Journal
ACTA PHARMACEUTICA SINICA B
Volume 11, Issue 1, Pages 258-270Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2020.08.001
Keywords
Non-ionizable drugs; Weak acid derivatives; Remote loading liposome; Cabazitaxel; Safety; Tolerated doses; Cancer; Lung metastasis
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Funding
- National Nature Science Foundation of China [U1608283]
- Career Development Program for Young and Middle-aged Teachers in Shenyang Pharmaceutical University
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Liposomes have been successful drug delivery vehicles in the clinic, particularly with the development of remote drug loading techniques. Weak acid drug derivatives were designed and loaded into liposomes for improved safety profiles and reduced toxicity, showing significant advantages in prostate cancer and metastatic cancer therapy over traditional treatments like Jevtana (R).
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 (R) 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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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