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1.
Br J Radiol ; 93(1106): 20190742, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778316

RESUMO

OBJECTIVE: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX. METHODS: We used HeLa and MDA-MB-231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator. RESULTS: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. CONCLUSION: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue. ADVANCES IN KNOWLEDGE: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas , Radiossensibilizantes/farmacologia , Antineoplásicos/farmacocinética , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Docetaxel/farmacocinética , Sinergismo Farmacológico , Feminino , Ouro/farmacocinética , Células HeLa , Humanos , Radiossensibilizantes/farmacocinética , Neoplasias de Mama Triplo Negativas/radioterapia , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/radioterapia
2.
Pharm Res ; 36(12): 181, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732882

RESUMO

BACKGROUND: Docetaxel is commonly used in elderly patients, who are frequently diagnosed with prostate cancer. Although previous studies revealed no clinically relevant impact of older age on docetaxel pharmacokinetics (PK), this may be masked by indication. Metastatic castration-resistant prostate cancer (mCRPC) patients were reported to have approximately two-times lower systemic exposure compared to patients with other solid tumors. This study assessed the impact of older age on docetaxel PK, also considering the effect of indication on docetaxel PK. METHODS: Prospectively collected docetaxel PK data from patients aged ≥70 was pooled with PK data from an earlier published multicenter study. A 3-compartment population PK model, including multiple covariates, was used to describe docetaxel plasma concentration-time data. We added the effect of prostate cancer (mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC)) on clearance to this model. Hereafter, we evaluated the additional impact of older age on docetaxel clearance, using a significance threshold of p < 0.005. RESULTS: Docetaxel plasma concentration-time data from 157 patients were analyzed. Median age in the total cohort was 67 years (range 31-87), with 49% of the total cohort aged ≥70. The impact of age on docetaxel clearance was statistically significant (p < 0.005). For a typical patient, a 10-year and 20-year increase of age led to a reduction in clearance of 17% and 34%, respectively. CONCLUSION: In this cohort study, age significantly and independently affected docetaxel clearance, showing lower docetaxel clearance in elderly patients. In our cohort, mCRPC and mHSPC patients both had higher clearance than patients with other solid tumors.


Assuntos
Antineoplásicos/farmacocinética , Docetaxel/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Drug Dev Ind Pharm ; 45(11): 1788-1798, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500443

RESUMO

Ternary mixed micelles constituted of Soluplus®, sodium cholate, and phospholipid were prepared as nano-delivery system of the anticancer drug, docetaxel. The formulation of docetaxel-loaded ternary mixed micelles (DTX-TMMs) with an optimized composition (Soluplus®/sodium cholate/phospholipid= 3:2:1 by weight) were obtained. The main particle size of DTX-TMMs was 76.36 ± 2.45 nm, polydispersity index (PDI) was 0.138 ± 0.039, and the zeta potential was -8.46 ± 0.55 mv. The encapsulation efficiency was 94.24 ± 4.30% and the drug loading was 1.25%. The critical micelle concentration value was used to assess the ability of carrier materials to form micelles. The results indicated that the addition of Soluplus® to sodium cholate-phospholipid mixed micelles could reduce the critical micelle concentration and improve the stability. In vitro release studies demonstrated that compared with DTX-Injection group, the DTX-TMMs presented a controlled release property of drugs. In vivo pharmacodynamics results suggested that DTX-TMMs had the most effective inhibitory effect on tumor proliferation and had good biosafety. In addition, the relative bioavailability of mixed micelles was increased by 1.36 times compared with the DTX-Injection in vivo pharmacokinetic study indicated that a better therapeutic effect could be achieved. In summary, the ternary mixed micelles prepared in this study are considered to be promising anticancer drug delivery systems.


Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Docetaxel/farmacocinética , Liberação Controlada de Fármacos , Células HT29 , Humanos , Injeções Intralesionais , Camundongos , Micelas , Neoplasias/patologia , Tamanho da Partícula , Fosfolipídeos/química , Polietilenoglicóis/química , Polivinil/química , Ratos , Colato de Sódio/química , Solubilidade , Ensaios Antitumorais Modelo de Xenoenxerto
4.
AAPS PharmSciTech ; 20(7): 302, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31489504

RESUMO

Docetaxel (DTX) was effective in the treatment of neoplasm but could only be administered intravenously with the poor oral bioavailability owing to its undesirable solubility, remarkably metabolic conversion, and other factors. Cimetidine (CMD), a classic CYP3A4 isozyme inhibitor, had exhibited a wide range of inhibition on the metabolism of many drugs. The aim of this study was to construct the novel docetaxel-cimetidine (DTX-CMD) complex and the chitosan-deoxycholate nanoparticles based on it to confirm whether this formulation could show advantages in terms of solubility, dissolution rate, small intestinal absorption, and oral bioavailability in comparison with the pure drug. The solid-state characterization was carried out by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), and simultaneous DSC-TGA (SDT). Dissolution rate and kinetic solubility study were determined by evaluating the amount of DTX in distilled water and phosphate buffer solution (pH = 7.4), respectively. And small intestinal absorption and pharmacokinetics study were conducted in rats. The results of this study demonstrated that we successfully constructed DTX-CMD complex and its chitosan-deoxycholate nanoparticles. Furthermore, the DTX-CMD complex increased the solubility of DTX by 2.3-fold and 2.1-fold in distilled water and phosphate buffer solution, respectively. The ultimate accumulative amount of DTX-CMD complex nanoparticles through rat small intestinal in 2 h was approximately 4.9-fold and the oral bioavailability of the novel nanoparticles was enhanced 2.8-fold, compared with the pure DTX. The superior properties of the complex nanoparticles could both improve oral bioavailability and provide much more feasibility for other formulations of DTX.


Assuntos
Antineoplásicos/química , Cimetidina/química , Docetaxel/química , Administração Oral , Animais , Disponibilidade Biológica , Quitosana/química , Cimetidina/farmacocinética , Ácido Desoxicólico/química , Docetaxel/farmacocinética , Composição de Medicamentos , Masculino , Nanopartículas/química , Ratos , Ratos Sprague-Dawley , Solubilidade
5.
Breast Cancer Res Treat ; 178(1): 121-133, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31368034

RESUMO

PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Oxazepinas/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Docetaxel/efeitos adversos , Docetaxel/farmacocinética , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Neoplasias Pulmonares/genética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Oxazepinas/efeitos adversos , Oxazepinas/farmacocinética , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Receptor ErbB-2/metabolismo , Análise de Sobrevida , Resultado do Tratamento
6.
Pharm Dev Technol ; 24(9): 1164-1174, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31340709

RESUMO

We prepared octreotide (OCT)-modified curcumin plus docetaxel micelles to enhance active targeting and inhibit tumor metastasis by destroying vasculogenic mimicry (VM) channels. Soluplus was applied as an amphiphilic material to form micelles via film dispersion. The cytotoxic effects, active cellular targeting, and inhibitory effects on metastasis were systematically evaluated in vitro using A549 cells, and in vivo antitumor effects were evaluated using xenograft tumor-bearing mice. In vitro assays indicated that the OCT-modified curcumin plus docetaxel micelles showed robust cytotoxicity on A549 cells and effectively inhibited VM channels and tumor metastasis. Studying the mechanism of action indicated that OCT-modified curcumin plus docetaxel micelles downregulated MMP-2 and HIF-1α. In vivo assays indicated that OCT-modified curcumin plus docetaxel micelles increased drug accumulation at tumor sites and showed obvious antitumor efficacy. The developed OCT-modified curcumin plus docetaxel micelles may offer a promising treatment strategy for non-small-cell lung cancer.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Curcumina/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Octreotida/administração & dosagem , Células A549 , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Curcumina/análogos & derivados , Curcumina/farmacocinética , Curcumina/uso terapêutico , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Octreotida/análogos & derivados , Octreotida/farmacocinética , Octreotida/uso terapêutico , Polietilenoglicóis/química , Polivinil/química
7.
AAPS PharmSciTech ; 20(6): 220, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201588

RESUMO

In this study, poly-(lactic-co-glycolic) acid (PLGA) was conjugated with aspartic acid and was characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy. Docetaxel-loaded polymeric micelles were prepared, and piperine was tagged. The neuroblastoma cytotoxicity studies revealed a substantially higher cytotoxic potential of the developed system to that of plain docetaxel, which was further corroborated by cellular uptake employing confocal laser scanning microscopy. The hemocompatible system was able to enhance the pharmacokinetic profile in terms of 6.5-fold increment in bioavailability followed by a 3.5 times increase in the retention time in comparison with the plain drug. The single-point brain bioavailability of docetaxel was amplified by 3.3-folds, signifying a better uptake and distribution to brain employing these carriers. The findings are unique as the physically adsorbed piperine was released before the DTX, increasing the propensity of curbing the CYP3A4 enzyme, which plays a vital role in the degradation of docetaxel. Meanwhile, piperine might have compromised the P-gp efflux mechanism, which can be ascribed to the enhanced retention of the drug at the target site. The elevated target site concentrations and extended residence by a biocompatible nanocarrier supplemented with co-delivery of piperine inherit immense promises to deliver this BCS class IV drug more safely and effectively.


Assuntos
Alcaloides/química , Antineoplásicos Fitogênicos/administração & dosagem , Benzodioxóis/química , Docetaxel/administração & dosagem , Micelas , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular Tumoral , Docetaxel/farmacocinética , Humanos , Ratos , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier
8.
Nanoscale ; 11(23): 11285-11304, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31165845

RESUMO

The success of glioma chemotherapy is hampered by poor drug penetration ability across the blood-brain barrier (BBB) and low intratumoral drug concentration. Novel tumor-targeted delivery systems are useful in specifically accumulating in the tumor foci and penetrating into the glioma core after entering into the brain. Here we show that a multi-targeting hybrid nanocarrier (Pep-MLHA HNPs) system based on hyaluronic acid (HA)-modified polymer and a functional peptide possesses multi-target capability and stronger penetration ability into the core of three-dimensional tumor spheroids, could migrate efficiently across the BBB in vitro. The intensity of the Pep-MLHA HNPs after transporting across the BBB was 5.2-fold and 5.6-fold higher than that of ML NPs in C6 and U87 cells, respectively. More interestingly, this multi-targeting hybrid system displayed high colloidal stability in PBS solution, and weak negative zeta potential (-1.99 ± 0.655 mV) minimizing nonspecific interactions with plasma proteins and promoting long-term circulation in vivo. Additionally, the multi-targeting hybrid system induced enhanced tumor localization in U87 in situ-bearing nude mice and xenograft-bearing nude mice after systemic administration. Furthermore, docetaxel (DTX)-loaded Pep-MLHA HNPs showed negligible systemic toxicity and enhanced therapeutic efficacy, with significantly improved survival rates in intracranial C6 glioma-bearing rats. The 50% survival rate of DTX/Pep-MLHA HNPs-treated rats (40 days) was significantly longer than that of rats treated with NS (22 days), Taxotere® (25 days), DTX/ML NPs (25 days), DTX/Pep NPs (32 days) and DTX/MLHA NPs (29 days). All the results suggested that the multi-targeting hybrid nanocarrier system is promising for glioma treatment.


Assuntos
Barreira Hematoencefálica , Neoplasias Encefálicas , Docetaxel , Portadores de Fármacos , Glioblastoma , Nanopartículas , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/farmacologia , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Glioblastoma/irrigação sanguínea , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Ácido Hialurônico/farmacologia , Masculino , Camundongos , Camundongos Nus , Células NIH 3T3 , Nanopartículas/química , Nanopartículas/uso terapêutico , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Drug Deliv ; 26(1): 542-550, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31090467

RESUMO

Self-nanoemulsifying drug delivery system (SNEDDS) have been considered as a promising platform for oral delivery of many BCS (biopharmaceutics classification system) class IV drugs, such as docetaxel (DTX). However, oral chemotherapy with DTX is also restricted by its active P-glycoprotein (P-gp) efflux and hepatic first-pass metabolism. To address these challenges, we developed a novel SNEDDS co-loaded with DTX and cyclosporine A (CsA) to achieve effective inhibition of P-gp efflux and P450 enzyme metabolization, improving oral bioavailability of DTX. The SNEDDS showed uniform droplet size of about 30 nm. Additionally, the prepared SNEDDS exhibited a sequential drug release trend of CsA prior to DTX. The intestinal experiments confirmed that the membrane permeability of DTX was significantly increased in the whole intestinal tract, especially in the jejunum segment. Furthermore, the oral bioavailability of co-loaded SNEDDS was 9.2-fold and 3.4-fold higher than DTX solution and DTX SNEDDS, respectively. More importantly, it exhibited a remarkable antitumor efficacy with a reduced toxicity compared with intravenously administered DTX solution. In summary, DTX-CsA co-loaded SNEDDS is a promising platform to facilitate oral docetaxel-based chemotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Ciclosporina/administração & dosagem , Docetaxel/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Liberação Controlada de Fármacos , Emulsões , Feminino , Absorção Intestinal , Camundongos Endogâmicos BALB C , Nanopartículas/química , Ratos Sprague-Dawley , Solubilidade , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Toxicol In Vitro ; 59: 126-134, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30986424

RESUMO

The present study aimed to explore the potential of hydroxylated carbon nanotubes (CNTnols) conjugated with aspartic acid for the delivery of docetaxel (DTX) to breast cancer cells. The conjugate was well-characterized by FT-IR, NMR, XRD and FE-SEM. The nanoconjugate offered a hydrodynamic diameter of 86.31 ±â€¯1.02 nm, with a PDI of 0.113 and zeta potential of -41.6 ±â€¯0.17 mV. The designed nanosystem offered a controlled & pH dependent release vouching release of drug in the cancerous cytosol, not in blood, assuring delivery of the pay-load to the site of action. The carriers offered substantial hemocompatibility and lower plasma protein binding, ensuring more drug available at the site of action. The in-vitro cell viability studies in MDA MB-231 cells inferred approx. 2.8 times enhancement in the cytotoxicity potential of the conjugate vis-à-vis plain drug. Pharmacokinetic studies also corroborated the superiority of the designed nanoconjugate in terms of enhanced bioavailable fractions, reduced clearance and longer bioresidence to that of plain docetaxel. The present studies, successfully provide a workable nanomedicine, loaded with a BCS class-IV drug, for improved efficacy and safety in breast cancer.


Assuntos
Antineoplásicos/administração & dosagem , Ácido Aspártico/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Docetaxel/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanotubos de Carbono , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Ácido Aspártico/química , Ácido Aspártico/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/química , Docetaxel/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Nanotubos de Carbono/química , Ratos Wistar
11.
Nat Biomed Eng ; 3(4): 264-280, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30952988

RESUMO

Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2-a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue. We also show that administration of the nanotherapeutic in rats and dogs resulted in minimal haematological toxicity, as well as the absence of neutropenia and improved overall tolerability in multiple rodent models. Targeting of the nanotherapeutic to EphA2 improved tumour penetration and resulted in markedly enhanced antitumour activity (compared with administration of free docetaxel and non-targeted nanotherapeutic controls) in multiple tumour-xenografted mice. This nanomedicine could become a potent and safe therapeutic alternative for cancer patients undergoing chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas/uso terapêutico , Receptor EphA2/metabolismo , Animais , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Docetaxel/sangue , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Humanos , Lipossomos , Camundongos Endogâmicos NOD , Camundongos SCID , Taxoides/farmacologia , Taxoides/uso terapêutico , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Pulm Pharmacol Ther ; 55: 50-61, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30738974

RESUMO

Pulmonary delivery of anti-cancer drugs in the form of nanoparticulate dry powders is considered a promising modality for treating lung cancer. However, it is not known whether the pharmacodynamics and pharmacokinetics of nano-preparations are altered after co-spray drying. In this study, we compared the physicochemical property, anti-cancer activity, tumor targeting and pharmacokinetic behavior of docetaxel-loaded folic acid-conjugated liposomes (LPs-DTX-FA) with those of dry powder prepared by co-spray-drying LPs-DTX-FA. The particle size and PDI after re-dispersion of the powder were increased. The re-dispersed liposomes showed increased cellular uptake via micropinocytosis and exhibited higher cytotoxicity than LPs-DTX-FA. Tumor targeting of re-dispersed liposomes was less effective compared with LPs-DTX-FA but the metabolism of re-dispersed liposomes was decreased. Tracheal administration resulted in a 45-fold higher concentration of docetaxel in the lung of Sprague Dawley rats at 30 min as compared with intravenous administration. Our results indicated that co-spray drying did change the properties, while tracheal administration of the dry powder provided higher drug exposure at the tumor site without increasing the exposure of other organs. Thus, inhaled dry powders might be clinically effective for treatment of lung cancer.


Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Ácido Fólico/química , Neoplasias Pulmonares/tratamento farmacológico , Administração por Inalação , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Docetaxel/química , Docetaxel/farmacocinética , Sistemas de Liberação de Medicamentos , Inaladores de Pó Seco , Lipossomos , Masculino , Tamanho da Partícula , Pós , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
13.
Molecules ; 24(2)2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30641899

RESUMO

Flexible liposomes (FLs) were developed as promising nano-carriers for anticancer drugs. Coating them with chitosan (CS) could improve their drug delivery properties. The aim of this study was to investigate the physicochemical characteristics, pharmacokinetics behavior, and cytotoxic efficacy of docetaxel (DTX)-loaded CS-coated FLs (C-FLs). DTX-loaded FLs and C-FLs were produced via thin-film evaporation and electrostatic deposition methods, respectively. To explore their physicochemical characterization, the particle size, zeta potential, encapsulation efficiency (EE%), morphology, and DTX release profiles were determined. In addition, pharmacokinetic studies were performed, and cytotoxic effect was assessed using colon cancer cells (HT29). Various FLs, dependent on the type of surfactant, were formed with particle sizes in the nano-range, 137.6 ± 6.3 to 238.2 ± 14.2 nm, and an EE% of 59⁻94%. Moreover, the zeta potential shifted from a negative to a positive value for C-FL with increased particle size and EE%, and the in vitro sustained-release profiles of C-FL compared to those of FL were evident. The optimized C-FL containing sodium deoxycholate (NDC) and dicetyl phosphate (DP) elicited enhanced pharmacokinetic parameters and cytotoxic efficiency compared to those of the uncoated ones and Onkotaxel®. In conclusion, this approach offers a promising solution for DTX delivery.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Quitosana , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Lipossomos , Animais , Antineoplásicos/química , Disponibilidade Biológica , Fenômenos Químicos , Quitosana/química , Docetaxel/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Lipossomos/química , Tamanho da Partícula
14.
Molecules ; 24(2)2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30642009

RESUMO

Many anti-cancer drugs are difficult to formulate into an oral dosage form because they are both poorly water-soluble and show poor permeability, the latter often as a result of being an intestinal efflux pump substrate. To obtain a more water-soluble formulation, one can take advantage of the higher solubility of the amorphous form of a given drug, whereas to increase permeability, one can make use of an efflux pump inhibitor. In this study, a combination of these two strategies was investigated using the co-amorphous approach, forming an amorphous mixture of two anti-cancer drugs, docetaxel (DTX) and bicalutamide (BIC). The efflux substrate, DTX, was combined with the efflux inhibitor, BIC, and prepared as a single phase co-amorphous mixture at a 1:1 molar ratio using vibrational ball milling. The co-amorphous formulation was tested in vitro and in vivo for its dissolution kinetics, supersaturation properties and pharmacokinetics in rats. The co-amorphous formulation showed a faster in vitro dissolution of both drugs compared to the control groups, but only DTX showed supersaturation (1.9 fold) compared to its equilibrium solubility. The findings for the co-amorphous formulation were in agreement with the pharmacokinetics data, showing a quicker onset in plasma concentration as well as a higher bioavailability for both DTX (15-fold) and BIC (3-fold) compared to the crystalline drugs alone. Furthermore, the co-amorphous formulation remained physically stable over 1.5 years at 4 °C under dry conditions.


Assuntos
Anilidas/farmacologia , Docetaxel/química , Docetaxel/farmacocinética , Nitrilos/farmacologia , Compostos de Tosil/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Docetaxel/administração & dosagem , Estabilidade de Medicamentos , Sinergismo Farmacológico , Humanos , Ratos , Solubilidade , Difração de Raios X
15.
Mater Sci Eng C Mater Biol Appl ; 96: 436-445, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30606553

RESUMO

In this study, prostate-specific membrane antigen (PSMA)-targeted and core-crosslinked micelles were developed based on prostate cancer-binding peptide (PCP) modified glycol chitosan-lipoic acid (PGC-LA) conjugate. The degree of substitution was 5.2 PCP groups and 10.7 lipoic acid groups per 100 sugar residues of glycol chitosan in PGC-LA copolymer. Docetaxel (DTX) was chosen as a model anti-tumor drug. The DTX-loaded micelles were prepared by an o/w method, and core-crosslinked micelles were further constructed by using a catalytic amount of dithiothreitol. The mean diameter of DTX-loaded core-crosslinked PGC-LA (DTX-PGC-LA/cc) micelles was 397 nm determined by dynamic light scattering (DLS). In vitro DTX released from core-crosslinked micelles was slower than that from non-crosslinked counterpart. Blank micelles exhibited good biocompatibility. Additionally, cellular uptake and cytotoxcity of PCP-modified micelles were higher than those of micelles without PCP in PSMA-positive LNCaP cells. Importantly, DTX-PGC-LA/cc demonstrated the stronger anti-tumor efficacy against LNCaP tumor xenograft models than DTX injection and other DTX-loaded micelles. Taken together, this study provides a potential way in developing actively targeted and core-crosslinked micelles for hydrophobic drug delivery in cancer therapy.


Assuntos
Quitosana , Docetaxel , Sistemas de Liberação de Medicamentos/métodos , Calicreínas/metabolismo , Micelas , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/farmacologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto
16.
AAPS PharmSciTech ; 20(2): 81, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30645705

RESUMO

To achieve remotely directed delivery of anticancer drugs, surface-decorated nanoparticles with ligands are reported. In this study, folic acid- and thiol-decorated chitosan nanoparticles loaded with docetaxel (DTX-NPs) were prepared for enhanced cellular internalization in cancer cells and improved oral absorption. The DTX-NPs were explored through in vitro and in vivo parameters for various parameters. The DTX-NPs were found to be monodisperse nanoparticles with an average particle size of 158.50 ± 0.36 nm, a polydispersity index of 0.36 ± 0.0, a zeta potential of + 18.30 ± 2.52 mV, and an encapsulation efficiency of 71.47 ± 5.62%. The drug release from DTX-NPs followed the Korsmeyer-Peppas model with about 78% of drug release in 12 h. In in vitro cytotoxicity studies against folate receptor, positive MDA-MBB-231 cancerous cells showed improved cytotoxicity with IC50 of 0.58 µg/mL, which is significantly lower as compared to docetaxel (DTX). Ex vivo permeation enhancement showed an efflux ratio of 0.99 indicating successful transport across the intestine. Oral bioavailability was significantly improved as Cmax and AUC were higher than DTX suspension. Overall, the results suggest that DTX-NPs can be explored as a promising carrier for oral drug delivery.


Assuntos
Antineoplásicos/química , Quitosana/química , Docetaxel/química , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Nanopartículas/química , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacocinética , Docetaxel/farmacologia , Humanos , Coelhos , Ratos , Compostos de Sulfidrila/química
17.
Colloids Surf B Biointerfaces ; 173: 366-377, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30316083

RESUMO

Breast cancer, up-regulated with human epidermal growth factor receptor type-2 (HER-2) has led to the concept of developing HER-2 targeted anticancer therapeutics. Docetaxel-loaded D-α-tocopherol polyethylene glycol 1000 succinate conjugated chitosan (TPGS-g-chitosan) nanoparticles were prepared with or without Trastuzumab decoration. The particle size and entrapment efficiency of conventional, non-targeted as well as targeted nanoparticles were in the range of 126-186 nm and 74-78% respectively. In-vitro studies on SK-BR-3 cells showed that docetaxel-loaded non-targeted and HER-2 receptor targeted TPGS-g-chitosan nanoparticles have enhanced the cellular uptake and cytotoxicity with a promising bioadhesion property, in comparison to conventional formulation i.e., Docel™. The IC50 values of non-targeted and targeted nanoparticles from cytotoxic assay were found to be 43 and 223 folds higher than Docel™. The in-vivo pharmacokinetic study showed 2.33, and 2.82-fold enhancement in relative bioavailability of docetaxel for non-targeted and HER-2 receptor targeted nanoparticles, respectively than Docel™. Further, after i.v administration, non-targeted and targeted nanoparticles achieved 3.48 and 5.94 times prolonged half-life in comparison to Docel™. The area under the curve (AUC), relative bioavailability (FR) and mean residence time (MRT) were found to be higher for non-targeted and targeted nanoparticles when compared to Docel™. The histopathology studies of non-targeted and targeted nanoparticles showed less toxicity on vital organs such as lungs, liver, and kidney when compared to Docel™.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Docetaxel/farmacologia , Glicoconjugados/farmacologia , Trastuzumab/farmacologia , Vitamina E/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Quitosana/química , Docetaxel/química , Docetaxel/farmacocinética , Portadores de Fármacos , Feminino , Glicoconjugados/química , Glicoconjugados/farmacocinética , Humanos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Terapia de Alvo Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Ratos , Receptor ErbB-2/metabolismo , Trastuzumab/química , Trastuzumab/farmacocinética , Carga Tumoral/efeitos dos fármacos , Vitamina E/química , Vitamina E/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Colloids Surf B Biointerfaces ; 175: 56-64, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30517905

RESUMO

In this work, a stable nanocarrier for the anti-cancer drug docetaxel was rational designed. The nanocarrier was developed based on the solid lipid nanoparticle preparation process aiming to minimize the total amount of excipients used in the final formulations. A particular interest was put on the effects of the polymers in the final composition. In this direction, two poloxoamers -Pluronic F127 and F68- were selected. Some poloxamers are well known to be inhibitors of the P-glycoprotein efflux pump. Additionally, their poly-ethylene-oxide blocks can help them to escape the immune system, making the poloxamers appealing to be present in a nanoparticle designed for the treatment of cancer. Within this context, a factorial experiment design was used to achieve the most suitable formulations, and also to identify the effects of each component on the final (optimized) systems. Two final formulations were chosen with sizes < 250 nm and PDI < 0.2. Then, using dynamic light scattering and nanotracking techniques, the stability of the formulations was assessed during six months. Structural studies were carried on trough different techniques: DSC, x-ray diffraction, FTIR-AR and Molecular Dynamics. The encapsulation efficiency of the anticancer drug docetaxel (> 90%) and its release dynamics from formulations were measured, showing that the polymer-lipid nanoparticle is suitable as a drug delivery system for the treatment of cancer.


Assuntos
Docetaxel/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Lipídeos/química , Nanopartículas/química , Polímeros/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Varredura Diferencial de Calorimetria , Docetaxel/química , Docetaxel/farmacocinética , Portadores de Fármacos/química , Desenho de Drogas , Liberação Controlada de Fármacos , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Poloxâmero/química , Polietilenoglicóis/química , Difração de Raios X
19.
Biomed Pharmacother ; 109: 2427-2433, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551502

RESUMO

A self-nanoemulsifying drug delivery system (SNEDDS) was developed as a novel route to enhance the efficacy of docetaxel lipophilic drug. SNEDDS comprised ethyl oleate, Tween 80 and poly(ethylene glycol) 600, as oil, surfactant and co-surfactant, and formed stabilized monodispersed oil nanodroplets upon dilution in water. SNEDDS represented encapsulation efficiency and loading capacity of 21.4 and 52.7%, respectively. The docetaxel release profile from the drug-loaded SNEDDS was recorded, its effectiveness against MCF-7 cell line was investigated, and an IC50 value of 0.98 ± 0.05 µg mL-1 was attained. The drug-loaded SNEDDS was administrated in rats, and the pharmacokinetic parameters of maximum concentration of 22.2 ± 0.8 µg mL-1, time to attain this maximum concentration of 230 min, and area under the curve of 1.71 ± 0.18 µg min mL-1 were obtained. The developed SNEDDS formulation can be represented as an alternative to docetaxel administration.


Assuntos
Antineoplásicos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Sobrevivência Celular/fisiologia , Docetaxel/farmacocinética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsificantes/farmacocinética , Feminino , Humanos , Células MCF-7 , Ratos , Ratos Sprague-Dawley
20.
Nanomedicine (Lond) ; 13(21): 2759-2776, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30398388

RESUMO

AIM: Investigated strategy exploits the utilization of quercetin as a chemosensitizer for docetaxel (DTX), which was incorporated into albumin nanoparticles (NPs; bovine serum albumin NPs [BSA-NPs]). MATERIAL & METHODS: BSA-NPs containing both drugs were optimized, extensively characterized for different quality attributes and performance was investigated using series of in vitro and in vivo investigations. RESULTS: Co-encapsulated BSA-NPs exhibited size: 209.26 ± 9.84 nm, polydispersibility index: 0.184 ± 0.05 and good entrapment efficiency (∼75% for DTX and ∼68% for quercetin). Higher in vitro cytotoxicity, cell uptake and apoptosis were achieved in MCF-7 cell line. Similarly, higher P-glycoprotein efflux inhibition was observed in MDA-MB-231. About 2.5-fold increase in bioavailability of DTX was achieved with improved antitumor efficacy and reduced in vivo toxicity. CONCLUSION: Developed BSA-NPs provide an effective and safer alternative approach using co-delivery of chemosensitizer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Docetaxel/administração & dosagem , Nanopartículas/administração & dosagem , Soroalbumina Bovina/química , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Docetaxel/química , Docetaxel/farmacocinética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Células MCF-7 , Nanopartículas/química , Quercetina/administração & dosagem , Quercetina/química , Quercetina/farmacocinética , Ratos , Soroalbumina Bovina/administração & dosagem , Soroalbumina Bovina/farmacocinética
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