RESUMO
To develop a new drug delivery system is one of the useful approaches to break through the limitation of hydroxycamptothecin (HCPT), a typical DNA topoisomerase I (Topo I) inhibitor in clinical appliance. Injectable glycyrrhizic acid-hydroxycamptothecin (GL-HCPT) micelles that were able to dramatically improve the solubility and stability of HCPT were prepared through self-assembly process and evaluated both in vitro and in vivo. With a mean particle size (PS) of 105.7⯱â¯9.7â¯nm and a drug loading (DL) of 9.0⯱â¯1.5%, GL-HCPT micelles were rapidly internalized by HepG2 cells after 1â¯h, significantly increasing the intracellular accumulation of HCPT. Compared with the current used HCPT injection and HCPT/GL physical mixture, GL-HCPT micelles showed enhanced antitumor activity against liver cancer cells (HepG2 and Huh7) as well as a superior suppression on the tumor growth of HepG2 tumor bearing mice. Interestingly, GL-HCPT micelles gathered in liver and simultaneously reduced the drug accumulation in normal tissues, thereby exhibiting minimal cytotoxicity to human normal liver cells (LO2). Therefore, we offered a convenient and cost-effective strategy to construct an intravenous drug delivery system (GL-HCPT micelles) as new generation of DNA Topo I inhibitor for enhanced cancer chemotherapy.
Assuntos
Camptotecina/análogos & derivados , Portadores de Fármacos/química , Ácido Glicirrízico/química , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/administração & dosagem , Administração Intravenosa , Animais , Camptotecina/administração & dosagem , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Estabilidade de Medicamentos , Células Hep G2 , Humanos , Masculino , Camundongos , Micelas , Neoplasias/patologia , Tamanho da Partícula , Solubilidade , Inibidores da Topoisomerase I/química , Testes de Toxicidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Triple negative breast cancer(TNBC) has generated growing interests due to its aggressive biologic behavior and absence of targeted therapy approach. Glycyrrhizin(GL) from licorice root and its metabolite, glycyrrhetinic acid(GA) have shown extensive bioactivities in clinic. Here, we demonstrate that GL and GA have contrary anti-cancer effect on TNBC MDA-MB-231 cells. Beside its inhibition of cell proliferation, GA at non-cytotoxic concentration showed synergistic effect in combination with anti-cancer drug, etoposide(VP-16). Specifically, GA enhanced cytotoxicity through regulating topoisomerase IIα(TOPO 2A) targeted by etoposide. GA sensitized the cells to etoposide through elevating TOPO 2A with a 2.4 fold rate at 12h. From 12 to 48h, GA halved the expression of TOPO 2A and stimulated apoptosis, which exhibited its antineoplastic effect. Our experiments showed that GSH depletion, modulation of MAPK and AKT pathways accounted for the regulation of topoisomerase IIα and apoptosis. However, GL showed protection and detoxication by decreasing reactive oxygen species generation, maintaining GSH and differentially modulating apoptosis, AKT pathway, ERK and JNK of MAPK pathway. Collectively, our results demonstrate that GA, instead of GL, is a better candidate for TNBC treatment because of its anti-cancer effect and sensitization of topoisomerase IIα inhibitor.