RESUMO
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Beside early detection, early diagnosis, and early surgery, it is urgent to try new strategies for the treatment of HCC. Triptolide (TPL) has been employed to treat HCC. However, its clinical applications were restricted by the narrow therapeutic window, severe toxicity, and poor water-solubility. In this study, we developed cancer cell membrane-camouflaged biomimetic PLGA nanoparticles loading TPL (TPL@mPLGA) with the homologous targeting property for the treatment of HCC. The TPL@mPLGA was successfully prepared with particle size of 195.5 ± 7.5 nm and zeta potential at -21.5 ± 0.2 mV with good stability. The drug loading (DL) of TPL@mPLGA was 2.94%. After Huh-7 cell membrane coating, the natural Huh-7 cell membrane proteins were found to be retained on TPL@mPLGA, thus endowing the TPL@mPLGA with enhanced accumulation at tumor site, and better anti-tumor activity in vitro and in vivo when compared with TPL or TPL@PLGA. The TPL@mPLGA showed enhanced anti-tumor effects and reduced toxicity of TPL, which could be adopted for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular , Diterpenos , Compostos de Epóxi , Neoplasias Hepáticas , Nanopartículas , Fenantrenos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Diterpenos/administração & dosagem , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Compostos de Epóxi/química , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Fenantrenos/administração & dosagem , Fenantrenos/farmacologia , Fenantrenos/química , Fenantrenos/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Nanopartículas/química , Animais , Linhagem Celular Tumoral , Camundongos , Membrana Celular/efeitos dos fármacos , Tamanho da Partícula , Portadores de Fármacos/química , Camundongos Nus , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Camundongos Endogâmicos BALB CRESUMO
Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly under pathological conditions, presents challenges for clinical translation of liposomal therapeutics. Liver serves as the most important organ for liposome accumulation and metabolism. Unfortunately, the fate of liposomes under pathological liver conditions has been significantly overlooked. This study aimed to investigate the in vivo pharmacokinetic profile and biodistribution profile of liposomes under drug-induced liver injury (DILI) conditions. Two classic DILI animal models, i.e. acetaminophen-induced acute liver injury (AILI) and triptolide-induced subacute liver injury (TILI), were established to observe the effect of pathological liver conditions on the in vivo performance of liposomes. The study revealed significant changes in the in vivo fate of liposomes following DILI, including prolonged blood circulation and enhanced hepatic accumulation of liposomes. Changes in the composition of plasma proteins and mononuclear phagocyte system (MPS)-related cell subpopulations collectively led to the altered in vivo fate of liposomes under liver injury conditions. Despite liver injury, macrophages remained the primary cells responsible for liposomes uptake in liver, with the recruited monocyte-derived macrophages exhibiting enhanced ability to phagocytose liposomes under pathological conditions. These findings indicated that high capture of liposomes by the recruited hepatic macrophages not only offered potential solutions for targeted delivery, but also warned the clinical application of patients under pathological liver conditions.
Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Diterpenos , Lipossomos , Fígado , Fenantrenos , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Acetaminofen/farmacocinética , Camundongos , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Distribuição Tecidual , Fenantrenos/farmacocinética , Fenantrenos/administração & dosagem , Fenantrenos/toxicidade , Diterpenos/farmacocinética , Diterpenos/administração & dosagem , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/administração & dosagem , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Camundongos Endogâmicos C57BLRESUMO
Background: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.
Assuntos
Apoptose , Clorofilídeos , Diterpenos , Neoplasias Hepáticas , Camundongos Nus , Fenantrenos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Espécies Reativas de Oxigênio , Animais , Humanos , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Células Hep G2 , Neoplasias Hepáticas/tratamento farmacológico , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/administração & dosagem , Porfirinas/farmacocinética , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/farmacocinética , Diterpenos/administração & dosagem , Concentração de Íons de Hidrogênio , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Apoptose/efeitos dos fármacos , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Compostos de Epóxi/administração & dosagem , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Liberação Controlada de Fármacos , Proliferação de Células/efeitos dos fármacos , Polietilenoglicóis/química , Terapia CombinadaRESUMO
Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.
Assuntos
Diterpenos , Ratos Wistar , Animais , Diterpenos/farmacocinética , Diterpenos/sangue , Diterpenos/química , Ratos , Masculino , Resinas Vegetais/farmacocinética , Resinas Vegetais/química , Espectrometria de Massas em Tandem , Fabaceae/química , Extratos Vegetais/farmacocinética , Extratos Vegetais/química , Cromatografia LíquidaRESUMO
Abstract: Background: Actinic keratoses are benign intraepithelial skin neoplasms that develop in photoexposed areas and can progress to invasive carcinoma. They are seen frequently in dermatological practice, occurring in 5.1% of consultations. Ingenol mebutate (IM) was recently approved in Brazil as a topical therapy for field cancerization in actinic keratosis. Objective: To evaluate the clearance rate and adverse events in the treatment of actinic keratoses with ingenol mebutate. Methods: A longitudinal, prospective, non-randomized, interventional, open, single-center study was conducted. Patients with actinic keratoses applied ingenol mebutate on a 25cm2 area of the face and/or scalp for three consecutive days (0.015%) or on the forearm for two days (0.05%). Results: 27 patients completed the protocol, of whom 13 on the face and/or scalp and 14 on the forearm. Complete clearance occurred in 53.8% in the first group and 42.8% in the second. Partial response was observed in 15.4% and 35.7%, respectively. The most common side effects were erythema, edema, desquamation, pruritus, and local erosion. Study limitations: The study had a small sample and was not randomized, double-blind, placebo-controlled, or vehicle-controlled. Conclusion: Ingenol mebutate is well-tolerated for the treatment of actinic keratosis, with good patient adherence thanks to the short treatment period.