Smart pH-Sensitive Nanogels for Enhancing Synergistic Anticancer Effects of Integrin αvβ3 Specific Apoptotic Peptide and Therapeutic Nitric Oxide

  • ACS Appl Mater Interfaces. 2019 Sep 25;11(38):34663-34675. doi: 10.1021/acsami.9b10830.
Yurui Xu  1 ,  Lei Sun  1 ,  Shujun Feng  1 ,  Jianmei Chen  1 ,  Ya Gao  1 ,  Leilei Guo  2 ,  Xueying An  3 ,  Yuanyuan Nie  1 ,  Yu Zhang  1 ,  Xiaoxuan Liu  2 ,  Xinghai Ning  1
Affiliations
  • 1. National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences , Nanjing University , Nanjing 210093 , China.
  • 2. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials , China Pharmaceutical University , Nanjing 210009 , China.
  • 3. State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital , The Affiliated Hospital of Nanjing University Medical School , Nanjing 210093 , China.
PMID: 31490654 DOI: 10.1021/acsami.9b10830
Abstract

Apoptotic peptide (kla), which can trigger the mitochondria-mediated apoptotic programmed cell death, has been widely recognized as a potential Anticancer agent. However, its therapeutic potential has been significantly impaired by its poor biostability, lack of tumor specificity, and particularly low cellular uptake. Herein, a linear peptide Arg-Trp-d-Arg-Asn-Arg (RWrNR) was identified as an Integrin αvβ3 specific ligand with a nanomolar dissociation constant (Kd = 0.95 nM), which can greatly improve kla antitumor activity (IC50 = 8.81 μM) by improving its cellular uptake, compared to the classic integrin-recognition motif c-RGDyK (IC50 = 37.96 μM). Particularly, the RWrNR-kla conjugate can be entrapped in acidic sensitive nanogels (RK/Parg/CMCS-NGs), composed of poly-l-arginine (Parg) and carboxymethyl chitosan (CMCS, pI = 6.8), which can not only carry out controlled release of RWrNR-kla in response to the tumor acidic microenvironment, and consequently enhance its tumor specificity and cell internalization, but also trigger tumor-associated macrophages to generate nitric oxide, leading to enhanced synergistic Anticancer efficacy. Importantly, RK/Parg/CMCS-NGs have been proven to effectively activate the Apoptosis signaling pathway in vivo and significantly inhibit tumor growth with minimal adverse effects. To summarize, RK/Parg/CMCS-NGs are a promising apoptotic peptide-based therapeutics with enhanced tumor accumulation, cytosolic delivery, and synergistic Anticancer effects, thereby holding great potential for the treatment of malignant tumors.

Keywords
acid-responsive; apoptotic peptide; integrin αvβ3 agonist; nanogels; synergistic anticancer.
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