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pH-responsive hybrid quantum dots for targeting hypoxic tumor siRNA delivery

Author:
Zhu, HongYan, Zhang, ShengYu, Ling, Yong, Meng, GuoLiang, Yang, Yu, Zhang, Wei
Source:
Journal of Controlled Release 2015 v.220 pp. 529-544
ISSN:
0168-3659
Subject:
2-deoxyglucose, Fourier transform infrared spectroscopy, Western blotting, angiogenesis, biocompatibility, blood vessels, carcinogenesis, chemical structure, gene silencing, hypoxia, hypoxia-inducible factor 1, in vivo studies, lipoic acid, liquid chromatography, lysine, mass spectrometry, neoplasm cells, neoplasms, nuclear magnetic resonance spectroscopy, polyacrylamide gel electrophoresis, quantum dots, small interfering RNA, therapeutics, toxicity, transporters
Abstract:
Hypoxia is a characteristic of cancer and plays a key role in tumorigenesis, angiogenesis and resistance to cancer therapies. SiRNA treatment is effective against hypoxic tumors by gene silencing. However, siRNA delivery to the hypoxic regions of solid tumors still presents a challenge due to the distance from blood vessels and the increased presence of efflux transporters. Therefore, tumor therapies would be improved through the immediate development of an effective siRNA delivery system to hypoxic regions. To this end, we synthesized a system to deliver HIF-1α siRNA into hypoxic tumor cells. The system consists of a functional shell composed of 2-deoxyglucose (DG)-polyethylene glycol (PEG) connected with the compound of lipoic acid, lysine and 9-poly-d-arginine (LA–Lys–9R) by a hydrazone bond and a core of CdTe quantum dots (QDs). The molecular structure of DG–PEG–LA–Lys–9R was confirmed by liquid chromatography–mass spectrometry (LC–MS), nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The multifunctional CdTe QDs measured approximately 200nm and showed excellent biocompatibility, perfect siRNA binding capability and enhanced hypoxic tumor targeting. Importantly, the system described here is pH-responsive with a hydrazone bond; therefore, it avoids GLUT1 receptor-mediated endocytic recycling, resulting in irreversible delivery of the siRNA. We used Western blots to confirm the superior gene silencing efficiency induced by the DG–PEG–LA–Lys–9R with hydrazone modified CdTe QDs. Here, we demonstrate high efficacy of the siRNA tumor delivery system using in vitro and in vivo experiments. In addition, these studies demonstrate that pH-responsive hybrid quantum dots show improved antitumor efficacy with decreased organ toxicity, indicating a promising siRNA delivery system for hypoxic cancer therapy.
Agid:
5830265