Precise Engineering of siRNA Delivery Vehicles to Tumors Using Polyion Complexes and Gold Nanoparticles

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• 作者：Hyun Jin Kim ; Hiroyasu Takemoto ; Yu Yi ; Meng Zheng ; Yoshinori Maeda ; Hiroyuki Chaya ; Kotaro Hayashi ; Peng Mi ; Frederico Pittella ; R. James Christie ; Kazuko Toh ; Yu Matsumoto ; Nobuhiro Nishiyama ; Kanjiro Miyata ; Kazunori Kataoka
• 刊名：ACS Nano
• 出版年：2014
• 出版时间：September 23, 2014
• 年：2014
• 卷：8
• 期：9
• 页码：8979-8991
• 全文大小：768K
• ISSN：1936-086X

文摘

For systemic delivery of siRNA to solid tumors, a size-regulated and reversibly stabilized nanoarchitecture was constructed by using a 20 kDa siRNA-loaded unimer polyion complex (uPIC) and 20 nm gold nanoparticle (AuNP). The uPIC was selectively prepared by charge-matched polyionic complexation of a poly(ethylene glycol)-b-poly(l-lysine) (PEG-PLL) copolymer bearing 鈭?0 positive charges (and thiol group at the 蠅-end) with a single siRNA bearing 40 negative charges. The thiol group at the 蠅-end of PEG-PLL further enabled successful conjugation of the uPICs onto the single AuNP through coordinate bonding, generating a nanoarchitecture (uPIC-AuNP) with a size of 38 nm and a narrow size distribution. In contrast, mixing thiolated PEG-PLLs and AuNPs produced a large aggregate in the absence of siRNA, suggesting the essential role of the preformed uPIC in the formation of nanoarchitecture. The smart uPIC-AuNPs were stable in serum-containing media and more resistant against heparin-induced counter polyanion exchange, compared to uPICs alone. On the other hand, the treatment of uPIC-AuNPs with an intracellular concentration of glutathione substantially compromised their stability and triggered the release of siRNA, demonstrating the reversible stability of these nanoarchitectures relative to thiol exchange and negatively charged AuNP surface. The uPIC-AuNPs efficiently delivered siRNA into cultured cancer cells, facilitating significant sequence-specific gene silencing without cytotoxicity. Systemically administered uPIC-AuNPs showed appreciably longer blood circulation time compared to controls, i.e., bare AuNPs and uPICs, indicating that the conjugation of uPICs onto AuNP was crucial for enhancing blood circulation time. Finally, the uPIC-AuNPs efficiently accumulated in a subcutaneously inoculated luciferase-expressing cervical cancer (HeLa-Luc) model and achieved significant luciferase gene silencing in the tumor tissue. These results demonstrate the strong potential of uPIC-AuNP nanoarchitectures for systemic siRNA delivery to solid tumors.

Keywords:

siRNA delivery; unimer polyion complex; gold nanoparticle; cancer therapy