title: pH-responsive polymer-drug conjugates as multifunctional micelles for cancer-drug delivery.
abstract: We developed a novel linear pH-sensitive conjugate methoxy poly(ethylene glycol)-4β-aminopodophyllotoxin (mPEG-NPOD-I) by a covalently linked 4β-aminopodophyllotoxin (NPOD) and PEG via imine bond, which was amphiphilic and self-assembled to micelles in an aqueous solution. The mPEG-NPOD-I micelles simultaneously served as an anticancer drug conjugate and as drug carriers. As a drug conjugate, mPEG-NPOD-I showed a significantly faster NPOD release at a mildly acidic pH of 5.0 and 4.0 than a physiological pH of 7.4. Notably, it was confirmed that this drug conjugate could efficiently deliver NPOD to the nuclei of the tumor cells and led to much more cytotoxic effects to A549, Hela, and HepG2 cancer cells than the parent NPOD. The half maximal inhibitory concentration (IC₅₀) of mPEG-NPOD-I was about one order magnitude lower than that of the NPOD. In vivo, mPEG-NPOD-I reduced the size of the tumors significantly, and the biodistribution studies indicated that this drug conjugate could selectively accumulate in tumor tissues. As drug carriers, the mPEG-NPOD-I micelles encapsulated hydrophobic PTX with drug-loading efficiencies of 57% and drug-loading content of 16%. The loaded PTX also showed pH-triggered fast release behavior, and good additive cytotoxicity effect was observed for the PEG-NPOD-I/PTX. We are convinced that these multifunctional drug conjugate micelles have tremendous potential for targeted cancer therapy.
authors: Key Laboratory of Mountain Ecological Restoration and Bioresource Utilization, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, People's Republic of China.
authors: Yang
authors: Y
authors: Kang
authors: Wei
authors: W
authors: Ha
authors: Ying-Qian
authors: YQ
authors: Liu
authors: Yuan
authors: Y
authors: Ma
authors: Min-Min
authors: MM
authors: Fan
authors: Li-Sheng
authors: LS
authors: Ding
authors: Sheng
authors: S
authors: Zhang
authors: Bang-Jing
authors: BJ
authors: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol