RESUMEN
Although photodynamic therapy (PDT) has been an attractive strategy for several cancer treatments in the clinical setting, PDT efficacy is attenuated by consumption of oxygen. To address this photodynamic issue, we adopted a phototherapy-chemotherapy combination strategy based on targeted delivery of the near-infrared photosensitizer indocyanine green (ICG), photothermal conversion agent polydopamine (PDA), and tirapazamine (TPZ), a hypoxia-activated prodrug. Under laser irradiation, ICG consumption of oxygen and aggravated hypoxia in tumor sites can activate TPZ to damage DNA. In parallel, ICG produces reactive oxygen species which work in synergy with PDA to enhance phototherapeutic efficiency. Herein, hybrid CaCO3/TPGS nanoparticles delivering ICG, PDA, and TPZ (ICG-PDA-TPZ NPs) were designed for effective and safe cancer therapy. ICG-PDA-TPZ NPs showed significantly improved cellular uptake and accumulation in tumors. Furthermore, we demonstrated that ICG-PDA-TPZ NPs showed intensive photodynamic and photothermal effects in vitro and in vivo, which synergized with TPZ in subcutaneous U87 malignant glioma growth and orthotopic B16F10 tumor inhibition, with negligible side effects. Thus, ICG-PDA-TPZ NPs could be an effective strategy for improvement of PDT.
Asunto(s)
Hipertermia Inducida , Verde de Indocianina , Indoles , Nanopartículas , Neoplasias , Fotoquimioterapia , Profármacos , Fármacos Sensibilizantes a Radiaciones , Tirapazamina , Animales , Humanos , Ratones , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Hipertermia Inducida/métodos , Verde de Indocianina/metabolismo , Verde de Indocianina/uso terapéutico , Indoles/metabolismo , Indoles/uso terapéutico , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/efectos adversos , Fotoquimioterapia/métodos , Polímeros/metabolismo , Polímeros/uso terapéutico , Profármacos/metabolismo , Profármacos/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/metabolismo , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Especies Reactivas de Oxígeno/efectos de la radiación , Tirapazamina/metabolismo , Tirapazamina/uso terapéutico , Distribución Tisular , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To investigate the effect of Mailuoning injectable powder on experimental vascular occlusion angeitides in rats. METHODS: Rats were injected laurostearic acid into arteria cruralis to induce the model of experimental vascular occlusion angeitides, then we observed the changes of objective sign of rats, and analysed throm ranking through pathological section under electro-microscope. RESULTS: Mailuoning injectable powder could decrease the quantity of throm in blood vessel, and improve hemorrheoiogy. CONCLUSION: The results show that Mailuoning injectable powder has obvious therapeutical effect on experimental vascular occlusion angeitides in rats, and its mechanism may be related to the anti-throm in blood vessel and improving hemorrheology.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Fitoterapia , Plantas Medicinales/química , Tromboangitis Obliterante/tratamiento farmacológico , Animales , Viscosidad Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Combinación de Medicamentos , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Hemorreología , Inyecciones Intravenosas , Ácidos Láuricos , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Tromboangitis Obliterante/inducido químicamente , Tromboangitis Obliterante/patologíaRESUMEN
BACKGROUND: Multidrug resistance (MDR) is the major reason for the failure of chemotherapy in colon cancer. Bufalin (BU) is one of the most effective antitumor active constituents in Chansu. Our previous study found that BU can effectively reverse P-glycoprotein (P-gp)-mediated MDR in colon cancer. However, the clinical application of BU is limited due to its low solubility in water and high toxicity. In the present study, a multifunctional delivery system based on vitamin-E- succinate grafted chitosan oligosaccharide (VES-CSO) and cyclic (arginine-glycine-aspartic acid peptide) (RGD)-modified d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by emulsion solvent evaporation method for targeted delivery of BU to improve the efficacy of drug-resistant colon cancer therapy. METHODS: The cytotoxicity of BU-loaded micelles against drug-resistant colon cancer LoVo/ADR and HCT116/LOHP cells was measured by CCK-8 assay. The cellular uptake, Rho123 accumulation, and cell apoptosis were determined by flow cytometry. The expression of apoptosis-related protein and P-gp was measured by Western blot assay. The antitumor activity of BU-loaded micelles was evaluated in LoVo/ADR-bearing nude mice. RESULTS: BU-loaded VES-CSO/TPGS-RGD mixed micelles (BU@VeC/T-RGD MM) were 140.3 nm in diameter with zeta potential of 8.66 mV. The BU@VeC/T-RGD MM exhibited good stability, sustained-release pattern, higher intracellular uptake, and greater cytotoxicity in LoVo/ADR cells. Furthermore, the mechanisms of the BU@VeC/T-RGD MM to overcome MDR might be due to enhanced apoptosis rate and P-gp efflux inhibition. Subsequently, in vivo studies confirmed an enhanced therapeutic efficiency and reduced side effects associated with BU@VeC/T-RGD MM compared with free BU, owing to the enhanced permeation and retention effect, improved pharmacokinetic behavior, and tumor targeting, which lead to MDR-inhibiting effect in LoVo/ADR-bearing nude mice. CONCLUSION: Our results demonstrated that VeC/T-RGD MM could be developed as a potential delivery system for BU to improve its antitumor activity against drug-resistant colon cancer.