RESUMO
PURPOSE: Melanoma is an invasive and very aggressive skin cancer due to its multi-drug resistance that results in poor patient survival. There is a need to test new treatment approaches to improve therapeutic efficacy and reduce side effects of conventional treatments. METHODS: PLA/PVA nanoparticles carrying both Dacarbazine and zinc phthalocyanine was produced by double emulsion technique. The characterization was performed by dynamic light scattering and atomic force microscopy. In vitro photodynamic therapy test assay using MV3 melanoma cells as a model has been performed. In vitro cell viability (MTT) was performed to measure cell toxicity of of nanoparticles with and without drugs using human endothelial cells as a model. The in vivo assay (biodistribution/tissue deposition) has been performed using radiolabeled PLA/PVA NPs. RESULTS: The nanoparticles produced showed a mean diameter of about 259 nm with a spherical shape. The in-vitro photodynamic therapy tests demonstrated that the combination is critical to enhance the therapeutic efficacy and it is dose dependent. The in vitro cell toxicity assay using endothelial cells demonstrated that the drug encapsulated into nanoparticles had no significant toxicity compared to control samples. In-vivo results demonstrated that the drug loading affects the biodistribution of the nanoparticle formulations (NPs). Low accumulation of the NPs into the stomach, heart, brain, and kidneys suggested that common side effects of Dacarbazine could be reduced. CONCLUSION: This work reports a robust nanoparticle formulation with the objective to leveraging the synergistic effects of chemo and photodynamic therapies to potentially suppressing the drug resistance and reducing side effects associated with Dacarbazine. The data corroborates that the dual encapsulated NPs showed better in-vitro efficacy when compared with the both compounds alone. The results support the need to have a dual modality NP formulation for melanoma therapy by combining chemotherapy and photodynamic therapy.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Portadores de Fármacos/química , Melanoma/tratamento farmacológico , Fármacos Fotossensibilizantes/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular , Dacarbazina/administração & dosagem , Dacarbazina/farmacocinética , Composição de Medicamentos/métodos , Células Endoteliais , Humanos , Isoindóis/administração & dosagem , Isoindóis/farmacocinética , Masculino , Melanoma/patologia , Camundongos , Nanopartículas/química , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Poliésteres/química , Álcool de Polivinil/química , Neoplasias Cutâneas/patologia , Distribuição Tecidual , Compostos de Zinco/administração & dosagem , Compostos de Zinco/farmacocinéticaRESUMO
PURPOSE: The purpose of this article was to develop, characterize and test (in vivo) dacarbazine microparticles that may be labeled with 99mTc and Ra-223 for both use: diagnostic and therapy of metastatic melanoma. METHODS: We developed by double emulsion solvent evaporation methodology the microparticle. The characterization has been done using, Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). The labeling with 99mTc and Ra-223 has been done by the direct labeling process. Also the formulation has been tested pre-clinically using Balb/c mice inducted with melanoma, performing the the biodistribution and planar imaging. Cytotoxicity evaluation was also done in M3 V cell line. In order to understand the safety aspects of the microparticles, microbiological study (endotoxin and sterility) has been done. Finally, planar imaging was performed to evaluate the diagnosing aspect. RESULTS: The results showed that a 559 nm microparticles was obtained with a spherical shape. The labeling process with 99mTc reached over 90% of efficacy. On the other hand, the labeling process with Ra-223 showed a 70% efficacy. The results in inducted animals demonstrated that the microparticles were able to reach the tumor with a high rate (20%). Also demonstrated a low recognition by the Mononuclear Phagocytic System. The cytotoxicity and the microbiological control, corroborates the safety aspect of these microparticles. CONCLUSION: The planar image and the possible labeling with Ra-223, corroborates the use as a theragnostic agent for imaging and therapy of Metastatic Melanoma.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/uso terapêutico , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Rádio (Elemento)/uso terapêutico , Tecnécio/uso terapêutico , Animais , Antineoplásicos Alquilantes/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/farmacocinética , Sistemas de Liberação de Medicamentos , Feminino , Camundongos Endogâmicos BALB C , Camundongos Nus , Rádio (Elemento)/farmacocinética , Tecnécio/farmacocinética , Distribuição TecidualRESUMO
BACKGROUND: Temozolomide is an antineoplastic agent of proven efficacy against high-grade gliomas. PURPOSE: The objective of this crossover, single-dose, bioequivalence study was to compare the rate and extent of absorption of oral temozolomide after administration of the study product (Dralitem®, Monte Verde Sociedad Anónima) and the reference product (Temodal®, originator product manufactured by Schering Plough Laboratories) in patients with primary central nervous system (CNS) tumors under fasting conditions. METHODS: Sixteen male and female subjects with primary CNS tumors (excluding CNS lymphoma) were recruited, and were administered temozolomide 200 mg/m2 (Dralitem®) on days 1, 2 and 5 of a 5-day treatment. On days 3 and 4, subjects received the same dose of the test product (Dralitem®), or the reference product (Temodal®) on alternate days. The single dose of 200 mg/m2 was reached with three different temozolomide capsule strengths: 20, 100 and 250 mg. On days 3 and 4, blood samples were obtained for pharmacokinetic (PK) evaluation after drug administration. RESULTS: Bioequivalence assessment was made for the 90% confidence interval (CI) for the ratio of log-transformed means (µT/µR) of the area under the concentration-time curve (AUC from time zero to the final quantifiable sample [AUCt] and AUC from time zero to infinity [AUC∞]) and maximum concentration (C max) of both the test (Dralitem®) and reference (Temodal®) products. The point estimate and 90% CI of the ratios of C max, AUCt and AUC∞ values were 94.37 (82.69-107.69), 100.99 (97.81-104.28) and 101.53 (98.60-104.54), respectively. The ratio met the predefined bioequivalence criteria (i.e. 90% CI between 80.00 and 125.00) for C max and AUC. The most commonly reported adverse events (AE) on this study were vomiting, abdominal pain, asthenia and weakness. One subject experienced expressive aphasia, possibly unrelated to the study drug and with no significant sequelae upon recovery. No serious AEs or unexpected AEs were reported. CONCLUSIONS: Temozolomide Dralitem® capsules, 20, 100 and 250 mg, were bioequivalent to Temodal® capsules under fasting conditions in patients with CNS primary tumors, supporting that they are therapeutic equivalents. ClinicalTrials.gov Identifier: NCT02343081.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Dacarbazina/análogos & derivados , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Área Sob a Curva , Cápsulas , Estudos Cross-Over , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/farmacocinética , Relação Dose-Resposta a Droga , Jejum , Feminino , Glioma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Temozolomida , Equivalência Terapêutica , Adulto JovemRESUMO
PURPOSE: Oral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration. METHODS: Subjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m(2) of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m(2) temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day. RESULTS: Ratio of log-transformed means (intravenous:oral) of area under the concentration-time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8-1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration. CONCLUSIONS: This study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.