RESUMO
Liposomes functionalized with monoclonal antibodies offer targeted therapy for cancer, boasting advantages like sustained drug release, enhanced stability, passive accumulation in tumors, and interaction with overexpressed receptors on cancer cells. This study aimed to develop and characterize anti-EGFR immunoliposomes loaded with cabazitaxel and assess their properties against prostate cancer in vitro and in vivo. Using a Box-Behnken design, a formulation with soy phosphatidylcholine, 10% cholesterol, and a 1:20 drug-lipid ratio yielded nanometric particle size, low polydispersity and high drug encapsulation. Immunoliposomes were conjugated with cetuximab through DSPE-PEG-Maleimide lipid anchor. Characterization confirmed intact antibody structure and interaction with EGFR receptor following conjugation. Cabazitaxel was dispersed within the liposomes in the amorphous state, confirmed by solid-state analyses. In vitro release studies showed slower cabazitaxel release from immunoliposomes. Immunoliposomes had enhanced cabazitaxel cytotoxicity in EGFR-overexpressing DU145 cells without affecting non-tumor L929 cells. Cetuximab played an important role to improve cellular uptake in a time-dependent fashion in EGFR-overexpressing prostate cancer cells. In vivo, immunoliposomes led to significant tumor regression, improved survival, and reduced weight loss in xenograft mice. While cabazitaxel induced leukopenia, consistent with clinical findings, histological analysis revealed no evident toxicity. In conclusion, the immunoliposomes displayed suitable physicochemical properties for cabazitaxel delivery, exhibited cytotoxicity against EGFR-expressing prostate cancer cells, with high cell uptake, and induced significant tumor regression in vivo, with manageable systemic toxicity.
Assuntos
Cetuximab , Liberação Controlada de Fármacos , Receptores ErbB , Lipossomos , Neoplasias da Próstata , Taxoides , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Animais , Receptores ErbB/imunologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Humanos , Linhagem Celular Tumoral , Taxoides/administração & dosagem , Taxoides/farmacocinética , Taxoides/farmacologia , Taxoides/química , Cetuximab/administração & dosagem , Camundongos , Camundongos Nus , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Polietilenoglicóis/química , Polietilenoglicóis/administração & dosagem , Tamanho da Partícula , Sistemas de Liberação de MedicamentosRESUMO
Acute kidney injury (AKI) is a complex condition which has an intricate pathology mostly involving hemodynamic, inflammatory, and direct toxic effects at the cellular level with high morbidity and mortality ratios. Renal ischemic reperfusion injury (RIRI) is the main factor responsible for AKI, most often observed in different types of shock, kidney transplantation, sepsis, and postoperative procedures. The RIRI-induced AKI is accompanied by increased reactive oxygen species generation together with the activation of various inflammatory pathways. In this context, plant-derived medicines have shown encouraging nephroprotective properties. Evidence provided in this systemic review leads to the conclusion that plant-derived extracts and compounds exhibit nephroprotective action against renal ischemic reperfusion induced-AKI by increasing endogenous antioxidants and decreasing anti-inflammatory cytokines. However, there is no defined biomarker or target which can be used for treating AKI completely. These plant-derived extracts and compounds are only tested in selected transgenic animal models. To develop the results obtained into a therapeutic entity, one should apply them in proper vertebrate multitransgenic animal models prior to further validation in humans.
RESUMO
Chagas disease (CD) is a neglected disease, prevalent and endemic in Latin America, but also present in Europe and North America. The main treatment used for this disease is benznidazole, but its efficacy is variable in the chronic phase and presents high toxicity. So, there is a need for the development of new therapeutic agents. The five-membered heterocyclic 1,2,4-oxadiazole ring has received attention for its unique properties and a broad spectrum of biological activities and is therefore a potential candidate for the development of new drugs. Thus, the aim of this study was to evaluate the activity of the N-cyclohexyl-3-(3-methylphenyl)-1,2,4-oxadiazol-5-amine (2) on the evolutionary forms of Trypanosoma cruzi strain Y, as well as its mechanisms of action and in silico theoretical approach. The results by computational method showed an interaction of the 1,2,4-oxadiazole (2) with TcGAPDH, cruzain, and trypanothione reductase, showing good charge distribution and affinity in those three targets. Furthermore, cytotoxicity in LLC-MK2 cells was performed by the MTT method. In the assays with different parasite forms, the tested compound showed similar time-dependent concentration effect. The evaluation of the antiamastigote effect between the two concentrations tested showed a reduction in the number of infected cells and also in the number of amastigotes per infected cell. By flow cytometry, the compound (2) displayed alterations suggestive of necrotic events. Finally, in scanning electron microscopy structural alterations were present, characteristic of necrosisin the epimastigote forms. Overall, the 1,2,4-oxadiazole derivative (2) here evaluated opens perspectives to the development of new antichagasic agents.
Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Linhagem Celular , Doença de Chagas/tratamento farmacológico , Humanos , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêuticoRESUMO
Chagas disease is a leading public health problem. More than 8 million people are affected by the disease, which is endemic in 21 countries in Latin America, generating an average annual cost of 7.2 billion dollars per year. The conventional treatment of Chagas disease is carried out by administering the drug benznidazole (BZN), which has caused numerous adverse reactions. Hence, the search for new, more efficient, and less toxic anti-chagasic agents is essential. Recently, chalcones have been researched to propose new therapies against neglected diseases, mainly Trypanosoma cruzi. The objective of this work was to evaluate for the first time the antiproliferative potential of chalcone derived from the natural product on T. cruzi strain Y. The molecular structure of the chalcone was confirmed by spectrometric data. The toxicity of chalcone in LLC-MK2 cells indicated that a concentration of 514.10 ± 62.40 µM was able to reduce cell viability by 50%. Regarding the effect of chalcone on epimastigote forms, an IC50 value of 46.57 ± 9.81 µM was observed; 45.92 ± 8.42 and 16.32 ± 3.41 µM at times of 24, 48 and 72 hours, respectively. The chalcone was able to eliminate trypomastigote forms at all concentrations tested, except for 31.25 µM, with LC50 values of 117.90 ± 12.60 µM, lower than the reference drug BZN (161.40 ± 31. 80 µM). The mechanism of action may be related to the membrane damage provoked by reduction of the mitochondrial potential. The anti-T. cruzi effect can be assigned through some structural aspects of the chalcone as the nitro group (NO2) is present, which can be enzymatically reduced forming a nitro radical, and the presence of methoxyl groups in the A ring of the chalcone. In silico studies showed that the chalcone had a higher affinity for cruzain when compared to BZN and the co-crystallized inhibitor KB2, as it presented a more thermodynamically stable complex in the order of -6.9 kcal mol-1. The pharmacokinetic prediction showed a significant probability of antiprotozoal activity, a good volume of distribution after being absorbed in the intestine, and a low chance of activity in the central nervous system. Therefore, these results suggest that the chalcone can become a potential cruzain enzyme inhibitor with trypanocidal activity.