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1.
J Appl Biomater Funct Mater ; 22: 22808000241284439, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39323034

RESUMO

Nanofibrous scaffolds have emerged as promising candidates for localized drug delivery systems in the treatment of cutaneous cancers. In this study, we prepared an electrospun nanofibrous scaffold incorporating 5-fluorouracil (5-FU) and etoposide (ETP) for chemotherapy targeting melanoma cutaneous cancer. The scaffold was composed of polyvinyl alcohol (PVA) and chitosan (CS), prepared via the electrospinning process and loaded with the chemotherapeutic agents. We conducted relevant physicochemical characterizations, assessed cytotoxicity, and evaluated apoptosis against melanoma A375 cells. The prepared 5-FU/ETP co-loaded PVA/CS scaffold exhibited nanofibers (NFs) with an average diameter of 321 ± 61 nm, defect-free and homogenous morphology. FTIR spectroscopy confirmed successful incorporation of chemotherapeutics into the scaffold. Additionally, the scaffold demonstrated a hydrophilic surface, proper mechanical strength, high porosity, and efficient liquid absorption capacity. Notably, sustained and controlled drug release was observed from the nanofibrous scaffold. Furthermore, the scaffold significantly increased cytotoxicity (95%) and apoptosis (74%) in A375 melanoma cells. Consequently, the prepared 5-FU/ETP co-loaded PVA/CS nanofibrous scaffold holds promise as a valuable system for localized eradication of cutaneous melanoma tumors and mitigation of adverse drug reactions associated with chemotherapy.


Assuntos
Etoposídeo , Fluoruracila , Melanoma , Nanofibras , Álcool de Polivinil , Fluoruracila/química , Fluoruracila/farmacologia , Fluoruracila/administração & dosagem , Humanos , Nanofibras/química , Melanoma/tratamento farmacológico , Melanoma/patologia , Linhagem Celular Tumoral , Etoposídeo/química , Etoposídeo/administração & dosagem , Etoposídeo/farmacologia , Etoposídeo/farmacocinética , Álcool de Polivinil/química , Alicerces Teciduais/química , Quitosana/química , Apoptose/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Liberação Controlada de Fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem
2.
CPT Pharmacometrics Syst Pharmacol ; 13(7): 1238-1251, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38711252

RESUMO

Adebrelimab, a novel anti-PD-L1 antibody, has been approved by the National Medical Products Administration of China as an intravenous infusion for use in combination with carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer in 2023. A two-compartment model with empirical time-varying CL for adebrelimab was established based on data from 263 patients receiving body weight-based doses from two clinical studies. Significant covariate effects of baseline body weight, albumin levels, tumor size, neutrophil counts, and presence of anti-drug antibodies were identified on CL of debrelimab, none of which were clinically significant or warranted dose adjustment. The degree of decrease in CL was higher in patients who responded to treatment with adebrelimab than in non-responders. Adebrelimab exposures (AUC, Ctrough, or Cmax) were not identified as a statistically significant factor related to efficacy or safety endpoint in the exposure-response analysis. Distribution of simulated exposure metrics from the flat dose regimen (1200 mg q3w) was similar to the marketed weight-based dosing regimen (20 mg/kg q3w), supporting the alternative flat dose regimen in the clinic.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Masculino , Idoso , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Modelos Biológicos , Carboplatina/administração & dosagem , Carboplatina/farmacocinética , Carboplatina/uso terapêutico , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Etoposídeo/uso terapêutico , Idoso de 80 Anos ou mais , Infusões Intravenosas
3.
Eur J Drug Metab Pharmacokinet ; 48(6): 657-663, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37700116

RESUMO

BACKGROUND: Moderate malnutrition is a common problem in young children. It is observed that severe malnutrition affects the pharmacokinetics of chemotherapy drugs in pediatric cancer patients, but moderate malnutrition is not well studied in this context. OBJECTIVES: In this study, we aimed to understand how moderate malnutrition affects the pharmacokinetics of two chemotherapy drugs, etoposide and vincristine, using a murine model of early age moderate malnutrition. METHODS: We developed a murine model of moderate childhood malnutrition by subjecting freshly weaned Sprague-Dawley rats to 8% protein diet for 8 weeks. In two separate experiments, we administered etoposide and vincristine (N = 8 for etoposide and N = 12 for vincristine each in protein deficient and control groups) through tail vein injection for pharmacokinetics study. RESULTS: We found ~ 60% increase in area under the concentration-time curve (AUC) of etoposide in malnourished animals as compared to well-nourished animals. Furthermore, clearance, volume of distribution, and half-life were decreased by ~ 37, 53, and 24%, respectively, in malnourished animals. Pharmacokinetic parameters of vincristine showed only marginal differences between well-nourished and malnourished groups. CONCLUSIONS: Our results suggest that while moderate malnutrition significantly affects the pharmacokinetics of etoposide, pharmacokinetics of vincristine remain unchanged. Since chemotherapy drugs have a narrow therapeutic index, the difference in AUC observed in our study might explain the increased toxicity of etoposide in malnourished pediatric cancer patients. This brings forth a need for robust clinical studies to validate our findings and optimize dose for malnourished patients.


Assuntos
Desnutrição , Neoplasias , Humanos , Criança , Ratos , Camundongos , Animais , Pré-Escolar , Etoposídeo/farmacocinética , Vincristina , Modelos Animais de Doenças , Ratos Sprague-Dawley , Desnutrição/metabolismo
4.
Invest Ophthalmol Vis Sci ; 62(14): 13, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34784412

RESUMO

Purpose: Cancer stem cells (CSCs) are known to contribute to tumor relapses by virtue of their chemoresistance. With the knowledge that nanoformulations can overcome drug resistance, we evaluated the efficacy and cytotoxicity of clinical-grade carboplatin (CPT)- and etoposide (ETP)-loaded lactoferrin nanoparticles (Lf-Nps) on total, CD133-enriched (non-CSC), and CD133-depleted (CSC) populations of retinoblastoma (Rb) Y79 cells. Methods: Physicochemical properties of drug-loaded Lf-Nps were measured with transmission electron microscopy and attenuated total reflectance-Fourier transform infrared. The encapsulation efficiency, uptake, and release of drug-loaded Lf-Nps were measured using high-performance liquid chromatography and a UV-visible spectrophotometer. Cytotoxicity of the standard and drug-loaded Lf-Nps was evaluated by the MTT assay. Results: The mean (SD) size and encapsulation efficiency of Lf-CPT and Lf-ETP were 61.2 (3.94) nm, 60% and 45.15 (5.85) nm, 38%, respectively, and the drug release efficiency was highest at pH 6. The increased drug uptake and lower release of drug-loaded Lf-Nps were observed in CSC and non-CSC populations compared to their standard forms. The relative increase of drug uptake and sustained intracellular retention of the drug-loaded Lf-Nps compared to standard drugs showed an enhanced cytotoxicity up to 50%, especially in Rb Y79 CSCs (IC50: CPT, 230.3; Lf-CPT, 118.2; ETP, 198.1; and Lf-ETP, 129) compared to non-CSCs. Conclusions: Our study documents an increase in drug uptake, retention, and cytotoxicity of Lf-CPT and Lf-ETP on Y79 CSCs and non-CSCs as compared to their standard drugs in vitro. The reversal of chemoresistance in the CSC population by nanoformulation appears promising with the potential to pave the way for improved targeted therapy and better clinical outcomes.


Assuntos
Carboplatina/farmacologia , Etoposídeo/farmacologia , Lactoferrina/química , Nanopartículas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Disponibilidade Biológica , Carboplatina/farmacocinética , Cromatografia Líquida de Alta Pressão , Meios de Cultura , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Etoposídeo/farmacocinética , Citometria de Fluxo , Humanos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias da Retina/metabolismo , Neoplasias da Retina/patologia , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Espectroscopia de Infravermelho com Transformada de Fourier
5.
Int J Nanomedicine ; 15: 7601-7613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116490

RESUMO

INTRODUCTION: Etoposide refers to a derivative of podophyllotoxin, which plays an important role in the treatment of cancer due to its prominent anti-tumor effect. As a BCS IV drug, etoposide exhibits insufficient aqueous solubility and permeability, thereby limiting its oral absorption. To enhance the oral bioavailability of etoposide, this study developed an amorphous nanopowder. METHODS: Based on preliminary screening and experimental design, the stabilizer and preparation process of etoposide nanosuspension were explored. Subsequently, using a Box-Behnken design, the effects of independent factors (ultrasonication time, ratio of two phases and stabilizer concentration) on response variables (particle size and polydispersity index) were studied, and then the formulation was optimized. Finally, nanosuspension was further freeze dried with 1% of mannitol resulting in the formation of etoposide amorphous nanopowder. RESULTS: The optimized etoposide nanopowder showed as spherical particles with an average particle size and polydispersity index of 211.7 ± 10.4 nm and 0.125 ± 0.028. X-ray powder diffraction and differential scanning calorimetry confirmed the ETO in the nanopowder was amorphous. Compared with coarse powder and physical mixture, etoposide nanopowder achieved significantly enhanced saturated solubility and dissolution in various pH environments. The Cmax and AUC0-t of etoposide nanopowder after oral administration in rats were respectively 2.21 and 2.13 times higher than the crude etoposide suspension. Additionally, the Tmax value of nanopowder was 0.25 h, compared with 0.5 h of reference group. DISCUSSION: In the present study, the optimized amorphous nanopowder could significantly facilitate the dissolution and oral absorption of etoposide and might act as an effective delivery method to enhance its oral bioavailability.


Assuntos
Composição de Medicamentos , Etoposídeo/administração & dosagem , Etoposídeo/farmacologia , Nanopartículas/química , Administração Oral , Análise de Variância , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cristalização , Etoposídeo/química , Etoposídeo/farmacocinética , Liofilização , Masculino , Modelos Estatísticos , Tamanho da Partícula , Permeabilidade , Pós , Ratos Sprague-Dawley , Solubilidade , Solventes , Suspensões , Difração de Raios X
6.
Sci Rep ; 10(1): 18059, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093456

RESUMO

Nanoparticle technology in cancer chemotherapy is a promising approach to enhance active ingredient pharmacology and pharmacodynamics. Indeed, drug nanoparticles display various assets such as extended blood lifespan, high drug loading and reduced cytotoxicity leading to better drug compliance. In this context, organic nanocrystal suspensions for pharmaceutical use have been developed in the past ten years. Nanocrystals offer new possibilities by combining the nanoformulation features with the properties of solid dispersed therapeutic ingredients including (i) high loading of the active ingredient, (ii) its bioavailability improvement, and (iii) reduced drug systemic cytotoxicity. However, surprisingly, no antitumoral drug has been marketed as a nanocrystal suspension until now. Etoposide, which is largely used as an anti-cancerous agent against testicular, ovarian, small cell lung, colon and breast cancer in its liquid dosage form, has been selected to develop injectable nanocrystal suspensions designed to be transferred to the clinic. The aim of the present work is to provide optimized formulations for nanostructured etoposide solutions and validate by means of in vitro and in vivo evaluations the efficiency of this multiphase system. Indeed, the etoposide formulated as a nanosuspension by a bottom-up approach showed higher blood life span, reduced tumor growth and higher tolerance in a murine carcinoma cancer model. The results obtained are promising for future clinical evaluation of these etoposide nanosuspensions.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Composição de Medicamentos/métodos , Etoposídeo/farmacologia , Etoposídeo/farmacocinética , Nanopartículas , Nanotecnologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Disponibilidade Biológica , Linhagem Celular Tumoral , Modelos Animais de Doenças , Formas de Dosagem , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Camundongos , Suspensões
7.
Pharm Res ; 37(7): 147, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32676789

RESUMO

BACKGROUND: Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, carboplatin, and etoposide) protocol. METHODS: Eighty-eight patients received 400 mg/m2/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated. RESULTS: The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation. CONCLUSIONS: The present study suggests that neither a priori dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/farmacocinética , Etoposídeo/farmacologia , Etoposídeo/farmacocinética , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Farmacogenética , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina/administração & dosagem , Monitoramento de Medicamentos , Etoposídeo/administração & dosagem , Feminino , Genótipo , Humanos , Ifosfamida/administração & dosagem , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Testes Farmacogenômicos , Adulto Jovem
8.
Drug Deliv ; 27(1): 974-982, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32611260

RESUMO

Etoposide (VP16) is the traditional antitumor agent which has been widely used in a variety of cancers. However, intravenous administration of VP16 was limited in clinical application because of its low aqueous solubility, poor bioavailability and dose-limiting adverse effects. Local chemotherapy with VP16-loaded drug delivery systems could provide a continuous release of drug at the target site, while minimizing the systemic toxicity. In this study, we prepared the poly-l-lactic acid (PLLA) based VP16-loaded implants (VP16 implants) by the direct compression method. The VP16 implants were characterized with regards to drug content, micromorphology, drug release profiles, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) analyses. Furthermore, the biodistribution of VP16 via intratumoral chemotherapy with VP16 implants was investigated using the murine Lewis lung carcinoma model. Our results showed that VP16 dispersed homogenously in the polymeric matrix. Both in vitro and in vivo drug release profiles of the implants were characterized by high initial burst release followed by sustained release of VP16. The VP16 implants showed good compatibility between VP16 and the excipients. Intratumoral chemotherapy with VP16 implants resulted in significantly higher concentration and longer duration of VP16 in tumor tissues compared with single intraperitoneal injection of VP16 solution. Moreover, we found the low level of VP16 in plasma and normal organ tissues. These results suggested that intratumoral chemotherapy with VP16 implants enabled high drug concentration at the target site and has the potential to be used as a novel method to treat cancer.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Poliésteres/química , Animais , Antineoplásicos/farmacologia , Varredura Diferencial de Calorimetria , Linhagem Celular Tumoral , Implantes de Medicamento , Liberação Controlada de Fármacos , Etoposídeo/farmacologia , Camundongos , Ratos , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Tecnologia Farmacêutica/métodos , Distribuição Tecidual
9.
Int J Pharm ; 583: 119399, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376439

RESUMO

It has been suggested that oral absorption of low-permeable P-glycoprotein (P-gp) substrates can be increased through saturation of P-gp. For BCS class IV drug substances, saturating P-gp is challenging due to low aqueous solubility. The present study investigated if the BCS IV drug substance etoposide could be solubilized to a concentration saturating P-gp after oral administration. A formulation consisting of 10% (w/v) of pluronic® F-127 and polyvinylpyrrolidone/vinyl acetate (PVP/VA), and 57% (v/v) ethanol enhanced etoposide's solubility approximately 100 times (16 mg mL-1) compared to its aqueous solubility. In vitro, this formulation was stable upon dilution in simulated intestinal fluid. In male Sprague-Dawley rats, oral administration of increasing solubilized etoposide doses using the formulation matrix increased the AUC0-∞ of etoposide dose-proportionally but resulted in a lower absolute oral bioavailability (F) and rate of absorption as compared to control. At the highest investigated dose (100 mg kg-1), AUC0-∞ and Cmax were significantly increased by 2.9- and 1.4-fold, respectively, compared to control dosed at 20 mg kg-1. A single oral dose of 20 mg kg-1 zosuquidar followed by 20 mg kg-1 oral etoposide increased F 8.6-fold. In conclusion, a stable formulation with improved etoposide solubility was developed, yet the formulation did not result in increased oral bioavailability of etoposide.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Absorção Intestinal , Mucosa Intestinal/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Dibenzocicloeptenos/administração & dosagem , Composição de Medicamentos , Estabilidade de Medicamentos , Etanol/química , Etoposídeo/química , Humanos , Injeções Intravenosas , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Modelos Biológicos , Poloxâmero/química , Polivinil/química , Povidona/química , Quinolinas/administração & dosagem , Ratos Sprague-Dawley , Solubilidade
10.
Int J Pharm ; 577: 119095, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32004680

RESUMO

The objective of the study was to assess the effect of enhanced mucoadhesion of a cationic mucoadhesive nanostructured lipid carrier (NLC) on its ocular disposition after topical administration. The NLC was made mucoadhesive by surface coating with chitosan oligosaccharide (COS), a low molecular weight derivate of chitosan which is more suitable for drug delivery applications as compared to the native chitosan. The NLC was characterised by surface evaluating techniques like SANS and XPS for confirming coating of COS over the surface of NLC. In order to assess the effect of COS coating on in vivo ocular mucoadhesion, coumarin loaded NLC were topically administered to rats and the sagittal sections of the eyes were imaged using confocal microscopy. The COS coated NLC were seen to adhere more around the ocular surface than the uncoated NLC during the 4-h study. The improved ocular retention for COS-NLC reflected on the content of Etoposide within the eye, which showed a higher concentration of Etoposide, as compared to the uncoated NLC. The NLC was also assessed for any ocular irritancy in rabbits and repeat dose toxicity in rats and found to be relatively non-irritant and non-toxic as compared to appropriate controls. Thus, the study asserts that to achieve higher concentration of therapeutics within the eye, the formulations like NLC are not just required to be permeating but also retentive on the surface of the eye to achieve appreciable concentrations.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Etoposídeo/administração & dosagem , Nanoestruturas , Administração Tópica , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Cumarínicos/química , Portadores de Fármacos/química , Etoposídeo/farmacocinética , Olho/metabolismo , Lipídeos/química , Mucinas/metabolismo , Oligossacarídeos/química , Coelhos , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Testes de Toxicidade
11.
J Am Chem Soc ; 141(43): 17133-17141, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31580665

RESUMO

Temporal and reversible control over protein and cell conjugations holds great potential for traceless release of antibody-drug conjugates (ADCs) on tumor sites as well as on-demand altering or removal of targeting elements on cell surface. We herein developed a bioorthogonal and traceless releasable reaction on proteins and intact cells to fulfill such purposes. A systematic survey of transition metals in catalyzing the bioorthogonal cleavage reactions revealed that copper complexes such as Cu(I)-BTTAA and dual-substituted propargyl (dsPra) or propargyloxycarbonyl (dsProc) moieties offered a bioorthogonal releasable pair for reversible blockage and rescue of primary amines and phenol alcohols on small molecule drugs, protein side chains, as well as intact cell surface. For proof-of-concept, we employed such Cu(I)-BTTAA/dsProc and Cu(I)-BTTAA/dsPra pairs as a "traceless linker" strategy to construct cleavable ADCs to unleash cytotoxic compounds on cancer cells in situ and as a "reversible modification" strategy for cell surface engineering. Furthermore, by coupling with the genetic code expansion strategy, we site-specifically modulated ligand-receptor interactions on live cell membranes. Together, our work expanded the transition-metal-mediated bioorthogonal cleavage tool kit from terminal decaging to internal-linker breakage, which offered a temporal and reversible conjugation strategy on therapeutic proteins and cells.


Assuntos
Membrana Celular/química , Cobre/química , Imunoconjugados/química , Compostos Organometálicos/química , Pró-Fármacos/química , Mapas de Interação de Proteínas/genética , Aminas/química , Cumarínicos/química , Doxorrubicina/química , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Etoposídeo/química , Etoposídeo/farmacocinética , Proteínas de Fluorescência Verde/genética , Células HeLa , Humanos , Imunoconjugados/metabolismo , Ligantes , Lisina-tRNA Ligase/genética , Mutagênese , Fenóis/química , Pró-Fármacos/farmacocinética , Estudo de Prova de Conceito , Receptor ErbB-2/química , Receptor ErbB-2/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-31494629

RESUMO

Background Subtenon anticancer drugs are given as an adjunct to systemic chemotherapy for conditions like retinoblatoma. This study evaluated the ocular kinetics of nano-emulsion formulation of etoposide (NanoEt) and compared it with an equal dose of commercially available alcohol-based etoposide formulation in healthy rabbits. Methods A nanoemulsion formulation of NanoEt was developed and then evaluated for its ocular kinetics by subtenon administration in healthy rabbits. After the sterile subtenon administration of the drug, the eyes were enucleated after CO2 euthanasia at time intervals of 2 h, 6 h, 12 h, and 24 h, and ocular tissues, blood, and plasma were separated. The concentration of etoposide in the ocular tissues and blood was quantified using liquid chromatography tandem mass spectrometry (LC MS/MS). Results This study found that subtenon injection of NanoEt showed 24 times higher concentration in rabbit retina compared to an equal dose of conventional marketed formulation. Based on the ocular tissue bioavailability calculations (AUC0-24), the present study revealed that the formulation enhanced 90% ocular bioavailability of etoposide, when it was injected in the form of nano-emulsion in most of the tissues. Conclusions NanoEt has better bioavailability compared to the commercial alcohol-based formulation for subtenon injection. Low systemic exposure showed further advantage for its projected use in retinoblastoma (Rb) as an adjunct therapy. Further studies in Rb animal models are required to evaluate its safety and efficacy, for its clinical utility.


Assuntos
Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Olho/metabolismo , Animais , Disponibilidade Biológica , Composição de Medicamentos , Emulsões/administração & dosagem , Emulsões/farmacocinética , Feminino , Injeções Intraoculares , Masculino , Nanotecnologia , Coelhos
13.
Nanomedicine (Lond) ; 14(11): 1403-1427, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31180263

RESUMO

Aim: High-dose administration of etoposide (VP16) was limited by its poor aqueous solubility and severe systemic toxicity on lymphoma therapy. Herein, a novel VP16-loaded lipid-based nanosuspensions (VP16-LNS) was developed for improving drug solubility, enhancing antitumor effect and reducing systemic toxicity. Materials & methods: VP16-LNS with soya lecithin and D-α-tocopheryl PEG 1000 succinate (TPGS) as stabilizers were prepared by nanoprecipitation method. Results: VP16-LNS exhibited uniform spherical morphology, small particle size and favorable colloidal stability. The concentration of VP16 in VP16-LNS was high enough (1017.67 µg/ml) for high-dose therapy on lymphoma. Moreover, VP16-LNS displayed long blood circulation time, selective intratumoral accumulation, remarkable antitumor effect and upregulated safety. Conclusion: VP16-LNS would be an efficient nanoformulation for clinical intravenous application against lymphoma.


Assuntos
Antineoplásicos Fitogênicos/química , Etoposídeo/química , Linfoma/tratamento farmacológico , Nanocápsulas/química , Fosfolipídeos/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Etoposídeo/farmacocinética , Feminino , Humanos , Lecitinas/química , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química , Solubilidade , Suspensões/química , Distribuição Tecidual
14.
Clin Cancer Res ; 25(16): 5094-5106, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31113843

RESUMO

PURPOSE: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood-brain barrier. We evaluate the unique intracavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid; PLGA) and poly(ethylene glycol; PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. EXPERIMENTAL DESIGN: To prolong stability of temozolomide prodrug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytic methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized preclinically to develop Gliadel. RESULTS: Combined etoposide and temozolomide in vitro release (22 and 7 days, respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG-invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain. CONCLUSIONS: The significant survival benefit of intracavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds.


Assuntos
Portadores de Fármacos , Etoposídeo/administração & dosagem , Glioma/mortalidade , Glioma/terapia , Temozolomida/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Etoposídeo/farmacocinética , Glioma/diagnóstico , Glioma/patologia , Humanos , Nanopartículas , Poliésteres , Polietilenoglicóis , Temozolomida/farmacocinética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
15.
ACS Chem Biol ; 14(6): 1110-1114, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31091068

RESUMO

Tyrosyl DNA phosphodiesterase 2 (TDP2) facilitates the repair of topoisomerase II (TOP2)-linked DNA double-strand breaks and, as a consequence, is required for cellular resistance to TOP2 "poisons". Recently, a deazaflavin series of compounds were identified as potent inhibitors of TDP2, in vitro. Here, however, we show that while some deazaflavins can induce cellular sensitivity to the TOP2 poison etoposide, they do so independently of TDP2 status. Consistent with this, both the cellular level of etoposide-induced TOP2 cleavage complexes and the intracellular concentration of etoposide was increased by incubation with deazaflavin, suggesting an impact of these compounds on etoposide uptake/efflux. In addition, deazaflavin failed to increase the level of TOP2 cleavage complexes or sensitivity induced by m-AMSA, which is a different class of TOP2 poison to which TDP2-defective cells are also sensitive. In conclusion, while deazaflavins are potent inhibitors of TDP2 in vitro, their limited cell permeability and likely interference with etoposide influx/efflux limits their utility in cells.


Assuntos
Compostos Aza/química , Proteínas de Ligação a DNA/antagonistas & inibidores , Etoposídeo/farmacocinética , Flavinas/farmacologia , Inibidores da Topoisomerase II/farmacocinética , Animais , Transporte Biológico , Linhagem Celular , Galinhas , Flavinas/química , Flavinas/farmacocinética , Humanos , Diester Fosfórico Hidrolases , Bibliotecas de Moléculas Pequenas/farmacologia
16.
Pharm Res ; 36(7): 96, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31076908

RESUMO

PURPOSE: Etoposide is one of the principal chemotherapeutic agents used for the treatment of small cell lung cancer (SCLC). There are some disadvantages of currently available etoposide injections (EI) such as low LD50, necessary dilution before clinical application, thus, etoposide lipid emulsion (ELE) was developed and expected to have a comparable or better effect on SCLC. METHODS: ELE was prepared through high-pressure homogenization method, and a series of evaluations such as encapsulation efficiency (EE%), in vitro release, stability studies, pharmacokinetics study, safety assessment and pharmacodynamic study were systematically performed. RESULTS: ELE had high EE% and good stability. Pharmacokinetics study revealed ELE had a longer T1/2 F compared with EI, which is in agreement with in vitro release in which ELE released slower than EI (EI released over 80% within 12 h, while ELE released 50%). Safety tests showed there was no hematology or significant tendency of accumulated toxicity, and LD50 of ELE was higher than EI. Furthermore, percentage of tumor inhibition (TI%) of ELE was comparable with EI in the same dose. CONCLUSIONS: Unlike EI, ELE could further increase the dose, which endowed etoposide with a greater potential for cytotoxic agent. LE is a promising delivery system for etoposide.


Assuntos
Antineoplásicos/farmacocinética , Etoposídeo/farmacocinética , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Portadores de Fármacos , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões , Etoposídeo/administração & dosagem , Feminino , Humanos , Injeções Intravenosas , Masculino , Ácidos Oleicos/química , Ratos Wistar
17.
Mater Sci Eng C Mater Biol Appl ; 100: 959-970, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948132

RESUMO

The present study was to develop etoposide loaded solid lipid nanoparticles (SLN) and optimize it for effective ocular delivery to the posterior eye. SLN were prepared by melt-emulsification and ultrasonication technique. Etoposide loaded SLN were optimized by using three-factor three levels Box-Behnken design to establish the functional relationships between variables on responses of particle size, polydispersity index (PDI) and entrapment efficiency (EE). SLN were characterized for size & surface morphology, entrapment efficiency and in vitro release. Further the pharmacokinetic study of optimized formulation after intravitreal administration was evaluated in Wister rats. The deposition in the ocular tissues was checked by scintigraphic analysis in Albino rabbits. Histology was also done to evaluate morphological changes if any occur after treatment. The particle size, PDI and EE obtained for the optimized formulation (Z15) were 239.43 ±â€¯2.35 nm, 0.261 ±â€¯0.001 and 80.96 ±â€¯2.21% respectively. Single intravitreal administrations of SLN were able to give sustained etoposide concentration in the vitreous for 7 consecutive days which was also supported by the results of Gamma scintigraphic study. Histology of posterior ocular tissues do not showed any serious toxic effect. Therefore it can concluded that etoposide loaded SLN was able to maintain vitreous concentration of drug without any serious toxic effect to the surrounding ocular tissues after an intravitreous administration in rat eye.


Assuntos
Sistemas de Liberação de Medicamentos , Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Olho/efeitos dos fármacos , Lipídeos/química , Nanopartículas/química , Análise de Variância , Animais , Varredura Diferencial de Calorimetria , Liberação Controlada de Fármacos , Etoposídeo/sangue , Excipientes , Olho/patologia , Masculino , Tamanho da Partícula , Coelhos , Ratos Wistar , Análise de Regressão , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
18.
ACS Appl Mater Interfaces ; 11(20): 18111-18122, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31006230

RESUMO

The study of multifunctional polymer micelles combined with chemotherapy due to reduced systemic toxicity and enhanced efficacy has attracted intensive attention. Herein, a multifunctional core-cross-linked hybrid micelle system based on mPEG- b-PGu(BA-TPE) and OCT-PEG- b-PGu(DA-TPE) with pH- and redox-triggered drug release and aggregation-induced emission (AIE) active imaging has been developed for active targeting of neuroendocrine neoplasms (NENs), especially neuroendocrine carcinomas (NECs) with poor prognosis. These micelles showed excellent biocompatibility and stability. After the formation of borate ester bonds, core-cross-linked micelles (CCLMs) showed enhanced emission properties. In addition, etoposide (ETO), one of the most important anticancer drugs of NECs, was loaded into the hydrophobic core of micelles by self-assembly with an average diameter of 274.6 nm and spherical morphology. Octreotide (OCT) conjugated onto the micelles enhanced cellular uptake by receptor-mediated endocytosis. ETO-loaded micelles demonstrated the dual-responsive triggered intracellular drug release and great tumor suppression ability in vitro. Compared with free ETO, ETO-loaded CCLMs exhibited a considerable antitumor effect and significantly reduced side effects. Considering the active tumor targeting, dual-responsive drug release and the AIE effect, the polymer micelle system will be a potential candidate for diagnosis and oncotherapy of NENs.


Assuntos
Antineoplásicos , Etoposídeo , Micelas , Neoplasias/tratamento farmacológico , Octreotida , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Etoposídeo/química , Etoposídeo/farmacocinética , Etoposídeo/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Neoplasias/patologia , Octreotida/química , Octreotida/farmacocinética , Octreotida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Pharm Res ; 36(3): 38, 2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635794

RESUMO

PURPOSE: This work aimed to develop a population PK/PD tumor-in-host model able to describe etoposide effects on both tumor cells and host in Walker-256 tumor-bearing rats. METHODS: Etoposide was investigated on thirty-eight Wistar rats randomized in five arms: two groups of tumor-free animals receiving either placebo or etoposide (10 mg/kg bolus for 4 days) and three groups of tumor-bearing animals receiving either placebo or etoposide (5 or 10 mg/kg bolus for 8 or 4 days, respectively). To analyze experimental data, a tumor-in-host growth inhibition (TGI) model, based on the Dynamic Energy Budget (DEB) theory, was developed. Total plasma and free-interstitial tumor etoposide concentrations were assessed as driver of tumor kinetics. RESULTS: The model simultaneously describes tumor and host growths, etoposide antitumor effect as well as cachexia phenomena related to both the tumor and the drug treatment. The schedule-dependent inhibitory effect of etoposide is also well captured when the intratumoral drug concentration is considered as the driver of the tumor kinetics. CONCLUSIONS: The DEB-based TGI model capabilities, up to now assessed only in mice, are fully confirmed in this study involving rats. Results suggest that well designed experiments combined with a mechanistic modeling approach could be extremely useful to understand drug effects and to describe all the dynamics characterizing in vivo tumor growth studies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Etoposídeo/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Caquexia/tratamento farmacológico , Carcinoma 256 de Walker/tratamento farmacológico , Carcinoma 256 de Walker/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Humanos , Masculino , Modelos Biológicos , Distribuição Aleatória , Ratos , Ratos Wistar , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Clin Pharmacol ; 59(5): 638-645, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30512187

RESUMO

This study aimed to predict the area under the curve (AUC) of the initial busulfan dose using a test dose with the sparse sampling scheme in adult patients who underwent hematopoietic cell transplant. A test dose of 0.8 mg/kg busulfan was used 2 days before twice-daily intravenous busulfan-based conditioning regimens were administered. The AUC and the clearance (CL) were calculated for both the test dose and the first dose (AUCT , CLT , AUC1, and CL1 ) by noncompartmental analysis. The sparse sampling schemes of the test dose were developed by Bayesian method based on the population pharmacokinetic model. The optimal sparse sampling schemes were determined by evaluating the mean prediction error, the root mean square error, the absolute mean prediction error, and Bland-Altman plot. The mean AUC1 was 7.20 ± 1.48 mg • h/L, which ranged from 4.70 to 9.46 mg • h/L. The AUC1 was below the therapeutic concentration of 7.38 mg • h/L in 45% (9 of 20) of the patients. The CLT of 3.05 ± 0.56 mL/min/kg was not significantly different with the CL1 of 3.03 ± 0.69 mL/min/kg (P = .901). A sampling scheme at 2 and 6 hours after the test dose was developed to predict the AUCT (mean prediction error of 1.64%, root mean square error of 6.17%, and absolute mean prediction error of 4.94%). Additionally, the Bland-Altman plot showed that the 2-sampling scheme provided an acceptably accurate prediction of the AUC1 . A test dose with a 2-sampling scheme was sufficient to personalize the initial busulfan dosing in hematopoietic cell transplant recipients.


Assuntos
Bussulfano/farmacocinética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adulto , Área Sob a Curva , Teorema de Bayes , Coleta de Amostras Sanguíneas/métodos , Bussulfano/administração & dosagem , Bussulfano/sangue , Ciclofosfamida/administração & dosagem , Ciclofosfamida/sangue , Ciclofosfamida/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos/métodos , Etoposídeo/administração & dosagem , Etoposídeo/sangue , Etoposídeo/farmacocinética , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/sangue , Vidarabina/farmacocinética , Gencitabina
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