Acetal-Linked Paclitaxel Prodrug Micellar Nanoparticles as a Versatile and Potent Platform for Cancer Therapy

被引:152
作者
Gu, Yudan
Zhong, Yinan
Meng, Fenghua [1 ]
Cheng, Ru
Deng, Chao
Zhong, Zhiyuan
机构
[1] Soochow Univ, Biomed Polymers Lab, Dept Polymer Sci & Engn, Coll Chem Chem Engn & Mat Sci, Suzhou 215123, Peoples R China
基金
中国国家自然科学基金;
关键词
BLOCK-COPOLYMER MICELLES; POLYMERIC MICELLES; DRUG-DELIVERY; CONTROLLED-RELEASE; PHASE-I; ANTICANCER; CONJUGATE; DESIGN; DOCETAXEL; EFFICACY;
D O I
10.1021/bm400615n
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Endosomal pH-activatable paclitaxel (PTX) prodrug micellar nanoparticles were designed and prepared by conjugating PTX onto water-soluble poly(ethylene glycol)-b-poly(acrylic acid) (PEG-PAA) block copolymers via an acid-labile acetal bond to the PAA block and investigated for potent growth inhibition of human cancer cells in vitro. PTX was readily conjugated to PEG-PAA with high drug contents of 21.6, 27.0, and 42.8 wt % (denoted as PTX prodrugs 1, 2, and 3, respectively) using ethyl glycol vinyl ether (EGVE) as a linker. The resulting PTX conjugates had defined molecular weights and self-assembled in phosphate buffer (PB, pH 7.4, 10 mM) into monodisperse micellar nanoparticles with average sizes of 158.3-180.3 nm depending on PTX contents. The in vitro release studies showed that drug release from PTX prodrug nanoparticles was highly pH-dependent, in which ca. 86.9%, 66.4% and 29.0% of PTX was released from PTX prodrug 3 at 37 degrees C in 48 h at pH 5.0, 6.0, and pH 7.4, respectively. MTT assays showed that these pH-sensitive PTX prodrug nanoparticles exhibited high antitumor effect to KB and HeLa cells (IC50 = 0.18 and 0.9 mu g PTX equiv/rnL, respectively) as well as PTX-resistant A549 cells. Notably, folate-decorated PTX prodrug micellar nanoparticles based on PTX prodrug 3 and 20 wt % folate-poly(ethylene glycol)-b-poly(D,L-lactide) (FA-PEG-PLA) displayed apparent targetability to folate receptor-overexpressing KB cells with IC50 over 12 times lower than nontargeting PTX prodrug 3 under otherwise the same conditions. Furthermore, PTX prodrug nasioparticles could also load doxorubicin (DOX) to simultaneously release PTX and DOX under mildly acidic pH. These acetal-linked PTX prodrug micellar nanoparticles have appeared as a highly versatile and potent platform for cancer therapy.
引用
收藏
页码:2772 / 2780
页数:9
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