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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.

SUBMITTER: Wan X

PROVIDER: S-EPMC6331221 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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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.

Wan Xiaomeng X Beaudoin James J JJ Vinod Natasha N Min Yuanzeng Y Makita Naoki N Bludau Herdis H Jordan Rainer R Wang Andrew A Sokolsky Marina M Kabanov Alexander V AV

Biomaterials 20181031

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 ratio ...[more]

PMID: 30415101

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Project description:Sustaining the release of highly dosed APIs from a matrix tablet is challenging. To address this challenge, this study evaluated the performance of thermoplastic poly (2-alkyl-2-oxazoline)s (PAOx) as matrix excipient to produce sustained-release tablets via three processing routes: (a) hot-melt extrusion (HME) combined with injection molding (IM), (b) HME combined with milling and compression and (c) direct compression (DC). Different PAOx (co-)polymers and polymer mixtures were processed with several active pharmaceutical ingredients having different aqueous solubilities and melting temperatures (metoprolol tartrate (MPT), metformin hydrochloride (MTF) and theophylline anhydrous (THA)). Different PAOx grades were synthesized and purified by the Supramolecular Chemistry Group, and the effect of PAOx grade and processing technique on the in vitro release kinetics was evaluated. Using the hydrophobic poly (2-n-propyl-2-oxazoline) (P n PrOx) as a matrix excipient allowed to sustain the release of different APIs, even at a 70% (w/w) drug load. Whereas complete THA release was not achieved from the P n PrOx matrix over 24 h regardless of the processing technique, adding 7.5% w/w of the hydrophilic poly (2-ethyl-2-oxazoline) to the hydrophobic P n PrOx matrix significantly increased THA release, highlighting the relevance of mixing different PAOx grades. In addition, it was demonstrated that the release of THA was similar from co-polymer and polymer mixtures with the same polymer ratios. On the other hand, as the release of MTF from a P n PrOx matrix was fast, the more hydrophobic poly (2-sec-butyl-2-oxazoline) (P sec BuOx) was used to retard MTF release. In addition, a mixture between the hydrophilic PEtOx and the hydrophobic P sec BuOx allowed accurate tuning of the release of MTF formulations. Finally, it was demonstrated that PAOx also showed a high ability to tune the in vivo release. IM tablets containing 70% MTF and 30% P sec BuOx showed a lower in vivo bioavailability compared to IM tablets containing a low PEtOx concentration (7.5%, w/w) in combination with P sec BuOx (22.5%, w/w). Importantly, the in vivo MTF blood level from the sustained release tablets correlated well with the in vitro release profiles. In general, this work demonstrates that PAOx polymers offer a versatile formulation platform to adjust the release rate of different APIs, enabling sustained release from tablets with up to 70% w/w drug loading.

Dataset Information

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.

Publications

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.

Similar Datasets

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