title: Stimulus-Responsive Short Peptide Nanogels for Controlled Intracellular Drug Release and for Overcoming Tumor Resistance.
abstract: Multidrug resistance (MDR) poses a major burden to cancer treatment. As one important factor contributing to MDR, overexpression of P-glycoprotein (P-gp) results in a reduced intracellular drug accumulation. Hence, the ability to effectively block the efflux protein and to accumulate the therapeutics in cancer cells is of great significance in clinical practice. In this work, we successfully developed a smart stimulus-responsive short peptide-assembled system, termed as PD/VER nanogels, which synergistically combined the acid-activatable antitumor prodrug doxorubicin (Dox) with the P-gp inhibitor verapamil (VER) for reversing MDR. Systematic studies demonstrated that such an inhibitor-encapsulated nanogel could effectively enhance the accumulation of Dox in resistant cancer cells, thereby revealing significantly higher antitumor activity compared to free Dox molecules. This work showed that the assembly of bioactive agents with a synergistic effect into nano-drugs could provide a useful strategy to overcome cancer drug resistance.
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637371, Singapore.
authors.forename: Linna
authors.initials: L
authors.lastname: Lyu
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637371, Singapore.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637371, Singapore.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637371, Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Mu
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637371, Singapore.
authors.forename: Haolun
authors.initials: H
authors.lastname: Cheong
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637371, Singapore.|Institute of Materials Research and Engineering, A*STAR, Singapore, 117602, Singapore.
authors.forename: Bengang
authors.identifier: http://orcid.org/0000-0002-8391-1234
authors.initials: B
authors.lastname: Xing
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D000080385:Nanogels; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D014700:Verapamil / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003692:Delayed-Action Preparations; D000080385:Nanogels; D011355:Prodrugs; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D004317:Doxorubicin; D011094:Polyethyleneimine; D014700:Verapamil
keywords: drug delivery; glycoprotein; multidrug resistance; nanogels; peptides; self-assembly