breast cancer,” Seminars in Oncology, vol. 23, no. 1, pp. 68–75, 1996. View at Scopus
  35. A. J. ten Tije, J. Verweij, W. J. Loos, and A. Sparreboom, “Pharmacological effects of formulation vehicles: implications for cancer chemotherapy,” Clinical Pharmacokinetics, vol. 42, no. 7, pp. 665–685, 2003. View at Publisher · View at Google Scholar · View at Scopus
  36. R. B. Weiss, R. C. Donehower, P. H. Wiernik et al., “Hypersensitivity reactions from taxol,” Journal of Clinical Oncology, vol. 8, no. 7, pp. 1263–1268, 1990. View at Scopus
  37. P. G. Morris, “Advances in therapy: eribulin improves survival for metastatic breast cancer,” Anti-Cancer Drugs, vol. 21, no. 10, pp. 885–889, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. N. Denduluri and S. Swain, “Ixabepilone: clinical role in metastatic breast cancer,” Clinical Breast Cancer, vol. 11, pp. 139–145, 2011.
  39. M. K. Weil and A. P. Chen, “PARP inhibitor treatment in ovarian and breast cancer,” Current Problems in Cancer, vol. 35, no. 1, pp. 7–50, 2011. View at Publisher · View at Google Scholar · View at Scopus
  40. J. S. Frenel, E. Bourbouloux, D. Berton-Rigaud, S. Sadot-Lebouvier, A. Zanetti, and M. Campone, “Lapatinib in metastatic breast cancer,” Women's Health, vol. 5, no. 6, pp. 603–612, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. M. A. Sendur, S. Aksoy, and K. Altundag, “Pertuzumab in HER2-positive breast cancer,” Current Medical Research and Opinion, vol. 28, no. 10, pp. 1709–1716, 2012. View at Publisher · View at Google Scholar
  42. M. F. Barginear, V. John, and D. R. Budman, “Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer,” Molecular Medicine, vol. 18, no. 1, pp. 1473–1479, 2012.
  43. S. Lopez-Tarruella, Y. Jerez, I. Marquez-Rodas, and M. Martin, “Neratinib (HKI-272) in the treatment of breast cancer,” Future Oncology, vol. 8, no. 6, pp. 671–681, 2012. View at Publisher · View at Google Scholar
  44. X. Y. Teng, Z. Z. Guan, Z. W. Yao et al., “A tolerability study of A cremophor-free albumin bound nanoparticle paclitaxel intravenously administered in patients with advanced solid tumor,” Ai Zheng, vol. 23, no. 11, pp. 1431–1436, 2004. View at Scopus
  45. D. W. Nyman, K. J. Campbell, E. Hersh et al., “Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies,” Journal of Clinical Oncology, vol. 23, no. 31, pp. 7785–7793, 2005. View at Publisher · View at Google Scholar · View at Scopus
  46. E. M. Hersh, S. J. O'Day, A. Ribas et al., “A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma,” Cancer, vol. 116, no. 1, pp. 155–163, 2010. View at Publisher · View at Google Scholar · View at Scopus
  47. L. A. Kottschade, V. J. Suman, T. Amatruda III, et al., “A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1),” Cancer, vol. 117, no. 8, pp. 1704–1710, 2011.
  48. E. M. Hersh, S. J. O'Day, A. Ribas, et al., “A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma,” Cancer, vol. 116, no. 1, pp. 155–163, 2010.
  49. M. A. Socinski, I. Bondarenko, N. A. Karaseva et al., “Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial,” Journal of Clinical Oncology, vol. 30, no. 17, pp. 2055–2062, 2012. View at Publisher · View at Google Scholar
  50. D. A. Yardley, L. Hart, L. Bosserman, et al., “Phase II study evaluating lapatinib in combination with nab-paclitaxel in HER2-overexpressing metastatic breast cancer patients who have received no more than one prior chemotherapeutic regimen,” Breast Cancer Research and Treatment, vol. 137, no. 2, pp. 457–464, 2013. View at Publisher · View at Google Scholar
  51. D. Ciliberto, C. Botta, P. Correale et al., “Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials,” European Journal of Cancer, vol. 49, no. 3, pp. 593–603, 2013. View at Publisher · View at Google Scholar
  52. K. K. Frese, A. Neesse, N. Cook, et al., “nab-paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer,” Cancer Discovery, vol. 2, no. 3, pp. 260–269, 2012. View at Publisher · View at Google Scholar
  53. D. C. Whiteman, C. A. Whiteman, and A. C. Green, “Childhood sun exposure as a risk factor for melanoma: a systematic review of epidemiologic studies,” Cancer Causes and Control, vol. 12, no. 1, pp. 69–82, 2001. View at Publisher · View at Google Scholar · View at Scopus
  54. A. Y. Bedikian, C. Plager, N. Papadopoulos, O. Eton, J. Ellerhorst, and T. Smith, “Phase II evaluation of paclitaxel by short intravenous infusion in metastatic melanoma,” Melanoma Research, vol. 14, no. 1, pp. 63–66, 2004.
  55. S. S. Legha, S. Ring, N. Papadopoulos, M. Raber, and R. S. Benjamin, “A phase II trial of taxol in metastatic melanoma,” Cancer, vol. 65, no. 11, pp. 2478–2481, 1990.
  56. A. I. Einzig, H. Hochster, P. H. Wiernik et al., “A phase II study of taxol in patients with malignant melanoma,” Investigational New Drugs, vol. 9, no. 1, pp. 59–64, 1991. View at Scopus
  57. S. Aamdal, I. Wolff, S. Kaplan et al., “Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group,” European Journal of Cancer A, vol. 30, no. 8, pp. 1061–1064, 1994. View at Publisher · View at Google Scholar · View at Scopus
  58. A. Y. Bedikian, G. R. Weiss, S. S. Legha et al., “Phase II trial of docetaxel in patients with advanced cutaneous malignant melanoma previously untreated with chemotherapy,” Journal of Clinical Oncology, vol. 13, no. 12, pp. 2895–2899, 1995. View at Scopus
  59. L. A. Kottschade, V. J. Suman, T. Amatruda et al., “A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E1,” Cancer, vol. 117, no. 8, pp. 1704–1710, 2011. View at Publisher · View at Google Scholar · View at Scopus
  60. P. A. Ott, J. Chang, K. Madden, et al., “Oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma: a phase I trial,” Cancer Chemotherapy and Pharmacology, vol. 71, no. 1, pp. 183–191, 2013. View at Publisher · View at Google Scholar
  61. G. V. Scagliotti, P. Parikh, J. von Pawel et al., “Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 26, no. 21, pp. 3543–3551, 2008. View at Publisher · View at Google Scholar · View at Scopus
  62. J. R. Jett, S. E. Schild, R. L. Keith, and K. A. Kesler, “Treatment of non-small cell lung cancer, stage IIIB: ACCP evidence-based clinical practice guidelines (2nd edition),” Chest, vol. 132, no. 3, pp. 266S–276S, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. J. H. Schiller, D. Harrington, C. P. Belani et al., “Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer,” The New England Journal of Medicine, vol. 346, no. 2, pp. 92–98, 2002. View at Publisher · View at Google Scholar · View at Scopus
  64. K. Kelly, J. Crowley, P. A. Bunn Jr. et al., “Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial,” Journal of Clinical Oncology, vol. 19, no. 13, pp. 3210–3218, 2001. View at Scopus
  65. R. C. Lilenbaum, J. E. Herndon, M. A. List et al., “Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730),” Journal of Clinical Oncology, vol. 23, no. 1, pp. 190–196, 2005. View at Publisher · View at Google Scholar · View at Scopus
  66. A. Sandler, R. Gray, M. C. Perry et al., “Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer,” The New England Journal of Medicine, vol. 355, no. 24, pp. 2542–2550, 2006. View at Publisher · View at Google Scholar · View at Scopus