RESUMEN
PURPOSE: Prostate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo. METHODS: Cabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo. RESULTS: The resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations. CONCLUSION: ORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Nanopartículas , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Línea Celular , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Ácido Hialurónico/química , Lípidos/química , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Recurrencia Local de Neoplasia , Orlistat/administración & dosificación , Tamaño de la Partícula , Polímeros/química , Profármacos , Neoplasias de la Próstata Resistentes a la Castración/patología , Taxoides/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND AIM: H2 S is an important gasotransmitter in the gastrointestinal tract. The aim of the present study was to investigate the effect of exogenous H2 S on gastric acid secretion. METHODS: Male Wistar rats were randomly divided into physiological saline (PS) group, sodium hydrosulfide (NaHS; 50, 100, and 150 µmol/kg body weight) group, glibenclamide + NaHS group, and SQ22536 + NaHS group. PH of gastric juice before injection and after injection were determined by a PH meter. RESULTS: The results showed that NaHS, an exogenous H2 S donor, injected into the enterocoelia significantly reduced the PH of gastric juice, the same volume of PS administered similarly did not change PH of gastric juice, the promotional effect of NaHS on gastric acid secretion could be abolished by glibenclamide, an ATP-sensitive potassium channel K(ATP) blocker SQ22536, an inhibitor of adenyl cyclase. CONCLUSIONS: The data from these experiments suggest that exogenous H2 S promoted gastric acid secretion, which may occur via K(ATP) channels and activate AC-cAMP pathway.
