Didi Yan,1 Xinyue Ma,1 Yixin Hu,1 Guogang Zhang,1 Beibei Hu,1 Bo Xiang,2 Xiaokun Cheng,1,3 Yongshuai Jing,1 Xi Chen1,4 

1College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, People’s Republic of China; 2Department of Psychiatry, Fundamental and Clinical Research on Mental Disorders Key Laboratory of Luzhou, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3New Drug Research & Development Co., Ltd., North China Pharmaceutical Group Corporation, Shijiazhuang, 050015, People’s Republic of China; 4Hebei Research Center of Pharmaceutical and Chemical Engineering, Shijiazhuang, 050018, People’s Republic of China

Correspondence: Xi Chen, College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, 26 Yuxiang Road, Shijiazhuang, 050018, People’s Republic of China, Tel +86-15203319951, Email chenxi0310@163.com

Background: Paclitaxel-induced blood system disorders and peripheral neuropathy impede the progress of new formulations in clinical trials.
Purpose of Study: To mitigate these adverse effects by developing and validating a prodrug strategy that encapsulates a glucose-paclitaxel conjugate within nanomicelles.
Material and Methods: Succinic anhydride was used as a bridge to couple C2’-paclitaxel with methyl 2’-glucopyranose and prepare a glucose-paclitaxel conjugate. Nanomicelles were prepared via solid-phase dispersion, and dynamic light scattering was used to determine their average diameter and the polydispersity index. High-performance liquid chromatography (HPLC) was employed to evaluate drug-loading capacity and encapsulation efficiency. Pharmacokinetic studies and in vivo toxicity assays were performed in Sprague-Dawley (SD) rats.
Results: The nanomicellar product exhibited a spherical shape with a particle size distribution between 20– 60 nm, a PDI of 0.26 ± 0.01, and an encapsulation efficiency of 95.59 ± 1.73%. The pharmacokinetic profile of glucose-paclitaxel nanomicelles in SD rats was markedly different from that of the paclitaxel solution group. Notably, the plasma drug concentration of glucose-paclitaxel nanomicelles was significantly higher than the paclitaxel solution 15 minutes post-administration, with a Vz at only 40% of that of the paclitaxel solution, while the AUC0-∞ was five times greater than that of the paclitaxel solution. Ultimately, glucose-paclitaxel nanomicelles effectively alleviated blood system disorders and peripheral neuropathy in SD rats.
Conclusion: The encapsulation of glucose-paclitaxel conjugates within nanomicelles presents a viable solution to the dose-limiting toxicities associated with paclitaxel, offering new perspectives on safety for the development of paclitaxel-based therapeutics.

Keywords: glucose-paclitaxel conjugate, nanomicelles, pharmacokinetics, toxicity of paclitaxel