Preliminary study on fabrication, characterization and synergistic anti-lung cancer effects of self-assembled micelles of covalently conjugated celastrol–polyethylene glycol–ginsenoside Rh2

Drug Delivery

Ding Qu¹  Mengfei Guo¹  Chenyi Fan¹  XiaoYue Zhou²  Tong Zhou²  Peng Li³  Yang Ling⁴ 

[1] Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, P.R. China;Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, P.R. China, an;Department of Oncology, Changzhou Cancer Hospital of Soochow University, Changzhou, P.R. China;Department of Oncology, Changzhou Cancer Hospital of Soochow University, Changzhou, P.R. China;Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, P.R. China;Department of Oncology, Changzhou Cancer Hospital of Soochow University, Changzhou, P.R. China;Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou, P.R. Chin;

关键词: Celastrol;    ginsenoside Rh2;    micelle;    anti-lung cancer;    drug release;   

DOI  :  10.1080/10717544.2017.1326540

来源: Taylor & Francis

【 摘 要 】

The aim of this study was to develop an amphipathic polyethylene glycol (PEG) derivative that was bi-terminally modified with celastrol and ginsenoside Rh2 (Celastrol-PEG-G Rh2). Such derivative was capable of forming novel, celastrol-loaded polymeric micelles (CG-M) for endo/lysosomal delivery and thereby synergistic treatment of lung cancer. Celastrol-PEG-G Rh2 with a yield of 55.6% was first synthesized and characterized. Its critical micellar concentration was 1 × 10−5 M, determined by pyrene entrapment method. CG-M had a small particle size of 121.53 ± 2.35 nm, a narrow polydispersity index of 0.214 ± 0.001 and a moderately negative zeta potential of –23.14 ± 3.15 mV. Celastrol and G Rh2 were rapidly released from CG-M under acidic and enzymatic conditions, but slowly released in normal physiological environments. In cellular studies, the internalization of celastrol and G Rh2 by human non-small cell lung cancer (A549) cells treated with CG-M was 5.8-fold and 1.8-fold higher than that of non-micelle control. Combinational therapy of celastrol and G Rh2 using CG-M exhibited synergistic anticancer activities in cell apoptosis and proliferation assays via rapid drug release within endo/lysosomes. Most importantly, the celastrol in CG-M exhibited a long elimination half-life of 445.3 ± 43.5 min and an improved area under the curve of 645060.8 ± 63640.7 ng/mL/h, that were 1.03-fold and 2.44-fold greater than those of non-micelle control, respectively. These findings suggest that CG-M is a promising vector for precisely releasing anticancer drugs within the tumor cells, and thereby exerts an improved synergistic anti-lung cancer effect.

【 授权许可】

CC BY