Complete regression of xenograft tumors upon targeted delivery of paclitaxel via ∏ - ∏ stacking stabilized polymeric micelles
Shi, Yang; van der Meel, Roy; Theek, Benjamin; Blenke, Erik Oude; Pieters, Ebel H. E.; Fens, Marcel H. A. M.; Ehling, Josef; Schiffelers, Raymond M.; Storm, Gert; van Nostrum, Cornelus F.; Lammers, Twan; Hennink, Wim E.
(2015) ACS Nano, volume 9, issue 4, pp. 3740 - 3752
(Article)
Abstract
Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achiv prolonged circulation kinetics. As a result, PTX deposition
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in tumors is increased, while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed PTX-loaded micelles which are stable without chemical cross-linking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to ∏-∏ stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl)methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid μCT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses, while they induced complete tumor regression in two different xenograft models (i.e., A431 and MDA-MB-468). Our findings consequently indicate that ∏-∏ stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index.
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Keywords: nanomedicine, drug targeting, polymeric micelles, paclitaxel, pi-pi stacking, IN-VIVO EVALUATION, PHASE-II TRIAL, DRUG-DELIVERY, COPOLYMER MICELLES, BLOCK-COPOLYMER, CANCER-THERAPY, CREMOPHOR-FREE, GENEXOL-PM, COMBINATION THERAPY, ANTITUMOR-ACTIVITY, General Engineering, General Materials Science, General Physics and Astronomy, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 1936-0851
Publisher: American Chemical Society
(Peer reviewed)