RESUMO
AIM: The objective of this study was to deliver a ring-closed form of 10-hydroxycamptothecin (HCPT) to the mitochondria and nucleus to treat colorectal cancer. MATERIALS & METHODS: HCPT-loaded nanoparticle HCPT@PLGA-PEG2k-triphenylphosphonium/PLGA-hyd-PEG4k-folic acid (PT/PHF) and HCPT@PT/PLGA-SS-PEG4k-folic acid (PSF) were prepared by using emulsion-solvent evaporation method. RESULTS: In vitro experimental results indicated HCPT@PT/PHF and HCPT@PT/PSF maintained a large amount of HCPT in active form, and delivered more HCPT to the nucleus and mitochondria of the tumor cell, which resulted in the enhancement of cytotoxicity of HCPT. In vivo experimental results indicated that HCPT@PT/PHF and HCPT@PT/PSF delivered more ring-closed form of HCPT to tumor tissue, which led to strong antitumor activity. CONCLUSION: HCPT@PT/PHF and HCPT@PT/PSF could enhance therapeutic efficacy of HCPT to colorectal cancer.
Assuntos
Camptotecina/análogos & derivados , Núcleo Celular/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/química , Mitocôndrias/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Transporte Biológico , Camptotecina/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Emulsões/química , Ácido Fólico/química , Ácido Fólico/metabolismo , Humanos , Camundongos , Camundongos Nus , Modelos Animais , Nanopartículas/química , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química , Propriedades de Superfície , Distribuição TecidualRESUMO
In order to increase the therapeutic effect of doxorubicin (DOX) on bone metastases, a multifunctional micelle was developed by combining pH-sensitive characteristics with bone active targeting capacity. The DOX loaded micelle was self-assembled by using doxorubicin-poly (ethylene glycol)-alendronate (DOX-hyd-PEG-ALN) as an amphiphilic material. The size and drug loading of DOX loaded DOX-hyd-PEG-ALN micelle was 114 nm and 24.3%. In pH 5.0 phosphate buffer solution (PBS), the micelle released DOX significantly faster than in pH 7.4 PBS. In addition, with the increase of incubation time, more red DOX fluorescence was observed in tumor cells and trafficked from cytoplasm to nucleus. The IC50 of DOX loaded DOX-hyd-PEG-ALN micelle on A549 cells was obviously lower than that of free DOX in 48 h. Furthermore, the in vivo image experimental results indicated that a larger amount of DOX was accumulated in the bone metastatic tumor tissue after DOX loaded DOX-hyd-PEG-ALN micelle was intravenously administered, which was confirmed by histological analysis. Finally, DOX loaded DOX-hyd-PEG-ALN micelle effectively delayed the tumor growth, decreased the bone loss and reduced the cardiac toxicity in tumor-bearing nude mice as compared with free DOX. In conclusion, DOX loaded DOX-hyd-PEG-ALN micelle had potential in treating bone metastatic tumor.
