Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 55, Issue 25, Pages 7091-7094Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201601273
Keywords
cancer therapy; nanoparticles; pH-responsive; siRNA delivery; tumor penetration
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Funding
- NIH [EB015419, CA151884, R00CA160350, CA200900]
- Movember-Prostate Cancer Foundation (PCF) Challenge Award
- David H. Koch-PCF Program in Cancer Nanotherapeutics
- PCF Young Investigator Award
- Department of Defense Prostate Cancer Research Program Synergistic Idea Development Award
- National Research Foundation of Korea [K1A1A2048701]
- National Research Foundation of Korea [2012K1A1A2045436] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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RNA interference (RNAi) gene silencing technologies have shown significant potential for treating various diseases, including cancer. However, clinical success in cancer therapy remains elusive, mainly owing to suboptimal in vivo delivery of RNAi therapeutics such as small interference RNA (siRNA) to tumors. Herein, we developed a library of polymers that respond to a narrow pH change (ultra-pH-responsive), and demonstrated the utility of these materials in targeted and deep tumor-penetrating nanoparticle (NP) for in vivo RNAi. The new NP platform is mainly composed of the following key components: i) internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration; ii) polyethylene glycol (PEG) chains to prolong blood circulation; and iii) sharp pH-responsive hydrophobic polymer to improve endosome escape. Through systematic studies of structure-function relationship, the optimized RNAi NPs (<70 nm) showed efficient gene silencing and significant inhibition of tumor growth with negligible toxicities in vivo.
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