title: Delivery of platinum(IV) drug to subcutaneous tumor and lung metastasis using bradykinin-potentiating peptide-decorated chitosan nanoparticles.
abstract: Selectively activating tumor vessels to increase drug delivery and reduce interstitial fluid pressure of tumors is actively pursued. Here we developed a vasoactive peptide-decorated chitosan nanoparticles for enhancing drug accumulation and penetration in subcutaneous tumor and lung metastasis. The vasoactive peptide used here is bradykinin-potentiating peptide (BPP) containing 9 amino acid residues and the drug is bioreductively sensitive platinum(IV) compound which becomes cisplatin in intracellular reductive environments. Both peptide and drug are covalently linked with chitosan nanoparticles with a diameter of 120 nm. We demonstrate that BPP-decorated chitosan nanoparticles increase the tumorous vascular permeability and reduce the interstitial fluid pressure of tumor simultaneously, both of which improve the penetration of nanoparticles in tumor tissues. The in vivo biodistribution and tumor inhibition examinations demonstrate that the BPP-decorated nanoparticle formulation has more superior efficacy in enhancing drug accumulation in tumor, restraining tumor growth and prolonging the lifetime of tumor-bearing mice than free drug and non-decorated nanoparticle formulation. Meanwhile, the drug accumulation in the lung with metastasis reaches 17% and 20% injected dose per gram of lung for the chitosan nanoparticles without and with BPP decoration, respectively, which is 10-fold larger than that of free cisplatin. The examination of lung metastasis inhibition further indicates that BPP-decorated chitosan nanoparticle formulations can more effectively inhibit lung metastasis.
authors.affiliation: Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, PR China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, PR China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhen
authors.affiliation: Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, PR China. Electronic address: jiangx@nju.edu.cn.
authors.forename: Xiqun
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002199:Capillary Permeability / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary*; D008297:Male; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D010316:Particle Size; D010984:Platinum / Q000494:pharmacology / Q000627:therapeutic use*; D019265:Spectroscopy, Near-Infrared; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000473:pathology*; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; C006791:bradykinin potentiating factors; D010984:Platinum; D048271:Chitosan; D016650:Fluorescein-5-isothiocyanate
keywords: Antitumor; Bradykinin-potentiating peptides; Drug delivery; Lung metastasis; Nanoparticles