@article{abd02fb318924d0984e498f135420a56,
title = "Co-delivery of paclitaxel and cisplatin in poly(2-oxazoline) polymeric micelles: Implications for drug loading, release, pharmacokinetics and outcome of ovarian and breast cancer treatments",
abstract = "Concurrent delivery of multiple drugs using nanoformulations can improve outcomes of cancer treatments. Here we demonstrate that this approach can be used to improve the paclitaxel (PTX) and alkylated cisplatin prodrug combination therapy of ovarian and breast cancer. The drugs are co-loaded in the polymeric micelle system based on amphiphilic block copolymer poly(2-methyl-2-oxazoline-block-2-butyl-2-oxazoline-block-2-methyl-2-oxazoline) (P(MeOx-b-BuOx-b-MeOx). A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50 wt.% drug in a stable micellar solution is demonstrated. The drugs co-loading in the micelles result in a slowed-down release to serum, improved pharmacokinetics and increased tumor distribution for both drugs. A superior anti-tumor activity of co-loaded PTX/CP drug micelles compared to single drug micelles or their mixture was demonstrated in cisplatin-resistant human ovarian carcinoma A2780/CisR xenograft tumor and multidrug resistant breast cancer LCC-6-MDR orthotopic tumor models. The improved tumor delivery of co-loaded drugs was related to decreased drug release rates as confirmed by simulation for micelle, serum and tumor compartments in a three-compartmental model. Overall, the results provide support for the use of PTX and cisplatin co-loaded micelles as a strategy for improved chemotherapy of ovarian and breast cancer and potential for the clinical translation.",
keywords = "Cancer, Combination chemotherapy, Nanoformulation, Poly (2-oxazoline), Polymeric micelle",
author = "Xiaomeng Wan and Beaudoin, {James J.} and Natasha Vinod and Yuanzeng Min and Naoki Makita and Herdis Bludau and Rainer Jordan and Andrew Wang and Marina Sokolsky and Kabanov, {Alexander V.}",
note = "Funding Information: This work was supported by the National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence). A.Z.W. was also supported by NCI (R21 CA182322). X.W. is grateful to the China Scholarship Council (CSC) for a pre-doctoral fellowship (2011601254). We also acknowledge Charlene Santos at MP1U of UNC for helping the development of the orthotopic breast cancer model and Nanomedicines Characterization Core (NCore) for ICP-MS measurements; Zibo Li and Hui Wang for designing and performing the 64Cu labeling of POx and assistance with the data analysis; William Zamboni for advice and oversight in PK calculations and analysis. The XPS and EDS studies were performed by Carrie Lynn Donley and Wallace W Ambrose respectively at the Chapel Hill Analytical and Nanofabrication Laboratory, CHANL, a member of the North Carolina Research Triangle Nanotechnology Network, RTNN, which is supported by the National Science Foundation, Grant ECCS-1542015, as part of the National Nanotechnology Coordinated Infrastructure (NNCI). AVK and RJ are listed as inventors on patents pertinent to the subject matter of the present contribution and co-founders of DelAqua Pharmaceuticals Inc. having intent of commercial development of POx based drug formulations. Funding Information: This work was supported by the National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer ( U54CA198999 , Carolina Center of Cancer Nanotechnology Excellence ). A.Z.W. was also supported by NCI ( R21 CA182322 ). X.W. is grateful to the China Scholarship Council (CSC) for a pre-doctoral fellowship ( 2011601254 ). We also acknowledge Charlene Santos at MP1U of UNC for helping the development of the orthotopic breast cancer model and Nanomedicines Characterization Core (NCore) for ICP-MS measurements; Zibo Li and Hui Wang for designing and performing the 64Cu labeling of POx and assistance with the data analysis; William Zamboni for advice and oversight in PK calculations and analysis. The XPS and EDS studies were performed by Carrie Lynn Donley and Wallace W Ambrose respectively at the Chapel Hill Analytical and Nanofabrication Laboratory, CHANL, a member of the North Carolina Research Triangle Nanotechnology Network, RTNN, which is supported by the National Science Foundation , Grant ECCS-1542015 , as part of the National Nanotechnology Coordinated Infrastructure (NNCI). AVK and RJ are listed as inventors on patents pertinent to the subject matter of the present contribution and co-founders of DelAqua Pharmaceuticals Inc. having intent of commercial development of POx based drug formulations. Publisher Copyright: {\textcopyright} 2018",
year = "2019",
month = feb,
doi = "10.1016/j.biomaterials.2018.10.032",
language = "English (US)",
volume = "192",
pages = "1--14",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",
}