title: Tumor-targeting and microenvironment-responsive smart nanoparticles for combination therapy of antiangiogenesis and apoptosis.
abstract: Tumor microenvironment, such as the lowered tumor extracellular pH (pHe) and matrix metalloproteinase 2 (MMP2), has been extensively explored, which promotes the development of the microenvironment-responsive drug delivery system. Utilizing these unique features, an activatable cell-penetrating peptide (designated as dtACPP) that is dual-triggered by the lowered pHe and MMP2 has been constructed, and a smart nanoparticle system decorating with dtACPP has been successfully developed, which could dual-load gene drug and chemotherapeutics simultaneously. After systemic administration, dtACPP-modified nanoparticles possess passive tumor targetability via the enhanced permeability and retention effect. Then dtACPP would be activated to expose cell-penetrating peptide to drive the nanoparticles' internalization into the intratumoral cells. As angiogenesis and tumor cells might be mutually improved in tumor growth, so combining antiangiogenesis and apoptosis is meaningful for oncotherapy. Vascular endothelial growth factor (VEGF) is significant in angiogenesis, and anti-VEGF therapy could decrease blood vessel density and delay tumor growth obviously. Chemotherapy using doxorubicin (DOX) could kill off tumor cells efficiently. Here, utilizing dtACPP-modified nanoparticles to co-deliver plasmid expressing interfering RNA targeting VEGF (shVEGF) and DOX (designated as dtACPPD/shVEGF-DOX) results in effective shutdown of blood vessels and cell apoptosis within the tumor. On the premise of effective drug delivery, dtACPPD/shVEGF-DOX has demonstrated good tumor targetability, little side effects after systemic administration, and ideal antitumor efficacy.
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors: Shixian
authors: S
authors: Huang
authors: Kun
authors: K
authors: Shao
authors: Yang
authors: Y
authors: Liu
authors: Yuyang
authors: Y
authors: Kuang
authors: Jianfeng
authors: J
authors: Li
authors: Sai
authors: S
authors: An
authors: Yubo
authors: Y
authors: Guo
authors: Haojun
authors: H
authors: Ma
authors: Chen
authors: C
authors: Jiang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001693:Biological Transport, Active; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D036103:Nanotechnology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2