title: Novel free-paclitaxel-loaded redox-responsive nanoparticles based on a disulfide-linked poly(ethylene glycol)-drug conjugate for intracellular drug delivery: synthesis, characterization, and antitumor activity in vitro and in vivo.
abstract: To address the obstacles facing cancer chemotherapeutics, including toxicity, side effects, water insolubility, and lack of tumor selectivity, a novel stimuli-responsive drug-delivery system was developed based on paclitaxel-loaded poly(ethylene glycol)-disulfide-paclitaxel conjugate nanoparticles (PEG-SS-PTX/PTX NPs). The formulation emphasizes several benefits, including polymer-drug conjugates/prodrugs, self-assembled NPs, high drug content, redox responsiveness, and programmed drug release. The PTX-loaded, self-assembled NPs, with a uniform size of 103 nm, characterized by DLS, TEM, XRD, DSC, and (1)H NMR, exhibited excellent drug-loading capacity (15.7%) and entrapment efficiency (93.3%). PEG-SS-PTX/PTX NPs were relatively stable under normal conditions but disassembled quickly under reductive conditions, as indicated by their triggered-aggregation phenomena and drug-release profile in the presence of dithiothreitol (DTT), a reducing agent. Additionally, by taking advantage of the difference in the drug-release rates between physically loaded and chemically conjugated drugs, a programmed drug-release phenomenon was observed, which was attributed to a higher concentration and longer action time of the drugs. The influence of PEG-SS-PTX/PTX NPs on in vitro cytotoxicity, cell cycle progression, and cellular apoptosis was determined in the MCF-7 cell line, and the NPs demonstrated a superior anti-proliferative activity associated with PTX-induced cell cycle arrest in G2/M phase and apoptosis compared to their nonresponsive counterparts. Moreover, the redox-responsive NPs were more efficacious than both free PTX and the non-redox-responsive formulation at equivalent doses of PTX in a breast cancer xenograft mouse model. This redox-responsive PTX drug delivery system is promising and can be explored for use in effective intracellular drug delivery.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Chuan
authors.forename: Qin
authors.initials: Q
authors.lastname: Song
authors.forename: Jialiang
authors.initials: J
authors.lastname: Lin
authors.forename: Xianhui
authors.initials: X
authors.lastname: Chen
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Wenbing
authors.initials: W
authors.lastname: Dai
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000737:chemistry* / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D011108:Polymers; D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: paclitaxel; polymeric nanoparticles; polymer−drug conjugates/prodrugs; programmed drug release; redox-response