title: Enzyme-responsive peptide dendrimer-gemcitabine conjugate as a controlled-release drug delivery vehicle with enhanced antitumor efficacy.
abstract: Stimuli-responsive peptide dendrimer-drug conjugates have presented significant potential for cancer therapy. To develop an effective nanoscale chemotherapeutic prodrug, we developed a novel enzyme-responsive PEGylated lysine peptide dendrimer-gemcitabine conjugate (Dendrimer-GEM) based nanoparticle via the highly efficient click reaction. Owing to the glycyl phenylalanyl leucyl glycine tetra-peptide (GFLG) as an enzyme-cleavable linker to conjugate gemcitabine (GEM), the prepared nanoparticles were able to release drug significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24h. This nanoparticle demonstrated enhanced antitumor efficacy in a 4T1 murine breast cancer model without obvious systemic toxicity, resulting in significantly suppressed relative tumor volumes (86.17±38.27%) and a 2-fold higher value of tumor growth inhibition (∼90%) than GEM·HCl treatment. These results suggest that the PEGylated peptide dendrimer-gemcitabine conjugate can be an effective antitumor agent for breast cancer therapy. Statement of Significance We found that the functionalized dendrimer based nanoscale drug delivery vehicles exhibited enhanced therapeutic indexes and reduced toxicity as compared to the free drug gemcitabine. Compared with current nanoparticles, such as dendritic anticancer drug delivery systems, the new design was capable of self-assembling into nanoscale particles with sizes of about 80-110nm, which is suitable as antitumor drug delivery vehicle due to the potential longer intravascular half-life and higher accumulation in tumor tissue via EPR effect. Owing to the optimized architecture, the system was given the enzyme-responsive drug release feature, and showed excellent antitumor activity on the 4T1 breast tumor model due to the evidences from tumor growth curves, immunohistochemical analysis and confocal laser scanning microscopy. Meanwhile, no significant side effect was observed by histological analysis. This study demonstrated that PEGylated peptide dendritic architecture may be used as efficient and safe nanoscale drug delivery vehicle for cancer therapy.
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Dayi
authors.initials: D
authors.lastname: Pan
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Jiani
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Radiology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Ashika
authors.initials: A
authors.lastname: Bains
authors.affiliation: Department of Radiology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Guys
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: luokui@scu.edu.cn.
authors.forename: Kui
authors.initials: K
authors.lastname: Luo
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Qiyong
authors.initials: Q
authors.lastname: Gong
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China. Electronic address: zwgu@scu.edu.cn.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D050091:Dendrimers; D010455:Peptides; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Antitumor efficacy; Drug delivery; Nanoscale; Peptide dendrimer