title: Enhancing cancer targeting and anticancer activity by a stimulus-sensitive multifunctional polymer-drug conjugate.
abstract: Undesirable physicochemical properties, low tumor targeting, insufficient cell internalization, acquired drug resistance, and severe side effects significantly limit the applications of anticancer drugs. In this study, to improve the tumor targeting and drug efficacy of the poorly water-soluble drug, doxorubicin (DOX), a novel drug delivery platform (PEG-ppTAT-DOX) was developed, which contained a polyethylene glycol (PEG), a matrix metalloproteinase 2 (MMP2)-sensitive peptide linker (pp), a cell penetrating peptide (TAT), and a model drug (doxorubicin). The prepared drug platform possessed several key features, including: (i) the nanoparticle formation via the self-assembly; (ii) prevention of the non-specific interaction via the PEGylation; (iii) tumor targeting via the MMP2-mediated PEG deshielding and exposure of the TAT; (iv) the TAT-mediated cell internalization; (v) the TAT-induced endosomal escape; (vi) the inhibition of P-glycoprotein mediated drug efflux; and (vii) the TAT-medicated nuclear translocation. These cooperative functions ensured the improved tumor targetability, enhanced tumor cell internalization, improved intracellular distribution, and potentiated anticancer activity. Compared to the multi-component nanocarriers, the proposed simple but multifunctional polymer-drug conjugate might have greater potential for tumor-targeted drug delivery and enhanced chemotherapy.
authors.affiliation: Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Health Science Center, Kingsville, TX 78363, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Health Science Center, Kingsville, TX 78363, United States. Electronic address: lzhu@tamhsc.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D015696:Gene Products, tat / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D015696:Gene Products, tat; D011092:Polyethylene Glycols; D004317:Doxorubicin; D053148:Caspase 3; D053179:Caspase 7; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Cell penetrating peptide; Drug delivery; Matrix metalloproteinase 2; Multifunctional; Polymer-drug conjugate; Tumor targeting