Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shell-corona micelles with shell-specific redox-responsive cross-links

Ahn Na Koo, Kyung Hyun Min, Hong Jae Lee, Sang-Uk Lee, Kwangmeyung Kim, Ick Chan Kwon, Sun Hang Cho, Seo Young Jeong, Sang Cheon Lee, Ahn Na Koo, Kyung Hyun Min, Hong Jae Lee, Sang-Uk Lee, Kwangmeyung Kim, Ick Chan Kwon, Sun Hang Cho, Seo Young Jeong, Sang Cheon Lee, Ahn Na Koo, Kyung Hyun Min, Hong Jae Lee, Sang-Uk Lee, Kwangmeyung Kim, Ick Chan Kwon, Sun Hang Cho, Seo Young Jeong, Sang Cheon Lee

Index: Biomaterials 33 , 1489-1499, (2012)

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Abstract

A robust core-shell-corona micelle bearing redox-responsive shell-specific cross-links was evaluated as a carrier of docetaxel (DTX) for cancer therapy. The polymer micelles of poly(ethylene glycol)- b-poly( l-lysine)- b-poly( l-phenylalanine) (PEG-PLys-PPhe) in the aqueous phase provided the three distinct functional domains: the PEG outer corona for prolonged circulation, the PLys middle shell for disulfide cross-linking, and the PPhe inner core for DTX loading. The shell cross-linking was performed by the reaction of disulfide-containing cross-linkers with Lys moieties in the middle shells. The shell cross-linking did not change the micelle size or the spherical morphology. The shell cross-linked micelles exhibited enhanced serum stability. The DTX release from the DTX-loaded disulfide cross-linked micelles (DTX-SSCLM) was facilitated by increasing the concentration of glutathione (GSH). At an intracellular GSH level, DTX release was facilitated due to the reductive cleavage of the disulfide cross-links in the shell domains. The in vivo tissue distribution and tumor accumulation of the DTX-SSCLM that were labeled with a near-infrared fluorescence (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DTX-SSCLM exhibited enhanced tumor specificity due to the prolonged stable circulation in blood and the enhanced permeation and retention (EPR) effect compared with the DTX-loaded non-cross-linked micelles (DTX-NCLM). The DTX-SSCLM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DTX and DTX-NCLM. The domain-specific shell cross-linking that is described in this work may serve as a useful guidance for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.