title: PEGylated Cationic Vectors Containing a Protease-Sensitive Peptide as a miRNA Delivery System for Treating Breast Cancer.
abstract: Several targeted drug delivery systems have recently been developed to increase the bioavailability of a drug at its site of action, allowing simultaneous reduction of the total necessary drug dose as well as side effects. Here, we designed a cationic gene vector containing matrix metalloproteinase-2 (MMP2)-cleavable substrate peptides that specifically target tumor sites where MMP2 levels are high. The targeted delivery system is fabricated by linking enzyme-cleavable polyethylene glycol (PEG) derivatives to cationic β-cyclodextrin-polyethylenimine conjugates, which reduce the toxicity of polyethylenimine and condense the therapeutic cargo. In the present study, tumor suppressor microRNA miR-34a, which suppresses onset and progression of many types of cancers, was investigated for its therapeutic potential for treating breast cancer. The PEG coating markedly reduces nonspecific interaction between cationic particles and serum proteins, permitting accumulation at the target site; subsequent peptide cleavage by MMP2 facilitates miR-34a delivery into tumor cells. The nanopreparation shows excellent stability, and its internalization, tumor targeting, and antitumor efficacy in vitro and in vivo are better than those of a nanopreparation containing MMP2-uncleavable peptide.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Fan
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
authors.forename: Tao
authors.identifier: 0000-0002-9866-9911
authors.initials: T
authors.lastname: Gong
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
authors.forename: Zhirong
authors.identifier: 0000-0001-9118-5394
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
authors.forename: Xun
authors.identifier: 0000-0002-4671-352X
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D002412:Cations / Q000008:administration & dosage / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D035683:MicroRNAs / Q000008:administration & dosage / Q000737:chemistry*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D002412:Cations; D035683:MicroRNAs; D010455:Peptides; D047392:beta-Cyclodextrins; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D010447:Peptide Hydrolases; D020778:Matrix Metalloproteinase 2
keywords: MMP2-cleavable; breast cancer; gene vector; miR-34a