A facile and universal method to achieve liposomal remote loading of non-ionizable drugs with outstanding safety profiles and therapeutic effect.
10.1016/j.apsb.2020.08.001
- Author:
Shuang ZHOU
1
;
Jinbo LI
1
;
Jiang YU
1
;
Liyuan YANG
1
;
Xiao KUANG
1
;
Zhenjie WANG
1
;
Yingli WANG
1
;
Hongzhuo LIU
1
;
Guimei LIN
2
;
Zhonggui HE
1
;
Dan LIU
3
;
Yongjun WANG
1
Author Information
1. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
2. School of Pharmaceutical Science, Shandong University, Jinan 250012, China.
3. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
- Publication Type:Journal Article
- Keywords:
AUC0‒t, area under the curve;
CR, creatinine;
CTX, cabazitaxel;
Cabazitaxel;
Cancer;
Chol, cholesterol;
DA, trans-2-butene-1,4-dicarboxylic acid;
DA-CTX, cabazitaxel trans-2-butene-1,4-dicarboxylic acid derivate;
DSPC, 1,2-dioctadecanoyl-sn-glycero-3-phophocholine;
DSPE-PEG2000, 2-distearoyl-snglycero-3-phosphoethanolamine-N-[methyl(polyethylene glycol)-2000;
EE, encapsulation efficiency;
EPR, enhanced permeability and retention;
GA, glutaric anhydride;
GA-CTX, cabazitaxel glutaric acid derivate;
Lung metastasis;
MED, minimum effective dose;
MPS, mononuclear phagocyte system;
MTD, maximum tolerated dose;
Non-ionizable drugs;
PCa, prostate cancer;
PSA, prostate-specific antigen;
Remote loading liposome;
SA, succinic anhydride;
SA-CTX, cabazitaxel succinic acid derivate;
Safety;
TI, therapeutic index;
Tolerated doses;
Weak acid derivatives;
lipo DA-CTX, DA-CTX liposome;
lipo GA-CTX, GA-CTX liposome;
lipo SA-CTX, SA-CTX liposome;
mCRPCa, metastatic castration-resistant prostate cancer
- From:
Acta Pharmaceutica Sinica B
2021;11(1):258-270
- CountryChina
- Language:English
-
Abstract:
Liposomes have made remarkable achievements as drug delivery vehicles in the clinic. Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs, but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents, thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy. In this study, a series of weak acid drug derivatives were designed by a simplistic one step synthesis, which could be remotely loaded into liposomes by pH gradient method. Cabazitaxel (CTX) weak acid derivatives were selected to evaluate regarding its safety profiles, pharmacodynamics, and pharmacokinetics. CTX weak acid derivative liposomes were superior to Jevtana® in terms of safety profiles, including systemic toxicity, hematological toxicity, and potential central nerve toxicity. Specifically, it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons. Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.
