A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer.

Paclitaxel (PTX) is one of the most effective chemotherapeutic drugs for the treatment of a variety of cancers. However, it is associated with serious side effects caused by PTX itself and the Cremophor EL emulsifier. In the present study, we report the development of a well-defined amphiphilic linear-dendritic copolymer (named as telodendrimer) composed of polyethylene glycol (PEG), cholic acid (CA, a facial amphiphilic molecule) and lysine, which can form drug-loaded core/shell micelles when mixed with hydrophobic drug, such as PTX, under aqueous condition. We have used PEG(5k)-CA(8), a representive telodendrimer, to prepare paclitaxel-loaded nanoparticles (PTX-PEG(5k)-CA(8) NPs) with high loading capacity (7.3 mg PTX/mL) and a size of 20-60 nm. This novel nanoformulation of PTX was found to exhibit similar in vitro cytotoxic activity against ovarian cancer cells as the free drug (Taxol) or paclitaxel/human serum albumin nanoaggregate (Abraxane). The maximum tolerated doses (MTDs) of PTX-PEG(5k)-CA(8) NPs after single dose and five consecutive daily doses in mice were approximately 75 and 45 mg PTX/kg, respectively, which were 2.5-fold higher than those of Taxol. In both subcutaneous and orthotopic intraperitoneal murine models of ovarian cancer, PTX-PEG(5k)-CA(8) NPs achieved superior toxicity profiles and anti-tumor effects compared to Taxol and Abraxane at equivalent PTX doses, which were attributed to their preferential tumor accumulation, and deep penetration into tumor tissue, as confirmed by near infrared fluorescence (NIRF) imaging.

[1]  Ze Lu,et al.  Effects of Carrier on Disposition and Antitumor Activity of Intraperitoneal Paclitaxel , 2007, Pharmaceutical Research.

[2]  J. Leroux,et al.  Micelles in anticancer drug delivery , 2004 .

[3]  R. Straubinger,et al.  Paclitaxel-liposomes for intracavitary therapy of intraperitoneal P388 leukemia. , 1996, Cancer letters.

[4]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[5]  G Blume,et al.  Liposomes for the sustained drug release in vivo. , 1990, Biochimica et biophysica acta.

[6]  E. W. Meijer,et al.  Polystyrene-Dendrimer Amphiphilic Block Copolymers with a Generation-Dependent Aggregation , 1995, Science.

[7]  Christopher J. Destache,et al.  Nanotechnology: A Focus on Nanoparticles as a Drug Delivery System , 2006, Journal of Neuroimmune Pharmacology.

[8]  Patrick Soon-Shiong,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. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  Y. Koyanagi,et al.  Direct measurement of the extravasation of polyethyleneglycol-coated liposomes into solid tumor tissue by in vivo fluorescence microscopy , 1996 .

[10]  F. Szoka,et al.  A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas , 2006, Proceedings of the National Academy of Sciences.

[11]  Paclitaxel (taxol) for ovarian cancer. , 1993, The Medical letter on drugs and therapeutics.

[12]  U. Maitra,et al.  A simple construction of a bile acid based dendritic light harvesting system. , 2005, Organic letters.

[13]  C. Allen,et al.  Formulation of drugs in block copolymer micelles: drug loading and release. , 2006, Current pharmaceutical design.

[14]  H. Rosing,et al.  Treatment of ovarian cancer using intraperitoneal chemotherapy with taxanes: from laboratory bench to bedside. , 2006, Cancer treatment reviews.

[15]  Kit S Lam,et al.  Combinatorial chemistry identifies high-affinity peptidomimetics against alpha4beta1 integrin for in vivo tumor imaging. , 2006, Nature chemical biology.

[16]  E. Bilensoy,et al.  Safety and efficacy of amphiphilic beta-cyclodextrin nanoparticles for paclitaxel delivery. , 2008, International journal of pharmaceutics.

[17]  B. Leyland-Jones,et al.  Hypersensitivity reactions from taxol. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[19]  V. Torchilin,et al.  Biodegradable long-circulating polymeric nanospheres. , 1994, Science.

[20]  R. Rai,et al.  Synthesis of cholic acid-based molecular receptors: head-to-head cholaphanes , 2002 .

[21]  J. Fréchet,et al.  Stimuli-responsive supramolecular assemblies of linear-dendritic copolymers. , 2004, Journal of the American Chemical Society.

[22]  J. Fréchet,et al.  pH-Responsive copolymer assemblies for controlled release of doxorubicin. , 2005, Bioconjugate chemistry.

[23]  Kyung-Ja Cho,et al.  In vivo tumor targeting and radionuclide imaging with self-assembled nanoparticles: mechanisms, key factors, and their implications. , 2007, Biomaterials.

[24]  A. Kabanov,et al.  Self-assembling complexes for gene delivery : from laboratory to clinical trial , 1998 .

[25]  R. Donehower,et al.  Taxol: a novel investigational antimicrotubule agent. , 1990, Journal of the National Cancer Institute.

[26]  Jianjun Cheng,et al.  Anticancer Polymeric Nanomedicines , 2007 .

[27]  Y. Matsumura.  Poly (amino acid) micelle nanocarriers in preclinical and clinical studies. , 2008, Advanced drug delivery reviews.

[28]  V. Trubetskoy,et al.  Polymeric micelles as carriers of diagnostic agents. , 1999, Advanced Drug Delivery Reviews.

[29]  B. Goff,et al.  Ovarian carcinoma diagnosis , 2000, Cancer.

[30]  P. Hammond,et al.  Synthesis and solution properties of new linear-dendritic diblock copolymers , 1998 .

[31]  R. Straubinger,et al.  Novel Taxol formulations: Taxol-containing liposomes. , 1993, Journal of the National Cancer Institute. Monographs.

[32]  Mark E. Davis,et al.  Nanoparticle therapeutics: an emerging treatment modality for cancer , 2008, Nature Reviews Drug Discovery.

[33]  H. S. Oh,et al.  In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[34]  John K. Jackson,et al.  Development of amphiphilic diblock copolymers as micellar carriers of taxol , 1996 .

[35]  M. Dewhirst,et al.  Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. , 2006, Journal of the National Cancer Institute.

[36]  R. Liggins,et al.  Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations. , 2002, Advanced drug delivery reviews.

[37]  E. Mahan,et al.  Hydraamphiphiles: Novel Linear Dendritic Block Copolymer Surfactants , 1994 .

[38]  C. Hawker,et al.  Synthesis and properties of novel linear-dendritic block copolymers. Reactivity of dendritic macromolecules toward linear polymers , 1993 .

[39]  Chulhee Kim,et al.  Amphiphilic Linear PEO-Dendritic Carbosilane Block Copolymers , 2000 .

[40]  Z. Duan,et al.  Modulation of Drug Resistance in Ovarian Adenocarcinoma by Enhancing Intracellular Ceramide Using Tamoxifen-Loaded Biodegradable Polymeric Nanoparticles , 2008, Clinical Cancer Research.