RESUMEN
Background: Bufalin (BFL, an active anti-tumor compound derived from toad venom) is limited in its application due to high toxicity and rapid metabolism of the cardiotonic steroid. Ester prodrug self-assembly nanoparticles have shown significant improved effects in addressing the above-mentioned issues. Methods: An ester bond was formed between linoleic acid and bufalin to synthesize linoleic acid-bufalin prodrug (LeB). The self-assembly nanoparticles (LeB-PSNs) containing different mass ratios of DSPE-PEG2k and prodrug (6:4, 7:3, 8:2, 9:1 and 10:0) were prepared via co-precipitation method and defined as 6:4-PSNs, 7:3-PSNs, 8:2-PSNs, 9:1-PSNs and LeB-PSNs, respectively. Further, the characterization (particle size, zeta potential, surface morphology and stability) of the nanoparticles was carried out. Finally, we evaluated the impact of different ratios of DSPE-PEG2k on the hydrolysis rate, cytotoxicity, cellular uptake, cell migration and proliferation suppression potential of the prodrug nanoparticles. Results: The linoleic acid-bufalin prodrug (LeB) was successfully synthesized. Upon the addition of DSPE-PEG2k at different weight ratios, both particle size and polydispersity index (PDI) significantly decreased, while the zeta potential increased remarkably. No significant differences in particle size, PDI and Zeta potential were observed among the 9:1, 8:2 and 7:3 PSNs. Notably, the 8:2 (w/w) DSPE-PEG2k nanoparticles exhibited superior stability, hydrolysis and cellular uptake rates, along with efficient cell cytotoxicity, cell migration and proliferation suppression. Conclusion: These findings indicate that DSPE-PEG2k could improve the performance of BFL prodrug nanoparticles, namely enhancing stability and achieving adaptive drug release by modulating the hydrolysis rate of esterase. This study therefore provides more opportunities for the development of BFL application.
Asunto(s)
Nanopartículas , Fosfatidiletanolaminas , Profármacos , Profármacos/farmacología , Profármacos/química , Portadores de Fármacos/química , Ácido Linoleico , Polietilenglicoles/química , Nanopartículas/química , Movimiento Celular , Proliferación Celular , MetilcelulosaRESUMEN
Prodrug nanoassemblies, which can refrain from large excipients, achieve higher drug loading and control drug release, have been placed as the priority in drug delivery system. Reasoning that glutathione (GSH) and reactive oxygen species (ROS) are highly upgraded in tumor tissues which makes them attractive targets for drug delivery system, we designed and synthetized a novel prodrug which utilized mono thioether bond as a linker to bridge linoleic acid (LA) and docetaxel (DTX). This mono thioether-linked conjugates (DTX-S-LA) could self-assemble into nanoparticles without the aid of much excipients. The mono thioether endowed the nanoparticles redox sensitivity resulting in specific release at the tumor tissue. Our studies demonstrated that the nanoassemblies had uniform particle size, high stability and fast release behavior. DTX-S-LA nanoassemblies outperformed DTX solution in pharmacokinetic profiles for it had longer circulation time and higher area under curve (AUC). Compared with DTX solution, the redox dual-responsive nanoassemblies had comparable cytotoxic activity. Besides, the antitumor efficacy was evaluated in mice bearing 4T1 xenograft. It turned out this nanoassemblies could enhance anticancer efficacy by increasing the dose because of higher tolerance. Overall, these results indicated that the redox sensitivity nanoassemblies may have a great potential to cancer therapy.
RESUMEN
In the present study, we attempted to develop a lecithin-stabilized micellar drug delivery system (LsbMDDs) for loading docetaxel (DTX) to enhance its therapeutic efficacy and minimize systemic toxicity. A novel DTX-loaded LsbMDDs was optimally prepared by a thin-film hydration method and then hydrated with a lecithin nanosuspension while being subjected to ultrasonication. Physical characteristics of the optimized DTX-loaded LsbMDDs formulations were examined and found to have a mean size of <200â¯nm, an encapsulation efficiency of >90%, and drug loading of >6% with stability at room temperature and at 4⯰C being longer than 2 and 7â¯days, respectively. The in vitro release of DTX from the DTX-loaded LsbMDDs was slower than that from the generic product of DTX (Tynen®). A cell viability assay demonstrated that the LsbMDDs showed better cytotoxicity than Tynen® against CT26 cancer cells. The in vivo antitumor efficacy of the DTX-loaded LsbMDDs was observed to be better than that of Tynen® in a CT26 tumor-bearing mice model. A high-dose regimen of the DTX-loaded LsbMDDs formulation showed greater inhibition of DU145 tumor growth than did Tynen®, but with less to similar systemic toxicity. An in vivo study also showed that a greater amount of drug was able to accumulate in the tumor site with the DTX-loaded LsbMDDs, and its maximal tolerable doses for single and repeated injections were 2-2.5-fold higher than those of Tynen®. In conclusion, the LsbMDDs could be a promising high drug-loaded nanocarrier for delivering hydrophobic chemotherapeutic agents that can enhance the efficacy of chemotherapy and reduce systemic toxicity.