title: Enzyme-Sensitive and Amphiphilic PEGylated Dendrimer-Paclitaxel Prodrug-Based Nanoparticles for Enhanced Stability and Anticancer Efficacy.
abstract: In this study, we prepared a smart polymeric vehicle for the hydrophobic drug paclitaxel (PTX) that allowed a maximum steady-state circulation and a fast intracellular release in tumors. PTX was linked to the Janus PEGylated (PEG = poly(ethylene glycol)) peptide dendrimer via an enzyme-sensitive linker glycylphenylalanylleucylglycine tetrapeptide by efficient click reaction, resulting in Janus dendritic prodrug with 20.9% PTX content. The prodrug self-assembled into nanoscale particles with appropriate nanosizes, compact morphology, and negative surface charge. In addition to high stability during circulation, as demonstrated by protein adsorption assays and drug release studies in the cancer's intracellular environment, the nanoparticles were able to quickly release the drug intact in its original molecular structure, as verified via high-performance liquid chromatography and mass spectrometry analyses. Compared to free PTX, the enzyme-responsive feature of nanoparticles promoted higher cytotoxicity against 4T1 cancer cells and much lower cytotoxicity against normal cells. The nanoparticles accumulated in the tumor and were retained for an extended period of time, as confirmed by fluorescence imaging. Therefore, these nanoparticles exhibited significantly enhanced antitumor efficiency in the 4T1 breast cancer model as indicated by the observed inhibition of angiogenesis and proliferation as well as induction of apoptosis. Moreover, the nanoparticles reduced the occurrence of side effects, particularly dose-limited toxicities, as monitored by body weight and hematological features. Hence, our Janus PEGylated dendrimer-PTX prodrug-based nanoparticles may potentially serve as nanoscale vehicles for breast cancer therapy.
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University , Chengdu 610041, China.|State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University , Chengdu 610041, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University , Nanjing 210009, China.|National Engineering Research Center for Biomaterials, Sichuan University , Chengdu 610064, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Radiology, Wayne State University , Detroit, Michigan 48201, United States.
authors.forename: Jiani
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Radiology, Wayne State University , Detroit, Michigan 48201, United States.
authors.forename: Ashika
authors.initials: A
authors.lastname: Bains
authors.affiliation: Department of Radiology, Wayne State University , Detroit, Michigan 48201, United States.
authors.forename: Jesse
authors.initials: J
authors.lastname: Hu
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: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University , Chengdu 610041, China.
authors.forename: Kui
authors.identifier: http://orcid.org/0000-0002-3536-1485
authors.initials: K
authors.lastname: Luo
authors.affiliation: Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University , Chengdu 610041, China.|College of Materials Science and Engineering, Nanjing Tech University , Nanjing 211816, China.|National Engineering Research Center for Biomaterials, Sichuan University , Chengdu 610064, China.
authors.forename: Zhongwei
authors.identifier: http://orcid.org/0000-0003-1547-6880
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050091:Dendrimers; D016503:Drug Delivery Systems; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D017239:Paclitaxel; D011092:Polyethylene Glycols; D011355:Prodrugs
chemical_list: D050091:Dendrimers; D011355:Prodrugs; D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: Janus dendrimer; drug delivery; enzyme-sensitive; prodrug; stability