title: Cell microenvironment-controlled antitumor drug releasing-nanomicelles for GLUT1-targeting hepatocellular carcinoma therapy.
abstract: In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as their serious systemic toxicity. In this work, we developed actively tumor-targeting trilayer micelles with microenvironment-sensitive cross-links as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable PEG-pLys-pPhe polymers, in which pLys could react with a disulfide-containing agent to form redox-responsive cross-links. In vitro drug release and pharmacokinetics studies showed that these cross-links were stable in physiological condition whereas cleaved once internalized into cells due to the high level of glutathione, resulting in facilitated intracellular doxorubicin release. In addition, dehydroascorbic acid (DHAA) was decorated on the surface of micelles for specific recognition of tumor cells via GLUT1, a member of glucose transporter family overexpressed on hepatocarcinoma cells. Moreover, DHAA exhibited a "one-way" continuous accumulation within tumor cells. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, China.
authors: Yubo
authors: Y
authors: Guo
authors: Yujie
authors: Y
authors: Zhang
authors: Jianfeng
authors: J
authors: Li
authors: Yu
authors: Y
authors: Zhang
authors: Yifei
authors: Y
authors: Lu
authors: Xutao
authors: X
authors: Jiang
authors: Xi
authors: X
authors: He
authors: Haojun
authors: H
authors: Ma
authors: Sai
authors: S
authors: An
authors: Chen
authors: C
authors: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D003683:Dehydroascorbic Acid / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D049329:Nanostructures / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D019265:Spectroscopy, Near-Infrared; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014463:Ultrasonography
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D051272:Glucose Transporter Type 1; D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003683:Dehydroascorbic Acid
keywords: GLUT1; cross-link; dehydroascorbic acid; hepatocellular carcinoma; polymer micelle; redox-responsive