title: Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shell-corona micelles with shell-specific redox-responsive cross-links.
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.
authors: Department of Maxillofacial Biomedical Engineering & Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors: Ahn Na
authors: AN
authors: Koo
authors: Kyung Hyun
authors: KH
authors: Min
authors: Hong Jae
authors: HJ
authors: Lee
authors: Sang-Uk
authors: SU
authors: Lee
authors: Kwangmeyung
authors: K
authors: Kim
authors: Ick Chan
authors: IC
authors: Kwon
authors: Sun Hang
authors: SH
authors: Cho
authors: Seo Young
authors: SY
authors: Jeong
authors: Sang Cheon
authors: SC
authors: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002232:Carbocyanines / Q000378:metabolism; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry*; D003952:Diagnostic Imaging; D004220:Disulfides / Q000737:chemistry; D000077143:Docetaxel; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010316:Particle Size; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D003432:Cross-Linking Reagents; D004220:Disulfides; D008823:Micelles; D010455:Peptides; D043823:Taxoids; D000077143:Docetaxel; D011107:Polylysine; C012001:polyphenylalanine; D011092:Polyethylene Glycols