A 3-in-1 polymeric micelle nanocontainer for poorly water-soluble drugs.

Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles have a proven capacity for drug solubilization and have entered phase III clinical trials as a substitute for Cremophor EL in the delivery of paclitaxel in cancer therapy. PEG-b-PLA is less toxic than Cremophor EL, enabling a doubling of paclitaxel dose in clinical trials. We show that PEG-b-PLA micelles act as a 3-in-1 nanocontainer for paclitaxel, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin for multiple drug solubilization. 3-in-1 PEG-b-PLA micelles were ca. 40 nm in diameter; dissolved paclitaxel, 17-AAG, and rapamycin in water at 9.0 mg/mL; and were stable for 24 h at 25 °C. The half-life for in vitro drug release (t(1/2)) for 3-in-1 PEG-b-PLA micelles was 1-15 h under sink conditions and increased in the order of 17-AAG, paclitaxel, and rapamycin. The t(1/2) values correlated with log P(o/w) values, implicating a diffusion-controlled mechanism for drug release. The IC(50) value of 3-in-1 PEG-b-PLA micelles for MCF-7 and 4T1 breast cancer cell lines was 114 ± 10 and 25 ± 1 nM, respectively; combination index (CI) analysis showed that 3-in-1 PEG-b-PLA micelles exert strong synergy in MCF-7 and 4T1 breast cancer cell lines. Notably, concurrent intravenous (iv) injection of paclitaxel, 17-AAG, and rapamycin using 3-in-1 PEG-b-PLA micelles was well-tolerated by FVB albino mice. Collectively, these results suggest that PEG-b-PLA micelles carrying paclitaxel, 17-AAG, and rapamycin will provide a simple yet safe and efficacious 3-in-1 nanomedicine for cancer therapy.

[1]  N. Davies,et al.  A cremophor-free formulation for tanespimycin (17-AAG) using PEO-b-PDLLA micelles: characterization and pharmacokinetics in rats. , 2009, Journal of pharmaceutical sciences.

[2]  J. LoPiccolo,et al.  Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. , 2008, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[3]  A. Olshen,et al.  Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. , 2003, Cancer research.

[4]  Dong-Wan Kim,et al.  Multicenter phase II trial of Genexol-PM, a novel Cremophor-free, polymeric micelle formulation of paclitaxel, with cisplatin in patients with advanced non-small-cell lung cancer. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  Sung-Bae Kim,et al.  Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer , 2008, Breast Cancer Research and Treatment.

[6]  D. Solit,et al.  Development and application of Hsp90 inhibitors. , 2008, Drug discovery today.

[7]  H. Brem,et al.  Paclitaxel: a review of adverse toxicities and novel delivery strategies , 2007, Expert opinion on drug safety.

[8]  R. Govindan,et al.  Novel formulations of taxanes: a review. Old wine in a new bottle? , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[9]  Chalet Tan,et al.  Combination of rapamycin and 17-allylamino-17-demethoxygeldanamycin abrogates Akt activation and potentiates mTOR blockade in breast cancer cells , 2008, Anti-cancer drugs.

[10]  L. Norton,et al.  Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. See: E. A. Sausville, Combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: sequence and tumor biology matters, Clin. Cancer Res., 7: 2155- , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  R. Arceci,et al.  Phase I Pharmacokinetic and Pharmacodynamic Study of 17-N-Allylamino-17-Demethoxygeldanamycin in Pediatric Patients with Recurrent or Refractory Solid Tumors: A Pediatric Oncology Experimental Therapeutics Investigators Consortium Study , 2007, Clinical Cancer Research.

[12]  Yan Zhou,et al.  Chemotherapy and signaling , 2010, Cancer biology & therapy.

[13]  Ting-Chao Chou,et al.  Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies , 2006, Pharmacological Reviews.

[14]  W L Hunter,et al.  Solid-state characterization of paclitaxel. , 1997, Journal of pharmaceutical sciences.

[15]  P. Workman,et al.  Pharmacokinetic-Pharmacodynamic Relationships for the Heat Shock Protein 90 Molecular Chaperone Inhibitor 17-Allylamino , 17-Demethoxygeldanamycin in Human Ovarian Cancer , 2005 .

[16]  Ho-Chul Shin,et al.  Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[17]  S. Yalkowsky,et al.  Solubilization of rapamycin. , 2001, International journal of pharmaceutics.

[18]  J. Dancey.  Therapeutic targets: MTOR and related pathways , 2006, Cancer biology & therapy.

[19]  S. Larson,et al.  Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer , 2007, Clinical Cancer Research.

[20]  J. Verweij,et al.  Pharmacological Effects of Formulation Vehicles , 2003, Clinical pharmacokinetics.

[21]  G. Mills,et al.  Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells , 2004, Clinical Cancer Research.

[22]  Afsaneh Lavasanifar,et al.  Polymeric micelles for drug delivery , 2006, Expert opinion on drug delivery.

[23]  E. Raymond,et al.  Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  E J Freireich,et al.  Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. , 1966, Cancer chemotherapy reports.

[25]  Shi-Yong Sun,et al.  Enhancing mTOR-targeted cancer therapy , 2009, Expert opinion on therapeutic targets.

[26]  M. Barberi-Heyob,et al.  In vitro comparative evaluation of trastuzumab (Herceptin) combined with paclitaxel (Taxol) or docetaxel (Taxotere) in HER2-expressing human breast cancer cell lines. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[27]  Jie Ge,et al.  Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90 , 2006, Proceedings of the National Academy of Sciences.

[28]  B. Krishnan,et al.  Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT , 2006, Molecular Cancer Therapeutics.

[29]  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.

[30]  D. Schrump,et al.  Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: in vitro and in vivo analysis. , 2001, The Annals of thoracic surgery.

[31]  B. Robinson,et al.  Promising combination therapies with gemcitabine. , 2004, Seminars in oncology.