Jain Sanyog, Bhankur Neha, Swarnakar Nitin K, Thanki Kaushik
Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S., Nagar (Mohali), Punjab, 160062, India.
Pharm Res. 2015 Oct;32(10):3282-92. doi: 10.1007/s11095-015-1706-2. Epub 2015 May 13.
The present work focuses on design and development of surface functionalized LCNPs for improving tumor delivery of DTX.
Phytantriol based "stealth" LCNPs were prepared using hydrotrope method and optimized. The potential of developed formulation was further assessed using cell culture experiments, in vivo pharmacokinetics, in vivo pharmacodynamics and toxicity studies.
A biphasic drug release pattern was observed with sustained release of drug till 72 h. In vitro cell culture experiments revealed efficient internalization within MCF-7 cells with 25.80-fold decrease in IC50 value for PEG-LCNPs as compared to free DTX. Mechanistic insights demonstrated preferential co-localization of LCNPs in the vicinity of the nucleus. Furthermore, in vivo pharmacokinetic studies revealed 14.45-fold enhancement in circulation half-life of PEG-LCNPs as compared to marketed formulation Taxotere®. In vivo efficacy studies PEG-LCNPs in DMBA induced breast cancer model revealed ~81% reduction in the tumor burden compared to Taxotere® which caused/achieve only 47% reduction or showed only 47% decrease. Furthermore, safety profile was noted for PEG-LCNPs as compared to Taxotere®, measured as a function of hepato- and nephro-toxicity.
Surface functionalization of LCNPsis a viable approach for improving the therapeutic potential of DTX.
本研究聚焦于表面功能化脂质体纳米粒（LCNPs）的设计与开发，以改善多西他赛（DTX）的肿瘤递送效果。
采用助溶剂法制备并优化了基于植烷三醇的“隐形”LCNPs。通过细胞培养实验、体内药代动力学、体内药效学和毒性研究进一步评估所开发制剂的潜力。
观察到双相药物释放模式，药物可持续释放至72小时。体外细胞培养实验表明，与游离DTX相比，PEG-LCNPs在MCF-7细胞内有效内化，IC50值降低了25.80倍。机制研究表明LCNPs优先在细胞核附近共定位。此外，体内药代动力学研究显示，与市售制剂泰索帝®相比，PEG-LCNPs的循环半衰期提高了14.45倍。在二甲基苯并蒽（DMBA）诱导的乳腺癌模型中进行的体内疗效研究表明，与泰索帝®相比，PEG-LCNPs使肿瘤负荷降低了约81%，而泰索帝®仅使肿瘤负荷降低47%或显示仅降低47%。此外，与泰索帝®相比，PEG-LCNPs的安全性良好，通过肝毒性和肾毒性进行衡量。
LCNPs的表面功能化是提高DTX治疗潜力的可行方法。
