Yani Yang1, Yuezhu Zhao1, Jie Liu1,2, Chen Ge1, Weiwei Zhang1, Yue Zhang1, Junji Wang1, Guohao Sun1, Xiujun Lin1, Xiaohong Lu1, Xiang Tang1, Jun He3, Weigen Lu4, Jing Qin5. 1. National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, 201203, People's Republic of China. 2. Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People's Republic of China. 3. National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, 201203, People's Republic of China. chinaynhe@163.com. 4. National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, 201203, People's Republic of China. sipiluwg@163.com. 5. Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People's Republic of China. qinjing@fudan.edu.cn.
Abstract
PURPOSE: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency. METHODS: Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively. RESULTS: The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects. CONCLUSIONS: The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.
PURPOSE: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency. METHODS: Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively. RESULTS: The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects. CONCLUSIONS: The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.
Authors: Florence Atrafi; Ruben A G van Eerden; Marte A M van Hylckama Vlieg; Esther Oomen-de Hoop; Peter de Bruijn; Martijn P Lolkema; Adriaan Moelker; Cristianne J Rijcken; Rob Hanssen; Alex Sparreboom; Ferry A L M Eskens; Ron H J Mathijssen; Stijn L W Koolen Journal: Clin Cancer Res Date: 2020-04-22 Impact factor: 12.531
Authors: Aditya Ganju; Murali M Yallapu; Sheema Khan; Stephen W Behrman; Subhash C Chauhan; Meena Jaggi Journal: Drug Resist Updat Date: 2014-04-05 Impact factor: 18.500