title: Dual Enzymatic Reaction-Assisted Gemcitabine Delivery Systems for Programmed Pancreatic Cancer Therapy.
abstract: Dual enzymatic reactions were introduced to fabricate programmed gemcitabine (GEM) nanovectors for targeted pancreatic cancer therapy. Dual-enzyme-sensitive GEM nanovectors were prepared by conjugation of matrix metalloproteinase-9 (MMP-9) detachable poly(ethylene glycol) (PEG), cathepsin B-cleavable GEM, and targeting ligand CycloRGD to CdSe/ZnS quantum dots (QDs). The GEM nanovectors decorated with a PEG corona could avoid nonspecific interactions and exhibit prolonged blood circulation time. After GEM nanovectors were accumulated in tumor tissue by the enhanced permeability and retention (EPR) effect, the PEG corona can be removed by overexpressed MMP-9 in tumor tissue and RGD would be exposed, which was capable of facilitating cellular internalization. Once internalized into pancreatic cancer cells, the elevated lysosomal cathepsin B could further promote the release of GEM. By employing dual enzymatic reactions, the GEM nanovectors could achieve prolonged circulation time while maintaining enhanced cellular internalization and effective drug release. The proposed mechanism of the dual enzymatic reaction-assisted GEM delivery system was fully investigated both in vitro and in vivo. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2',2'-difluorodeoxyuridine (dFdU) could be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.
authors.affiliation: MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou, 310027, China.
authors.forename: Haijie
authors.initials: H
authors.lastname: Han
authors.affiliation: Philipps Universität Marburg , Fachbereich Physik, Renthof 7, 35037, Marburg, Germany.
authors.forename: Daniel
authors.identifier: 0000-0002-2876-5545
authors.initials: D
authors.lastname: Valdepérez
authors.affiliation: MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou, 310027, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Department of Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University , 88 Jiefang Road, Hangzhou, Zhejiang Province, 310009, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou, 310027, China.
authors.forename: Zuhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University , 88 Jiefang Road, Hangzhou, Zhejiang Province, 310009, China.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Philipps Universität Marburg , Fachbereich Physik, Renthof 7, 35037, Marburg, Germany.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pelaz
authors.affiliation: Philipps Universität Marburg , Fachbereich Physik, Renthof 7, 35037, Marburg, Germany.
authors.forename: Wolfgang J
authors.identifier: 0000-0003-1672-6650
authors.initials: WJ
authors.lastname: Parak
authors.affiliation: MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University , Hangzhou, 310027, China.
authors.forename: Jian
authors.identifier: 0000-0001-9870-4038
authors.initials: J
authors.lastname: Ji
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D003841:Deoxycytidine; D020780:Matrix Metalloproteinase 9; D000093542:Gemcitabine
keywords: enzyme sensitive; gemcitabine; pancreatic cancer therapy; programmed targeting; tumor microenvironment