title: Tumor targeting and microenvironment-responsive nanoparticles for gene delivery.
abstract: A tumor targeting nanoparticle system has been successfully developed to response to the lowered tumor extracellular pH (pHe) and upregulated matrix metalloproteinase 2 (MMP2) in the tumor microenvironment. The nanoparticles are modified with activatable cell-penetrating peptide (designated as dtACPP) that's dual-triggered by the lowered pHe and MMP2. In dtACPP, the internalization function of cell-penetrating peptide (CPP) is quenched by a pH-sensitive masking peptide, linking by a MMP2 substrate. The masking peptide is negatively charged to quench the cationic CPP well after systemic administration. Hence, dtACPP-modified nanoparticles possesses passive tumor targetability via the enhanced permeability and retention (EPR) effect. Once reaching the tumor microenvironment, the pre-existing attraction would be eliminated due to the lowered pHe, accompanying the linker cleaved by MMP2, dtACPP would be activated to expose CPP to drive the nanoparticles' internalization into the intratumoral cells. The studies of plasmid DNA loading, toxicity assessment, cellular uptake, tumor targeting delivery, and gene transfection demonstrate that dtACPP-modified nanoparticle system is a potential candidate for tumor targeting gene delivery.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Shixian
authors.initials: S
authors.lastname: Huang
authors.forename: Kun
authors.initials: K
authors.lastname: Shao
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Kuang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Sai
authors.initials: S
authors.lastname: An
authors.forename: Yubo
authors.initials: Y
authors.lastname: Guo
authors.forename: Haojun
authors.initials: H
authors.lastname: Ma
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D004586:Electrophoresis; D004705:Endocytosis / Q000187:drug effects; D005453:Fluorescence; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011107:Polylysine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D011107:Polylysine; D011092:Polyethylene Glycols; D004247:DNA