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1.
Ultrasonics ; 101: 106033, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31561207

RESUMO

The objective of this study was to use ultrasound in combination with nanoparticulate formulations of taxane drugs for an additive approach to overcome multidrug resistance (MDR). Polymeric nanoparticulate formulations containing both chemotherapeutic taxane drugs and a polymeric inhibitor (MePEG17-b-PCL5) of drug resistant proteins have been previously developed in an attempt to overcome MDR in cells. High frequency (>1 MHz) ultrasound has been shown to increase the uptake of cytotoxic drugs in MDR proliferating cells and has been suggested as a different way to overcome MDR, resensitize drug resistant cancer cells and allow for chemotherapeutic efficacy. MDCK-MDR cells were incubated with docetaxel (DTX) or paclitaxel (PTX) loaded, solid core, nanoparticles made from a 50:50 ratio of two diblock copolymers, MePEG114-b-PCL200 and MePEG17-b-PCL5 (PCL200/PCL5). The accumulation of drug in MDCK-MDR cells was measured using radiolabeled drug and the viability of cells was determined using an MTS cell proliferation assay. The effect of ultrasound (4 MHz, 32 W/cm2, 10 s, 25% duty cycle) on drug uptake and cell viability was studied. Using free DTX or PTX, MDCK-MDR cells were killed at sublethal doses of drug with the P-gp inhibitor (MePEG17-b-PCL5) present at a concentration of just 0.006% (m/v) and cell death began after just 3 h of incubation. Using sublethal incubation doses of PTX or DTX in PCL200/PCL5 nanoparticles for 90 min, followed by a second exposure to blank PCL200/PCL5 nanoparticles, cell viability dropped by approximately 60% at 24 h. Drug accumulation increased by 1.43-1.9 fold following five bursts of ultrasound applied at 90 min. Both, increased ultrasound exposure and increased concentrations of blank nanoparticles during the second incubation allowed for increased levels of cell death. The combined use of ultrasound with taxane and P-gp inhibitor loaded polymeric nanoparticles may allow for increased accumulation of drug and inhibitor which may then release both agents inside cells in a controlled manner to overcome drug resistance in MDR cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Docetaxel/farmacologia , Nanopartículas/química , Paclitaxel/farmacologia , Polietilenoglicóis/farmacologia , Ondas Ultrassônicas , Animais , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/química , Cães , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Paclitaxel/química , Polietilenoglicóis/química , Polímeros/química , Polímeros/farmacologia , Células Tumorais Cultivadas
2.
Pharm Res ; 36(12): 165, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646391

RESUMO

PURPOSE: Cancer stem cells (CSCs) have been suggested to represent the main cause of tumour progression, metastasis and drug resistance. Therefore, these cells can be an appropriate target to improve cancer treatment. METHODS: A novel biodegradable brush copolymeric micelle was synthesized by the ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The obtained micelle was used for co-delivery of the anticancer drug docetaxel (DTX) and Chrysin (CHS) as an adjuvant on the CSCs originated from Human colon adenocarcinoma cell line. Cancer stem cells were enriched by MACS technique and characterized by flow cytometry analysis against CD133 marker. RESULTS: Data demonstrated that the micelles harbouring DTX@CHS had potential to reduce cancer stem cell viability compared to free DTX@CHS, single-drug formulations and the control group (p < 0.05). The combination effect of DTX and CHS formulated in micelle was synergistic in CSCs (CI < 1). The reactive oxygen species content was shown to increase after cell treatment with DTX@CHS loaded on micelles (p < 0.05). DTX@CHS-micelles inhibited cancer stem cell migration rate in vitro (p < 0.05), indicating an impaired metastasis activity. CONCLUSION: In conclusion, the synthesized DOX@CHS-micelles can be applied in the introduction of anticancer agents to resistant cancer population by further investigations.


Assuntos
Antineoplásicos/química , Docetaxel/química , Portadores de Fármacos/química , Flavonoides/química , Micelas , Células-Tronco Neoplásicas/efeitos dos fármacos , Antígeno AC133/metabolismo , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Docetaxel/farmacologia , Flavonoides/farmacologia , Células HT29 , Humanos , Células-Tronco Neoplásicas/metabolismo , Poli-Hidroxietil Metacrilato/análogos & derivados , Poli-Hidroxietil Metacrilato/química
3.
Mater Sci Eng C Mater Biol Appl ; 104: 109950, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499976

RESUMO

Poly (lactide-co-glycolide) (PLGA) is a biocompatible, biodegradable, and non-toxic polymer used in a variety of biomedical and pharmaceutical applications. Polymeric nanoparticles prepared from PLGA have been extensively used as delivery vehicles of various chemotherapeutic agents. The variability of PLGA polymer and nanoparticle fabrication process potentially results in variability of particle characteristics. Nanoparticle characteristics determine nanoparticles' performance when used as drug delivery systems. Having control on nanoparticle's characteristics grants control over the fate of nanoparticles and the associated drug. Here, L16 Taguchi experimental design was used to evaluate the effect of polymer characteristics and fabrication variables on PLGA nanoparticles. The design was used to determine an optimized preparation condition for PLGA nanoparticles as an intravenous delivery system for docetaxel. An emulsification-solvent-evaporation method was used to fabricate nanoparticles. Docetaxel concentration, organic phase:aqueous phase ratio, polymer molecular weight, polymer terminus, lactide:glycolide ratio, and Poly(vinyl alcohol)(PVA) concentration were selected as main determinants. First two factors were evaluated at 4 levels and the rest at 2 levels. Particle-important characteristics including size, polydispersity index (PDI), surface charge (zeta potential), and docetaxel loading-efficiency were determined. Factors affecting nanoparticle characteristics were ranked according to level of effectiveness. Factors that affected nanoparticle properties with statistical significance were identified. Models to predict nanoparticle characteristics were built. An optimized fabrication method was identified and used to prepare PLGA nanoparticles for docetaxel delivery.


Assuntos
Docetaxel/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Administração Intravenosa/métodos , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Docetaxel/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Tamanho da Partícula , Álcool de Polivinil/química , Solventes/química
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.
Pharm Res ; 36(11): 154, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482205

RESUMO

PURPOSE: Conjugation of nanocarriers with antibodies that bind to specific membrane receptors that are overexpressed in cancer cells enables targeted delivery. In the present study, we developed and synthesised two PAMAM dendrimer-trastuzumab conjugates that carried docetaxel or paclitaxel, specifically targeted to cells which overexpressed HER-2. METHODS: The 1H NMR, 13C NMR, FTIR and RP-HPLC were used to analyse the characteristics of the products and assess their purity. The toxicity of PAMAM-trastuzumab, PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined using MTT assay and compared with free trastuzumab, docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. The cellular uptake and internal localisation were studied using flow cytometry and confocal microscopy, respectively. RESULTS: The PAMAM-drug-trastuzumab conjugates in particular showed extremely high toxicity toward the HER-2-positive SKBR-3 cells and very low toxicity towards to HER-2-negative MCF-7 cells. As expected, the HER-2-positive SKBR-3 cell line accumulated trastuzumab from both conjugates rapidly; but surprisingly, although a large amount of PAMAM-ptx-trastuzumab conjugate was observed in the HER-2-negative MCF-7 cells. Confocal microscopy confirmed the intracellular localisation of analysed compounds. The key result of fluorescent imaging was the identification of strong selective binding of the PAMAM-doc-trastuzumab conjugate with HER-2-positive SKBR-3 cells only. CONCLUSIONS: Our results confirm the high selectivity of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates for HER-2-positive cells, and demonstrate the utility of trastuzumab as a targeting agent. Therefore, the analysed conjugates present an promising approach for the improvement of efficacy of targeted delivery of anticancer drugs such as docetaxel or paclitaxel.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Dendrímeros/química , Docetaxel/química , Paclitaxel/química , Receptor ErbB-2/metabolismo , Trastuzumab/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Interações de Medicamentos , Liberação Controlada de Fármacos , Corantes Fluorescentes/química , Humanos , Paclitaxel/farmacologia , Propriedades de Superfície , Trastuzumab/farmacologia , Resultado do Tratamento
6.
IET Nanobiotechnol ; 13(4): 428-434, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31171748

RESUMO

Breast cancer is a major cause of cancer mortality. Regarding the advantages of polymeric nanoparticles as drug delivery systems with targeting potential, in this study the antitumor mechanism of targeted docetaxel polymeric nanoparticles of Ecoflex® was exploited. Since the overexpression of HER-2 receptor in breast cancer cases is associated with poor prognosis and more aggressive disease, the proposed nanoparticles were conjugated to HER-2 specific aptamer molecules. In vitro cytotoxicity was evaluated by MTT assay. Flow-cytometry analysis was performed to evaluate the cellular uptake of nanoparticles loaded with a fluorescent probe. Anti-migration effects of samples were studied. Annexin IV-FITC and propidium iodide were implemented to investigate apoptosis induction and cell cycle analysis. Enhanced cytotoxicity compared with free docetaxel was explained considering improved cellular uptake of the nanoparticles and induced apoptosis in a larger portion of cells. Lower relative migration demonstrated enhanced anti-migration effect of nanoparticles, and cell cycle was arrested in G2/M phase using both formulations so the anti-microtubule mechanism of the drug was not altered. Therefore, this system could offer a potential substitute for the currently marketed docetaxel formulations, which may reduce adverse effects of the drug, while further in vivo and clinical investigations are required.


Assuntos
Apoptose/efeitos dos fármacos , Docetaxel , Nanopartículas/química , Poliésteres/química , Receptor ErbB-2/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Docetaxel/química , Docetaxel/farmacologia , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Receptor ErbB-2/genética
7.
Molecules ; 24(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181726

RESUMO

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and ßIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ßIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ßIII.


Assuntos
Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Morte Celular/efeitos dos fármacos , Docetaxel/síntese química , Docetaxel/química , Docetaxel/farmacologia , Células HeLa , Humanos , Compostos Macrocíclicos/química , Simulação de Acoplamento Molecular , Paclitaxel/síntese química , Paclitaxel/química , Paclitaxel/farmacologia , Homologia Estrutural de Proteína , Taxoides/química , Tubulina (Proteína)/química
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.
J Pharm Pharmacol ; 71(8): 1243-1254, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215039

RESUMO

OBJECTIVES: Multidrug resistance (MDR) remains a primary challenge in breast cancer treatment. In the present study, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS)-coated docetaxel-loaded liposomes were developed as a novel drug delivery system to reverse MDR and enhance breast cancer therapy compared with the traditional liposomes, DSPE-mPEG-coated liposomes (stealth liposomes) and commercial Taxotere® . KEY FINDINGS: Liposomes were prepared by thin - film dispersion method. Evaluations were performed using human breast cancer MCF-7 and resistant MCF-7/ADR cells. The reversal multidrug-resistant effect was assessed by P-gp inhibition assay, cytotoxicity, cellular uptake and apoptosis assay. RESULTS: The TPGS-chol-liposomes were of an appropriate particle size (140.0 ± 6.0 nm), zeta potential (-0.196 ± 0.08 mv), high encapsulation efficiency (99.0 ± 0.9) and favourable in vitro sustained release. The TPGS-coated liposomes significantly improved cytotoxicity and increased the intracellular accumulation of docetaxel in both types of breast cancer cells. The TPGS-coated liposomes were confirmed to induce apoptosis via a synergistic effect between docetaxel and TPGS. It was demonstrated that TPGS enhanced the intracellular accumulation of drug by inhibiting overexpressed P-glycoprotein. CONCLUSIONS: The TPGS-conjugated liposomes showed significant advantages in vitro compared with the PEG-conjugated liposomes. The TPGS-conjugated liposomes could reverse the MDR and enhance breast cancer therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Docetaxel/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Lipossomos/química , Polietilenoglicóis/química , Vitamina E/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/química , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Tamanho da Partícula , Succinatos/química , Vitamina E/química
10.
Drug Des Devel Ther ; 13: 1271-1280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114163

RESUMO

Background: Ovarian cancer is a leading cause of death in gynecologic malignancies. The high mortality is mainly caused by advanced stage at presentation in most patients. Even after the combination of cytoreductive surgery and systemic platinum and taxane treatment, most patients relapse and eventually succumb to the disease. Therefore, there is an urgent need for new treatments. Purpose: A novel folate (FA)-targeted co-delivery of docetaxel (DTX) and gemcitabine (GEM) nanoparticles (NPs) was developed to overcome ovarian cancer. Materials and methods: Physicochemical characteristics of NPs such as size, morphology, and release profiles were explored. In vitro and in vivo studies were carried out to assess the efficacy of their antitumor activity in target cells. Results: FA modified DTX and GEM co-loaded NPs were prepared using the solvent evaporation method. The NPs with a particle size of ~120nm were stable in the observation period. The hemolysis results indicated that FA-PEG2000-PLGA was potentially feasible for targeted antitumor drug delivery through blood circulation. In vitro release study suggested that in comparison with the free drug, PLGA-DTX/GEM NPs and FA-PEG2000-PLGA-DTX/GEM NPs had sustained-release properties. However, there was no obvious difference between the two NPs with the same drug in the release profile. Ovarian cancer cells in vitro efficiently took up the non-targeted and FA-targeted NPs; improved cytotoxicity was observed in the FA-targeted NPs, showing a 3.59- fold drop in the IC50 in SKOV-3 cells as compared to DTX/GEM alone. Cellular uptake showed that through surface modification, more drugs entered the cell successfully. Pharmacodynamics results showed a statistically significant effect on the rate of reduction of tumor volume for FA-PEG2000-PLGA-DTX/GEM NPs than other groups and no toxicity of organs. Conclusion: The present study indicates that the FA-PEG2000-PLGA-DTX/GEM NPs provides a promising platform for the treatment of ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Poliglactina 910/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Docetaxel/química , Docetaxel/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Ovarianas/patologia , Tamanho da Partícula , Relação Estrutura-Atividade , Propriedades de Superfície
11.
Biomater Sci ; 7(7): 2749-2758, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-30997445

RESUMO

Combining chemotherapy and immunotherapy has been considered as an attractive approach to improve cancer therapy. Here we prepared folated PVA-based nanogels for the simultaneous delivery of docetaxel (DTX) and the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 (N9) for enhancing cancer chemo-immunotherapy. FDA-approved poly(vinyl alcohol) (PVA) with good biocompatibility was modified with vinyl ether acrylate (VEA) groups for UV-crosslinking and acidic degradation. Carboxyl groups were introduced via modification with succinic anhydride for improved drug loading and folic acid (FA) ligands were incorporated for tumor targeting. UV-crosslinked folated PVA nanogels were efficiently taken up by tumor cells followed by endo/lysosomal pH-triggered intracellular drug release, which induced significant cytotoxicity towards 4T1 breast cancer cells in vitro. DTX and N9 co-loaded PVA nanogels exhibited a much higher antitumor efficiency in 4T1 mouse breast cancer models in vivo as compared to the free drug controls. The drug-laden nanogels not only directly killed the tumor cells by DTX, but also induced immunogenic cell death (ICD) promoting intratumoral accumulation of cytotoxic T lymphocytes, and further combining with N9 elevated the intratumoral infiltration of CD8+ T cells and NK cells and inhibited the infiltration of MDSCs, downregulating IDO1-mediated immunosuppression.


Assuntos
Docetaxel/química , Inibidores Enzimáticos/química , Ácido Fólico/química , Imidazóis/química , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Isoindóis/química , Nanopartículas/química , Animais , Transporte Biológico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Docetaxel/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Inibidores Enzimáticos/farmacologia , Ácido Fólico/metabolismo , Concentração de Íons de Hidrogênio , Imidazóis/farmacologia , Isoindóis/farmacologia , Camundongos , Álcool de Polivinil/química
12.
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
13.
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
14.
Biomed Eng Online ; 18(1): 11, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704488

RESUMO

BACKGROUND: Docetaxel (DTX) is an anticancer drug that is currently formulated with polysorbate 80 and ethanol (50:50, v/v) in clinical use. Unfortunately, this formulation causes hypersensitivity reactions, leading to severe side-effects, which have been primarily attributed to polysorbate 80. METHODS: In this study, a DTX-loaded human serum albumin (HSA) nanoparticle (DTX-NP) was designed to overcome the hypersensitivity reactions that are induced by polysorbate 80. The methods of preparing the DTX-NPs have been optimized based on factors including the drug-to-HSA weight ratio, the duration of HSA incubation, and the choice of using a stabilizer. Synthesized DTX-NPs were characterized with regard to their particle diameters, drug loading capacities, and drug release kinetics. The morphology of the DTX-NPs was observed via scanning electron microscopy (SEM) and the successful preparation of DTX-NPs was confirmed via differential scanning calorimetry (DSC). The cytotoxicity and cellular uptake of DTX-NPs were investigated in the non-small cell lung cancer cell line A549 and the maximum tolerated dose (MTD) of DTX-NPs was evaluated via investigations with BALB/c mice. RESULTS: The study showed that the loading capacity and the encapsulation efficiency of DTX-NPs prepared under the optimal conditions was 11.2 wt% and 63.1 wt%, respectively and the mean diameter was less than 200 nm, resulting in higher permeability and controlled release. Similar cytotoxicity against A549 cells was exhibited by the DTX-NPs in comparison to DTX alone while higher maximum tolerated dose (MTD) with the DTX-NPs (75 mg/kg) than with DTX (30 mg/kg) was demonstrated in mice, suggesting that the DTX-NPs prepared with HSA yielded similar anti-tumor activity but were accompanied by less systemic toxicity than solvent formulated DTX. CONCLUSIONS: DTX-NPs warrant further investigation and are promising candidates for clinical applications.


Assuntos
Docetaxel/química , Portadores de Fármacos/química , Nanopartículas/química , Albumina Sérica Humana/química , Células A549 , Transporte Biológico , Técnicas de Química Sintética , Docetaxel/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Humanos , Nanotecnologia , Albumina Sérica Humana/síntese química , Albumina Sérica Humana/metabolismo
15.
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
16.
Vascul Pharmacol ; 115: 46-54, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30797043

RESUMO

Chemotherapeutic agents used in cancer treatment associated to nanoparticles (LDE) that mimic the composition of low-density lipoprotein and buffer their toxicity can have strong anti-atherosclerosis action, as we showed in cholesterol-fed rabbits. Here, a novel preparation of docetaxel (DTX) carried in LDE was evaluated. Eighteen rabbits were fed 1% cholesterol during 8 weeks. After the first 4 weeks, 9 animals were treated for 4 weeks with intravenous LDE-DTX (1 mg/kg/week) and 9 with LDE only (controls) once a week for 4 weeks. Animals were then euthanized and the aortas were analyzed for morphometry, immunohistochemistry and Western blot. LDE-DTX treated group showed 80% reduction of atheroma area compared to controls. LDE-DTX treatment reduced in 60% the protein expression of macrophage marker CD68 and of MCP-1 in 80%. LDE-DTX pronouncedly lowered expression of pro-inflammatory markers NF-κB, TNF-α, IL-1ß, IL-6 and von Willebrand factor and elicited 40% reduction in cell proliferation marker PCNA. The presence of smooth muscle cells in the intima was 85% smaller than in controls. Pro-apoptotic caspase 3, caspase 9, Bax, and anti-apoptotic Bcl-2 all were reduced by LDE-DTX. Protein expression of MMP-2 and MMP-9, TGF-ß, and collagen 1 and 3 were also markedly lowered by the LDE-DTX treatment. Animals showed no hematological, hepatic or renal toxicity consequent to LDE-DTX treatment. In conclusion, LDE-DTX showed a wide array of strong effects on pro-inflammatory and proliferation-promoting factors that drive the lesion development. These findings and the lack of observable toxicity indicate that LDE-DTX can be a candidate for future clinical trials.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Aortite/prevenção & controle , Aterosclerose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Docetaxel/farmacologia , Lipídeos/química , Nanopartículas , Placa Aterosclerótica , Animais , Anti-Inflamatórios/química , Aorta/metabolismo , Aorta/patologia , Aortite/metabolismo , Aortite/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Morte Celular/efeitos dos fármacos , Colesterol na Dieta , Dieta Hiperlipídica , Modelos Animais de Doenças , Docetaxel/química , Composição de Medicamentos , Colágenos Fibrilares/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fator de von Willebrand/metabolismo
17.
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
18.
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
19.
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
20.
Biomater Sci ; 7(3): 1117-1131, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30638237

RESUMO

Oral chemotherapy of docetaxel (DTX) is restricted by active P-glycoprotein (P-gp) efflux, hepatic first-pass metabolism and then poor oral absorption. Herein, a lipophilic thioether-bridged oleate prodrug (DTX-S-OA) and an ester-bond linked oleate prodrug of docetaxel (DTX-OA) were synthesized and efficiently incorporated into a self-nanoemulsifying drug delivery system (SNEDDS) using core-matching technology with a high drug-loading rate. DTX-S-OA SNEDDS produced a uniform droplet size of about 30 nm and a significantly high drug loading capability (60 mg mL-1), compared with DTX SNEDDS (20 mg mL-1). Additionally, DTX-S-OA SNEDDS exhibited a markedly slower drug release property and higher (>2-fold) drug solubilization in the aqueous phase after 60 min lipolysis compared with DTX SNEDDS. In situ single-pass intestinal perfusion and intestinal biodistribution studies demonstrated that the membrane permeability and intestinal bioadhesion of SNEDDS were significantly increased. Moreover, DTX-S-OA showed a comparable ability with verapamil in inhibiting P-gp efflux. Lymphatic transport studies confirmed that DTX-S-OA SNEDDS could significantly enhance intestinal lymphatic transport. Notably, the bioavailability of DTX-S-OA SNEDDS was 6.2-fold and 2.0-fold higher than that of the DTX solution and DTX SNEDDS, respectively. Furthermore, DTX-S-OA achieved a more rapid release of free DTX from the prodrug in systemic circulation than DTX-OA. Therefore, such a unique combination strategy of the single thioether-bridged DTX-oleate prodrug and SNEDDS is a promising platform to enable effective oral delivery of DTX.


Assuntos
Docetaxel/química , Portadores de Fármacos/química , Pró-Fármacos/química , Sulfetos/química , Administração Oral , Animais , Cumarínicos/química , Docetaxel/metabolismo , Liberação Controlada de Fármacos , Emulsões/química , Mucosa Intestinal/metabolismo , Intestinos/patologia , Camundongos , Ácido Oleico/química , Tamanho da Partícula , Pró-Fármacos/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Tiazóis/química
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