遵义医科大学学报2025，Vol.48Issue(5)：443-454,12.
α-(+)-硫辛酸-二甲双胍纳米粒子抗肿瘤作用研究
Study on the anti-tumor effect of α-(+)-lipoic acid-metformin nanoparticles
摘要
Abstract
Objective Nanodrugs was constructed by the self-assembling of a novel amphiphilic molecule com-posed of two non-cytotoxic natural anti-tumor active substances,α-(+)-lipoic acid(LA)and metformin(MET),and was stabilized by the ring-opening polymerization of the 1,2-dithiolane of LA to achieve synergistic anti-tumor effects with high biosafety.Methods After the self-assembly of"Metformin lipoate"in water,cross-linked micelles MET@cLANs were successfully obtained through 365 nm ultraviolet induced ring-opening poly-merization of the 1,2-dithiolane of LA;Energy dispersive spectroscopy(EDS)was used to determinate the drug ratio of LA to MET;Dynamic light scattering(DLS)was used to measure the particle size and ζ potential;In vitro release assay was used to detect the responsive drug release ability of the MET@cLANs to glutathione(GSH);Cytotoxicity experiments are used to screen for in vitro anti-tumor activity and indications;Combination index CI was used to evaluate the synergistic effect of LA and MET;Hemolytic test and hemagglutination assay were used to verify the blood compatibility;Balb/c mice were used for the acute toxicity test and subacute toxici-ty assessment;In vivo pharmacokinetic study was conducted on SD rats;Validation of in vivo anti-tumor effect on HT29 subcutaneous solid tumor using Balb/c-nude mice.Results The particle size of the MET@cLANs is 15～20 nm;ζ potential-10.1 mV;LA∶MET is 1∶0.86 in MET@cLANs;the cumulative release of MET in vitro within 24 h exceeds 80％(10 mmol/L GSH);MET@cLANs has the most prominent killing effect on human co-lonic cancer cell HT29 in 9 disease-oriented tumor cell lines with IC50cLANs=(0.38±0.03)mmol/L,IC50MET=(0.33±0.04)mmol/L at 48 h;no obvious hemolysis or agglutination were observed compared with saline;LD50=1 381 mg/kg,no subacute toxicity at 138 mg/kg within 14 days;blood retention characteristics of MET@cLANs are superior to MET;The tumor weight of(0.782±0.061)g for MET@cLANs group was significantly lower than the(0.886±0.081)g for Saline group(P=0.031 1)after 20-day treatment.Conclusion The MET@cLANs hold the great potential to be further developed into a high biosafety anti colon cancer nanodrug.关键词
α-(+)-硫辛酸/二甲双胍/抗肿瘤/协同作用Key words
α-(+)-lipoic acid/metformin/anti tumor/synergistic effect分类
药学引用本文复制引用
卓俊睿,毛朝坤,代鑫..α-(+)-硫辛酸-二甲双胍纳米粒子抗肿瘤作用研究[J].遵义医科大学学报,2025,48(5):443-454,12.基金项目
贵州省科技计划资助项目[NO:黔科合基础-ZK(2022)一般674]. （2022）
