Development Of Novel Liposome-Encapsulated Combretastatin A4 Acylated Derivatives: Prodrug Approach For Improving Antitumor Efficacy
| Autor: | Zhiqin Fu, Kedan Chu, Yongwei Gu, Youfa Xu, Gao Baoan, Jianzhong Yao, Juanjuan Ma, Wei Xu, Chen Jianming |
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| Rok vydání: | 2019 |
| Předmět: |
Liposome
Biodistribution Chemistry Organic Chemistry Biophysics Pharmaceutical Science Bioengineering 02 engineering and technology General Medicine Prodrug Pharmacology 010402 general chemistry 021001 nanoscience & nanotechnology 01 natural sciences Chloride In vitro 0104 chemical sciences Biomaterials Pharmacokinetics In vivo Drug Discovery Drug delivery medicine 0210 nano-technology medicine.drug |
| Zdroj: | International Journal of Nanomedicine. 14:8805-8818 |
| ISSN: | 1178-2013 |
| DOI: | 10.2147/ijn.s210938 |
| Popis: | Purpose The objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect. Methods The prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3'-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies. Results The liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue. Conclusion These results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy. |
| Databáze: | OpenAIRE |
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