RESUMO
Irinotecan (IRN) is a semisynthetic derivative of camptothecin that acts as a topoisomerase I inhibitor. IRN is used worldwide for the treatment of several types of cancer, including colorectal cancer, however its use can lead to serious adverse effects, as diarrhea and myelosuppression. Liposomes are widely used as drug delivery systems that can improve chemotherapeutic activity and decrease side effects. Liposomes can also be pH-sensitive to release its content preferentially in acidic environments, like tumors, and be surface-functionalized for targeting purposes. Herein, we developed a folate-coated pH-sensitive liposome as a drug delivery system for IRN to reach improved tumor therapy without potential adverse events. Liposomes were prepared containing IRN and characterized for particle size, polydispersity index, zeta potential, concentration, encapsulation, cellular uptake, and release profile. Antitumor activity was investigated in a murine model of colorectal cancer, and its toxicity was evaluated by hematological/biochemical tests and histological analysis of main organs. The results showed vesicles smaller than 200 nm with little dispersion, a surface charge close to neutral, and high encapsulation rate of over 90%. The system demonstrated prolonged and sustained release in pH-dependent manner with high intracellular drug delivery capacity. Importantly, the folate-coated pH-sensitive formulation had significantly better antitumor activity than the pH-dependent system only or the free drug. Tumor tissue of IRN-containing groups presented large areas of necrosis. Furthermore, no evidence of systemic toxicity was found for the groups investigated. Thus, our developed nanodrug IRN delivery system can potentially be an alternative to conventional colorectal cancer treatment.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Ácido Fólico/metabolismo , Irinotecano/administração & dosagem , Lipídeos/química , Inibidores da Topoisomerase I/administração & dosagem , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Preparações de Ação Retardada , Composição de Medicamentos , Liberação Controlada de Fármacos , Ácido Fólico/química , Concentração de Íons de Hidrogênio , Irinotecano/química , Irinotecano/metabolismo , Lipossomos , Camundongos Endogâmicos BALB C , Necrose , Fatores de Tempo , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
OBJECTIVES: This work aimed to evaluate semisolid formulations containing topotecan (TPT) loaded nanostructured lipid carriers (NLC) for topical treatment of skin cancers, as TPT is effective against a variety of tumours. A formulation which increases TPT skin permeation would be extremely desirable. METHODS: TPT-NLC were prepared and incorporated in hydrogels with hydroxyethyl cellulose and chitosan (TPT-NLC-HEC and TPT-NLC-Ch, respectively). Control formulations were obtained by dispersing TPT in HEC and Ch hydrogels (TPT-HEC and TPT-Ch). KEY FINDINGS: TPT-NLC-HEC and TPT-NLC-Ch showed to maintain the drug and nanoparticle dispersions stable for up to 30 days. When nanoparticles were incorporated into gels, TPT release was significantly decreased (P < 0.05). Still, TPT-NLC-HEC increased 2.37 times permeation compared with TPT-HEC (11.9 and 5.0 µg/cm2 , respectively). Cell culture experiments with B16F10 melanoma demonstrated that nanoencapsulation significantly increased TPT cytotoxicity (P < 0.05). TPT-NLC was more toxic than free TPT, with IC50 value of 5.74 µg/ml, whereas free TPT had an IC50 > 20 µg/ml. As skin permeated values of TPT from developed formulation (TPT-NLC) were superior to melanoma IC50, it can be extrapolated that chemotherapeutic permeated amounts may be sufficient for a therapeutic effect. CONCLUSIONS: TPT-NLC-HEC may be a valuable tool for the topical treatment of skin cancers.
Assuntos
Portadores de Fármacos/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Nanopartículas/administração & dosagem , Absorção Cutânea/fisiologia , Neoplasias Cutâneas/tratamento farmacológico , Topotecan/administração & dosagem , Administração Tópica , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Portadores de Fármacos/metabolismo , Hidrogéis/administração & dosagem , Hidrogéis/metabolismo , Lipídeos/administração & dosagem , Melanoma Experimental/metabolismo , Camundongos , Nanopartículas/metabolismo , Técnicas de Cultura de Órgãos , Absorção Cutânea/efeitos dos fármacos , Neoplasias Cutâneas/metabolismo , Suínos , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/metabolismo , Topotecan/metabolismo , Resultado do TratamentoRESUMO
Thiazacridine and imidazacridine derivatives have shown promising results as tumors suppressors in some cancer cell lines. For a better understanding of the mechanism of action of these compounds, binding studies of 5-acridin-9-ylmethylidene-3-amino-2-thioxo-thiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxo-thiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxo-imidazolidin-4-one and 3-acridin-9-ylmethyl-thiazolidin-2,4-dione with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopy and circular dichroism spectroscopy were performed. The binding constants ranged from 1.46 × 10(4) to 6.01 × 10(4) M(-1). UV-Vis, fluorescence and circular dichroism measurements indicated that the compounds interact effectively with ctDNA, both by intercalation or external binding. They demonstrated inhibitory activities to human topoisomerase I, except for 5-acridin-9-ylmethylidene-2-thioxo-1,3-thiazolidin-4-one. These results provide insight into the DNA binding mechanism of imidazacridines and thiazacridines.
Assuntos
Acridinas/síntese química , Acridinas/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Acridinas/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Dicroísmo Circular , DNA/química , DNA/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Estrutura Molecular , Inibidores da Topoisomerase I/metabolismoRESUMO
Topotecan is an important cytotoxic drug that has gained broad acceptance in clinical use for the treatment of refractory ovarian and small-cell lung cancer. The lactone active form of topotecan can be hydrolyzed in vivo, decreasing the drug's therapeutic efficacy. Lipid encapsulation may promote in vivo stabilization by removing topotecan from aqueous media. Earlier reports of topotecan lipid nanoencapsulation have focused on liposomal encapsulation; however, the higher stability and cost-effectiveness of solid lipid nanoparticles (SLN) highlight the potential of these nanoparticles as an advantageous carrier for topotecan. The initial motivation for this work was to develop, for the first time, solid lipid nanoparticles and nanostructured lipid carriers (NLC) with a high drug loading for topotecan. A microemulsion technique was employed to prepare SLNs and NLCs and produced homogeneous, small size, negatively charged lipid nanoparticles with high entrapment efficiency and satisfactory drug loading. However, low recovery of topotecan was observed when the microemulsion temperature was high and in order to obtain high quality nanoparticles, and precise control of the microemulsion temperature is critical. Nanoencapsulation sustained topotecan release and improved its chemical stability and cytotoxicity. Surprisingly, there were no significant differences between the NLCs and SLNs, and both are potential carriers for topotecan delivery.