2. Academic Validation
  3. Redox-responsive polyprodrug nanoparticles for targeted siRNA delivery and synergistic liver cancer therapy

Redox-responsive polyprodrug nanoparticles for targeted siRNA delivery and synergistic liver cancer therapy

  • Biomaterials. 2020 Mar;234:119760. doi: 10.1016/j.biomaterials.2020.119760.
Senlin Li 1,  Phei Er Saw 2,  Chunhao Lin 2,  Yan Nie 2,  Wei Tao 3,  Omid C Farokhzad 4,  Lei Zhang 5,  Xiaoding Xu 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China.
  • 3 Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 4 Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. Electronic address: ofarokhzad@bwh.harvard.edu.
  • 5 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China. Electronic address: zhangl9@mail.sysu.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China. Electronic address: xuxiaod5@mail.sysu.edu.cn.
PMID: 31945619 DOI: 10.1016/j.biomaterials.2020.119760
Abstract

Combination therapy has been developed as an innovative modality for effective Cancer therapy. However, the administration of combinatorial therapeutics is limited by the varying pharmacokinetics of different drugs. Although numerous nanoparticles (NPs) can synchronize the delivery of combinatorial therapeutics to tumor cells, their clinical translation is still challenged, which is partly due to the complexity to precisely control the loading of combinatorial therapeutics to maximize therapeutic efficacy and suboptimal NP properties. Herein, a new redox-responsive polyprodrug nanoplatform was developed for targeted siRNA delivery and synergistic Cancer therapy. This NP platform is made with redox-responsive 10-hydroxycamptothecin (HCPT)-based polyprodrug (polyHCPT) as the inner core, amphiphilic lipid-poly (ethylene glycol) (lipid-PEG) as the outer shell, and lactobionic acid (LA) decoration on the surface. After siRNA loading and subsequent systemic administration, the resulting NP platform could accumulate in tumor tissues and target hepatoma cells via specific recognition between LA and asialoglycoprotein (ASGP) receptors. With the high concentration of glutathione (GSH) in the cytoplasm to break the disulfide bonds in the polyHCPT, intact HCPT molecules and encapsulated B-cell lymphoma 2 (Bcl-2) siRNA (siBcl-2) could be rapidly released, leading to the synergistic inhibition of tumor growth via the induction of Apoptosis by HCPT and the concurrent silencing of the anti-apoptotic gene by siBcl-2.

Keywords

Nanoparticles; Polyprodrug; Redox-responsive; Synergistic therapy; Targeted delivery.

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