title: The targeted transduction of MMP-overexpressing tumor cells by ACPP-HPMA copolymer-coated adenovirus conjugates.
abstract: We have designed and tested a new way to selectively deliver HPMA polymer-coated adenovirus type 5 (Ad5) particles into matrix metalloproteinase (MMP)-overexpressing tumor cells. An activatable cell penetrating peptide (ACPP) was designed and attached to the reactive 4-nitrophenoxy groups of HPMA polymers by the C-terminal amino acid (asparagine, N). ACPPs are activatable cell penetrating peptides (CPPs) with a linker between polycationic and polyanionic domains, and MMP-mediated cleavage releases the CPP portion and its attached cargo to enable cell entry. Our data indicate that the transport of these HPMA polymer conjugates by a single ACPP molecule to the cytoplasm occurs via a nonendocytotic and concentration-independent process. The uptake was observed to finish within 20 minutes by inverted fluorescence microscopy. In contrast, HPMA polymer-coated Ad5 without ACPPs was internalized solely by endocytosis. The optimal formulation was not affected by the presence of Ad5 neutralizing antibodies during transduction, and ACPP/polymer-coated Ad5 also retained high targeting capability to several MMP-overexpressing tumor cell types. For the first time, ACPP-mediated cytoplasmic delivery of polymer-bound Ad5 to MMP-overexpressing tumor cells was demonstrated. These findings are significant, as they demonstrate the use of a polymer-based system for the targeted delivery into MMP-overexpressing solid tumors and highlight how to overcome major cellular obstacles to achieve intracellular macromolecular delivery.
authors.affiliation: Department of Pathology and Stomatology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China; Department of Pathology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Shuhua
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology and Stomatology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China; Department of Pathology and Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Juanzhi
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology and Stomatology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China; Department of Pathology and Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Long
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Pathology and Stomatology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China; Department of Pathology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000256:Adenoviridae / Q000737:chemistry*; D000595:Amino Acid Sequence; D001692:Biological Transport; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008969:Molecular Sequence Data; D012449:Safety; D014161:Transduction, Genetic / Q000379:methods*
chemical_list: D000178:Acrylamides; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D020782:Matrix Metalloproteinases; C032976:N-(2-hydroxypropyl)methacrylamide