RESUMO
Annonaceous acetogenins (ACGs) are a large family of fatty acid derived natural products that are exclusively isolated from the Annonaceae species. Many members of this diverse family have a broad spectrum of biological activities, the most impressive of which is anticancer activity. However, their poor solubility and severe toxicity restrict their clinical application, and their complicated composition hinders their formulation and drug delivery. In this study, ß-cyclodextrin was modified with folic acid (FA) and then combined with soybean lecithin to prepare FA-modified ACGs nanosuspensions (FA-ACGs-NSps). The obtained FA-ACGs-NSps had a high drug payload of 57.59% and average particle size of 199.5 nm, and they exhibited sustained drug release within 142 hours. In comparison with ACGs-NSps, FA-ACGs-NSps showed significantly enhanced cytotoxicity and higher cell uptake toward folate receptor-positive 4T1 cell lines. An in vivo study demonstrated that FA-ACGs-NSps more effectively accumulated in tumors and enhanced the antitumor therapeutic efficacy with less toxicity in 4T1 tumor bearing mice. Therefore, FA-ACGs-NSps may be a promising drug delivery system for ACGs to improve their therapeutic window and may be suitable for clinical application to treat folate-positive tumors.
Assuntos
Acetogeninas/química , Acetogeninas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/química , Acetogeninas/farmacocinética , Animais , Annonaceae/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Ácido Fólico/farmacologia , Humanos , Lecitinas/química , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Tamanho da Partícula , Solubilidade , Suspensões/química , Suspensões/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Ciclodextrinas/químicaRESUMO
The convergent synthesis of fluorescence-labeled solamin, an antitumor Annonaceous acetogenin, was accomplished by two asymmetric alkynylations of 2,5-diformyl tetrahydrofuran with an alkyne tagged with fluorescent groups and another alkyne with an α,ß-unsaturated γ-lactone. Assay for the growth inhibitory activity against human cancer cell lines revealed that the probe with the fluorescent groups at the end of the hydrocarbon chain may have the same mode of action as natural acetogenins. The merged fluorescence of dansyl-labeled solamin and MitoTracker Red suggests that Annonaceous acetogenins localize in the mitochondria.
