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1.
AAPS PharmSciTech ; 21(5): 151, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32440910

RESUMO

Triple-negative breast (TNBC) cancer that is upregulated with epidermal growth factor receptor (EGFR), and devoid of both the hormonal receptors and epidermal growth factor receptor 2 (HER 2), has led to a concept of treating TNBC with EGFR-targeted therapeutics. The combination of paclitaxel (PTX) and piperine (PIP) may improve the bioavailability of paclitaxel for cancer therapy. TPGS (vit E-PEG 1000-succinate)-coated liposomes were prepared with PTX alone or in combination with PIP, and either with (targeted) or without (non-targeted) cetuximab (CTX) conjugation. The Bradford assay indicated that 75% of CTX has been conjugated on the liposomes. The size and percent encapsulation of PTX&PIP co-loaded liposomes were found to be in the range of 204 to 218 nm and 31-73%, respectively. The drug release rate was found to be higher at pH 5.5 in comparison with release at pH 6.4 and pH 7.4. Cellular uptake and toxicity studies on MDA-MB-231 cells showed that PTX&PIP co-loaded targeted liposomes have demonstrated superior uptake and cytotoxicity than their non-targeted counterparts. The IC50 values of both of the liposomal formulations were found to be significantly higher than PTX control. Indeed, combining PIP with PTX control has improved the cytotoxicity of PTX control, which proved the synergistic anticancer effect of PIP. Lyophilized liposomes showed an excellent stability profile with the size range between 189 and 210 nm. Plasma stability study revealed a slight increase in the particle size due to the adsorption of plasma proteins on the surface of liposomes. The long-term stability study also indicated that liposomes were stable at 4°C.


Assuntos
Alcaloides/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Benzodioxóis/uso terapêutico , Paclitaxel/uso terapêutico , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Benzodioxóis/farmacologia , Linhagem Celular Tumoral , Composição de Medicamentos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Receptores ErbB/efeitos dos fármacos , Feminino , Liofilização , Humanos , Lipossomos , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Receptor ErbB-2
2.
Sci Rep ; 10(1): 5427, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32214149

RESUMO

Paclitaxel is the top-selling chemotherapeutic drug used for the treatment of lung, ovarian and breast cancer as well as Kaposi's sarcoma. Cell suspension culture (CSC) of Corylus avellana has been addressed as a promising alternative for producing paclitaxel. In this study, endophytic fungus strain YEF33 was isolated from Taxus baccata and identified as Coniothyrium palmarum. The effects of the elicitors derived from this fungus including cell extract, culture filtrate and cell wall (CW) and also chitin, alone or in combination with Methyl-ß-Cyclodextrin (MBCD), on paclitaxel biosynthesis in C. avellana CSC were assayed for the first time. CW of C. palmarum was the most efficient fungal elicitor for paclitaxel biosynthesis in C. avellana CSC. The results revealed that MBCD affected paclitaxel biosynthesis differently depending on fungal elicitor type and vice versa. MBCD, either alone or in combination with fungal elicitors, induced a high secretion of paclitaxel, suggesting the decrement of toxicity and retro-inhibition processes of paclitaxel for cells. The joint effects of C. palmarum CW (2.5% (v/v) on 17th day) and 50 mM MBCD synergistically enhanced paclitaxel biosynthesis (402.4 µg l-1; 5.8-fold), 78.6% of which (316.5 µg l-1) were secreted into culture medium, a level 146% higher than that in control.


Assuntos
Ascomicetos/metabolismo , Parede Celular/metabolismo , Corylus/efeitos dos fármacos , Corylus/metabolismo , Paclitaxel/metabolismo , Taxus/metabolismo , beta-Ciclodextrinas/farmacologia , Técnicas de Cultura de Células/métodos , Células Cultivadas , Meios de Cultura/metabolismo , Suspensões/metabolismo
3.
Toxicol Lett ; 327: 9-18, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32201199

RESUMO

Superoxide dismutase 2 (SOD2) is a key enzyme for scavenging reactive oxygen species produced by mitochondria, which plays an important role in maintaining cellular homeostasis. However, its effects on the detoxification capability of liver cells have not been reported. In this study, we found that change in SOD2 expression affects the proliferation of liver cells. Genome-wide microarray analysis showed that SOD2 positively regulates the drug transporter ABCC2, and co-expression analysis suggested that lncRNA CLCA3P participates in the process. Further experiments showed that SOD2 can promote the expression of CLCA3P, which increases the transcription of ABCC2 by interacting with the transcription factor IRF1. By increasing ABCC2 expression SOD2 facilitates drugs efflux of liver cells and thus promotes their survival under a drug-toxic environment. This study elucidates the improvement of the detoxification of liver cells by a regulatory axis, SOD2-CLCA3P-IRF1-ABCC2, and provides novel insight into the modification of human liver cells that can be applied to bioartificial liver system or the study of SOD2 in drug metabolism.


Assuntos
Fígado/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Paclitaxel/metabolismo , RNA Longo não Codificante , Superóxido Dismutase/metabolismo , Animais , Antineoplásicos Fitogênicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Análise de Sequência com Séries de Oligonucleotídeos , Interferência de RNA , Superóxido Dismutase/genética
4.
Nanoscale ; 12(9): 5353-5358, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32100771

RESUMO

To push the limit of synthetic control, we create a thin layer (5 nm) of silica on the surface of drug nanocrystals, achieving a loading content (88%) that approaches the theoretical limit. The uniform silica shell provides a tailored diffusion barrier for controlled drug release. The method can be generally applied to 11 organic crystals, including 4 drugs.


Assuntos
Portadores de Fármacos/química , Dióxido de Silício/química , Liberação Controlada de Fármacos , Cinética , Nanopartículas/química , Paclitaxel/química , Paclitaxel/metabolismo , Tamanho da Partícula , Porosidade
5.
Sci China Life Sci ; 63(3): 419-428, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31420851

RESUMO

LIN9 functions to regulate cell mitotic process. Dysregulation of LIN9 expression is associated with development of human cancers. In this study we assessed the association of LIN9 expression with paclitaxel resistance and clarified the underlying mechanisms for the first time. LIN9 expression in breast cancer tissues was retrieved from publicly available online databases and statistically analyzed. Human TNBC cell lines MDA-MB-231 and MDA-MB-468 and their corresponding paclitaxel-resistant sublines 231PTX and 468PTX were used to assess the expression of LIN9 by qRT-PCR and Western blot, cell growth by cell counting, cell viability by MTS assay, and cell apoptosis by flow cytometry. The data showed that high LIN9 expression in breast cancer patients receiving chemotherapy was related to poor overall survival (OS). LIN9 expression was upregulated in paclitaxel-resistant TNBC cells compared to their parental cells. Knockdown of LIN9 or treatment of paclitaxel-resistant TNBC cells with a bromo- and extra-terminal domain inhibitor (BETi) JQ1 which also decreased LIN9 expression enhanced the sensitivity of paclitaxel-resistant TNBC cells to paclitaxel. Mechanistically, decreased LIN9 in resistant cell lines reduced tumor cell viability, promoted multinucleated cells formation and induced tumor cell apoptosis, potentially by directly regulating microtubule-binding protein CCSAP. In conclusion, high LIN9 expression contributed to poor clinical outcomes and paclitaxel resistance in TNBC and BETi, targeting LIN9 expression, could be a reversible drug for PTX-resistant TNBC patients.


Assuntos
Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Paclitaxel/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Mitose/efeitos dos fármacos , Paclitaxel/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
Molecules ; 24(21)2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683764

RESUMO

Specialized plant terpenoids have found fortuitous uses in medicine due to their evolutionary and biochemical selection for biological activity in animals. However, these highly functionalized natural products are produced through complex biosynthetic pathways for which we have a complete understanding in only a few cases. Here we review some of the most effective and promising plant terpenoids that are currently used in medicine and medical research and provide updates on their biosynthesis, natural occurrence, and mechanism of action in the body. This includes pharmacologically useful plastidic terpenoids such as p-menthane monoterpenoids, cannabinoids, paclitaxel (taxol®), and ingenol mebutate which are derived from the 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway, as well as cytosolic terpenoids such as thapsigargin and artemisinin produced through the mevalonate (MVA) pathway. We further provide a review of the MEP and MVA precursor pathways which supply the carbon skeletons for the downstream transformations yielding these medically significant natural products.


Assuntos
Vias Biossintéticas , Ácido Mevalônico/metabolismo , Monoterpenos/metabolismo , Terpenos/metabolismo , Animais , Canabinoides/metabolismo , Diterpenos/metabolismo , Eritritol/análogos & derivados , Eritritol/metabolismo , Medicina Herbária , Humanos , Monoterpenos/uso terapêutico , Paclitaxel/metabolismo , Fosfatos Açúcares/metabolismo , Terpenos/uso terapêutico , Tapsigargina/metabolismo
7.
Braz J Med Biol Res ; 52(11): e8657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664305

RESUMO

Although Taxol has improved the survival of cancer patients as a first-line chemotherapeutic agent, an increasing number of patients develop resistance to Taxol after prolonged treatment. The potential mechanisms of cancer cell resistance to Taxol are not completely clear. It has been reported that microRNAs (miRNAs) are involved in regulating the sensitivity of cancer cells to various chemotherapeutic agents. In this study, we aimed to explore the role of miR-129-5p in regulating the sensitivity of breast cancer cells to Taxol. Cell apoptosis and autophagy, and the sensitivity of MCF-7 cells to Taxol were assessed with a series of in vitro assays. Our results showed that the inhibition of autophagy increased the Taxol-induced apoptosis and the sensitivity of MCF-7 cells to Taxol. Up-regulation of miR-129-5p also inhibited autophagy and induced apoptosis. Furthermore, miR-129-5p overexpression increased the sensitivity of MCF-7 cells to Taxol. High mobility group box 1 (HMGB1), a target gene of miR-129-5p and a regulator of autophagy, was negatively regulated by miR-129-5p. We found that interference of HMGB1 enhanced the chemosensitivity of Taxol by inhibiting autophagy and inducing apoptosis in MCF-7 cells. Taken together, our findings suggested that miR-129-5p increased the chemosensitivity of MCF-7 cells to Taxol through suppressing autophagy and enhancing apoptosis by inhibiting HMGB1. Using miR-129-5p/HMGB1/autophagy-based therapeutic strategies may be a potential treatment for overcoming Taxol resistance in breast cancer.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Neoplasias da Mama/metabolismo , Proteína HMGB1/metabolismo , Células MCF-7/metabolismo , MicroRNAs/metabolismo , Paclitaxel/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/genética , Autofagia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Proteína HMGB1/genética , Humanos , MicroRNAs/genética , Paclitaxel/uso terapêutico , Regulação para Cima/genética
8.
Eur J Pharmacol ; 863: 172611, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476282

RESUMO

Multidrug resistance (MDR) lead to inadequate response to chemotherapy and cause failure in cancer treatment. One of the targeted approaches to overcome MDR in cancer cells is interfering or inhibiting ATP binding cassette (ABC) transporters. Among all members in ABC transporters superfamily, ABCB1 (ABC transporter subfamily B #1) and ABCG2 (ABC transporter subfamily G #2) play an important role in the development of cancer MDR. In this study, we synthesized a novel 5-cyano-6-phenylpyrimidin derivative 479, which exhibited selective dual-activity in reversing MDR mediated by ABCB1 and ABCG2, without affecting MDR mediated by ABCC1 (ABC transporter subfamily C #1) and ABCC10 (ABC transporter subfamily C #10). Further mechanism studies demonstrated that 479 increased the accumulation of paclitaxel and mitoxantrone in cancer cells by interrupting the efflux function of transporters and stimulating ABCB1/ABCG2 ATPase activity. In silico study provided evidence that 479 formed multiple physiochemical bonds with the drug-binding pocket of ABCB1 and ABCG2. Overall, our results provide a promising prototype in designing potent dual reversal agents targeting ABCB1- and ABCG2-meidated MDR.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Linhagem Celular Tumoral , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Mitoxantrona/metabolismo , Simulação de Acoplamento Molecular , Paclitaxel/metabolismo , Conformação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo
9.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540428

RESUMO

Cytochrome P450 2C8 (CYP2C8) epoxygenase is responsible for the metabolism of over 60 clinically relevant drugs, notably the anticancer drug Taxol (paclitaxel, PAC). Specifically, there are naturally occurring polymorphisms, CYP2C8*2 and CYP2C8*3, that display altered PAC hydroxylation rates despite these mutations not being located in the active site. Herein, we demonstrate that these polymorphisms result in a greater uncoupling of PAC metabolism by increasing the amount of hydrogen peroxide formed per PAC turnover. Anaerobic stopped-flow measurements determined that these polymorphisms have altered first electron transfer kinetics, compared to CYP2C8*1 (wildtype), that suggest electron transfer from cytochrome P450 reductase (CPR) is disfavored. Therefore, these data demonstrate that these polymorphisms affect the catalytic cycle of CYP2C8 and suggest that redox interactions with CPR are disrupted.


Assuntos
Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C8/metabolismo , Polimorfismo de Nucleotídeo Único , Antineoplásicos Fitogênicos/metabolismo , Transporte de Elétrons , Humanos , Hidroxilação , Modelos Moleculares , Oxirredução , Paclitaxel/metabolismo
10.
Artif Cells Nanomed Biotechnol ; 47(1): 3465-3477, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31432702

RESUMO

Lung cancer is a kind of malignant tumour characterized as uncontrolled cell growth in lung. These malignant cell growth can spread beyond the lung by process of metastasis into other tissues or parts of the body. In this study, we developed dequalinium (DQA) modified paclitaxel plus ligustrazine micelles to destroy vasculogenic mimicry (VM) channels and inhibit tumour metastasis. In vitro assays showed that the targeting micelles with centralized particle size distribution showed not only vigoroso cytotoxicity on A549 cells but also strong inhibition on VM channels and tumour metastasis. Mechanism studies indicated that the DQA modified paclitaxel plus ligustrazine micelles could down-regulate the expressions of VEGF, MMP2, TGF-ß1 and E-cadherin in A549 cells. In vivo assays indicated that the targeting drug-loaded micelles could enhance the accumulation of chemotherapeutic drugs at tumour sites and exhibit strong tumour inhibitory activity with negligible toxicity. Hence, the DQA modified paclitaxel plus ligustrazine micelles developed in this study may provide a potential strategy for treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Dequalínio/química , Portadores de Fármacos/química , Neoplasias Pulmonares/patologia , Paclitaxel/química , Paclitaxel/farmacologia , Células A549 , Animais , Apoptose/efeitos dos fármacos , Transporte Biológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Liberação Controlada de Fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Micelas , Invasividade Neoplásica , Metástase Neoplásica , Paclitaxel/metabolismo , Paclitaxel/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Drug Deliv ; 26(1): 773-781, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31357890

RESUMO

Although convection-enhanced delivery (CED) can successfully facilitate a bypass of the blood brain barrier, its treatment efficacy remains highly limited in clinic. This can be partially attributed to the brain anisotropic characteristics that lead to the difficulties in controlling the drug spatial distribution. Here, the responses of six different drugs to the tissue anisotropy are examined through a parametric study performed using a multiphysics model, which considers interstitial fluid flow, tissue deformation and interlinked drug transport processes in CED. The delivery outcomes are evaluated in terms of the penetration depth and delivery volume for effective therapy. Simulation results demonstrate that the effective penetration depth in a given direction can be improved with the increase of the corresponding component of anisotropic characteristics. The anisotropic tissue permeability could only reshape the drug distribution in space but has limited contribution to the total effective delivery volume. On the other hand, drugs respond in different ways to the anisotropic diffusivity. The large delivery volumes of fluorouracil, carmustine, cisplatin and doxorubicin could be achieved in relatively isotropic tissue, while paclitaxel and methotrexate are able to cover enlarged regions into anisotropic tissues. Results obtained from this study serve as a guide for the design of CED treatments.


Assuntos
Barreira Hematoencefálica , Convecção , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/metabolismo , Anisotropia , Velocidade do Fluxo Sanguíneo , Barreira Hematoencefálica/metabolismo , Carmustina/administração & dosagem , Carmustina/metabolismo , Cisplatino/administração & dosagem , Cisplatino/metabolismo , Difusão , Doxorrubicina/administração & dosagem , Doxorrubicina/metabolismo , Líquido Extracelular/metabolismo , Fluoruracila/administração & dosagem , Fluoruracila/metabolismo , Metotrexato/administração & dosagem , Metotrexato/metabolismo , Modelos Teóricos , Paclitaxel/administração & dosagem , Paclitaxel/metabolismo , Permeabilidade , Pressão , Análise Espacial
12.
Int J Biol Macromol ; 136: 266-274, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201909

RESUMO

Paclitaxel, an effective chemotherapeutic drug, is insoluble in aqueous solvents and is usually administered with excipients which have side effects. The use of this drug is also limited due to multi-drug resistance. In this study polysaccharide nanoparticles are used in the delivery of chemotherapeutic drug while minimizing side-effects, solubility issues and drug resistance. The use of biopolymers like galactoxyloglucan to synthesize nanoparticle makes it more biocompatible. This study involves the synthesis of PST-PTX nanoparticles using tamarind seed polysaccharide and Paclitaxel by epichlorohydrin crosslinking. The particles were further characterized by Dynamic Light Scattering (DLS), High-resolution transmission electron microscopy (HR-TEM) Fourier Transform Infrared Spectroscopy (FTIR) and UV-Visible spectroscopy. The cytotoxicity of PST-PTX nanoparticles in cancer cell lines and resistant cancer cell lines were determined by MTT assay. The quantitative analysis of cell death was determined by Annexin V dead cell assay, Caspase 3/7 assay and expression of pro-apoptotic protein Bax. The ability of the nanoparticle to overcome multi-drug resistance was evaluated by the expression of multidrug-resistant proteins P-glycoprotein (P-gp) and Breast cancer resistant protein (BCRP) in lung adenocarcinoma resistant cells (A549R). The present study provides evidence for the ability of PST-PTX nanoparticle to overcome multi-drug resistance and cause apoptotic cell death. The particle was found to be more effective than Paclitaxel in causing cell death in resistant cancer cells. Moreover, the particles were found to downregulate the expression of multi-drug resistant proteins P-gp and BCRP in resistant cell lines suggesting the ability of PST-PTX nanoparticles to overcome multi-drug resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Galactose/química , Glucanos/química , Neoplasias Pulmonares/patologia , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Transporte Biológico , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Portadores de Fármacos/química , Humanos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Paclitaxel/metabolismo
13.
Biochem Biophys Res Commun ; 516(3): 760-764, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31253401

RESUMO

We report the utility of cevipabulin as a stabilizing agent for microtubules. Cevipabulin-stabilized microtubules were more flexible compared to the microtubules stabilized by paclitaxel, the most commonly used microtubule stabilizing agent. Similar to the paclitaxel-stabilized microtubules, cevipabulin-stabilized microtubules were driven by kinesins in an in vitro gliding assay. The velocity of cevipabulin-stabilized microtubules was significantly higher than that of paclitaxel-stabilized microtubules. These findings will enrich the variety of microtubules with difference in mechanical and dynamic properties and widen their applications in nanotechnology.


Assuntos
Hidrocarbonetos Halogenados/metabolismo , Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Triazóis/metabolismo , Tubulina (Proteína)/metabolismo , Animais , Hidrocarbonetos Halogenados/química , Hidrocarbonetos Halogenados/farmacologia , Microscopia de Fluorescência , Estrutura Molecular , Nanotecnologia , Paclitaxel/química , Paclitaxel/metabolismo , Paclitaxel/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Suínos , Imagem com Lapso de Tempo/métodos , Triazóis/química , Triazóis/farmacologia
14.
Int J Biol Macromol ; 137: 20-31, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31252010

RESUMO

The research was aimed to develop a liquisolid formulation of paclitaxel using novel, highly porous liquisolid carriers (modified polysaccharides) to enhance bioavailability of orally administered paclitaxel. Modified polysaccharides namely co-grinded treated guar gum (C-TGG), co-grinded treated tamarind kernel powder (C-TTKP) and co-grinded treated locust bean gum (C-TLBG) were developed by sequentially subjecting the corresponding polysaccharides to wetting, drying and co-grinding with mannitol (1:1). A total of 12 liquisolid systems of paclitaxel (LSP-1 to LSP-12) were formulated using non-volatile solvent (polysorbate 80/Solutol HS 15®), carrier material (C-TGG/C-TTKP/C-TLBG), and Aerosil® 200 as coating material, and evaluated for pre-compression parameters. The liquisolid systems were directly compressed to produce liquisolid tablets (LTP-1 to LTP-12) and assessed for post compression parameters, cytotoxic/cellular analysis and pharmacokinetics. The modified polysaccharides exhibited narrow symmetrical particle size distribution, high liquid absorption potential, diminutive swelling index, favorable in vitro biodegradability and compression amenability. Among the directly compressed liquisolid tabs, LTP-10 exhibited highest CDR of 98.70 ±â€¯2.68% and permeability of 61.59%. The IC50 of <20 mmol/L indicated remarkable cytotoxic potential on human gastro-enteric tumor cancerous cell lines (NCI-N87). Additionally, LTP-10 exhibited significantly high values for cell death 37.92 and 54.17% (P < 0.01) in early and late apoptosis and mitochondrial membrane potential regain (33%) in comparison to paclitaxel (P < 0.05) and 5-fluorouracil (P < 0.01). Pharmacokinetics revealed Cmax of 536.48 ±â€¯4.63 µg/L at 1.64 ±â€¯0.44 h for LTP-10 indicating enhancement in bioavailability (5.43 fold) of paclitaxel on oral administration.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Portadores de Fármacos/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Paclitaxel/química , Paclitaxel/farmacologia , Polissacarídeos/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Paclitaxel/metabolismo , Paclitaxel/farmacocinética , Permeabilidade , Coelhos , Solubilidade , Distribuição Tecidual
15.
Stem Cells Transl Med ; 8(9): 880-886, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31045328

RESUMO

Mesenchymal stem cells (MSCs) are one of the most easily accessible stem cells that can be obtained from various human tissues. They have raised considerable interests for their potential applications in tissue repair, anti-cancer therapy, and inflammation suppression. Stem cell-based therapy was first used to treat muscular dystrophies and has been studied intensively for its efficacy in various disease models, including myocardial infarction, kidney injuries, liver injuries, and cancers. In this review, we summarized the potential mechanisms underlying MSC-derived EVs therapy as a drug delivery platform. Additionally, based on currently published data, we predicted a potential therapeutic role of cargo proteins shuttled by EVs from MSCs. These data may support the therapeutic strategy of using the MSC-derived EVs to accelerate this strategy from bench to bedside. Stem Cells Translational Medicine 2019;8:880&886.


Assuntos
Portadores de Fármacos/química , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/transplante , Humanos , Proteína 2 de Membrana Associada ao Lisossomo/genética , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Engenharia Metabólica , Neoplasias/patologia , Neoplasias/terapia , Paclitaxel/química , Paclitaxel/metabolismo , Paclitaxel/uso terapêutico , Regeneração , Tetraspaninas/genética , Tetraspaninas/metabolismo
16.
Angew Chem Int Ed Engl ; 58(34): 11661-11665, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31125154

RESUMO

Polytherapy (or drug combination cancer therapy (DCCT)), targeting multiple mechanisms associated with tumor proliferation, can efficiently maximize therapeutic efficacy, decrease drug dosage, and reduce drug resistance. However, most DCCT strategies cannot coordinate the specific delivery of a drug combination in an accurately tuned ratio into cancer cells. To address these limitations, the present work reports the engineering of circular bivalent aptamer-drug conjugates (cb-ApDCs). The cb-ApDCs exhibit high stability, specific recognition, excellent cellular uptake, and esterase-triggered release. Furthermore, the drug ratios in cb-ApDCs can be tuned for an enhanced synergistic effect without the need for complex chemistry. Therefore, cb-ApDCs provide a promising platform for the development of DCCT strategies for different drug combinations and ratios.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Aptâmeros de Nucleotídeos/química , Portadores de Fármacos/química , Terapia de Alvo Molecular , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/metabolismo , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/metabolismo , Dasatinibe/administração & dosagem , Dasatinibe/química , Dasatinibe/metabolismo , Sistemas de Liberação de Medicamentos , Humanos , Masculino , Paclitaxel/administração & dosagem , Paclitaxel/química , Paclitaxel/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Estilbenos/administração & dosagem , Estilbenos/química , Estilbenos/metabolismo , Células Tumorais Cultivadas
17.
Adv Healthc Mater ; 8(13): e1900102, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31091019

RESUMO

Effective cancer therapy can be achieved by designing a smart nanofiber system with the combination of chemotherapy and hyperthermia. This study demonstrates the in vivo antitumor effect of a nanofiber mesh that can deliver heat and antitumor drug in a controlled manner. The mesh is composed of biodegradable poly(ε-caprolactone) (PCL) with paclitaxel (PTX) and magnetic nanoparticles (MNPs). The PCL mesh releases PTX slowly for at least 6 weeks when tested in vitro. The prolonged therapeutic effect is observed in vivo as a continuous release of medication from the mesh over an extended period of time compared with direct injection of PTX into the tumor site. In addition, the synergistic anticancer effect is achieved upon excitation of the mesh with an alternating magnetic field because the MNPs within the nanofiber generate localized heat which causes heat-induced cell killing as well as enhanced chemotherapeutic effect of PTX. Based on these results, the smart nanofiber system may be very promising for cancer therapeutics in the future and may provide knowledge for new development of localized drug delivery.


Assuntos
Portadores de Fármacos/química , Hipertermia Induzida/métodos , Nanofibras/química , Paclitaxel/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Nanopartículas de Magnetita/química , Camundongos , Camundongos SCID , Nanofibras/toxicidade , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Poliésteres/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Mol Pharm ; 16(6): 2385-2393, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31002261

RESUMO

nab-Paclitaxel ( nab-P), an albumin-bound formulation of paclitaxel, was developed to improve the tolerability and antitumor activity of taxanes. The neonatal Fc receptor (FcRn) is a transport protein that can bind to albumin and regulate the homeostasis of circulating albumin. Therefore, the pharmacokinetics and pharmacodynamics of nab-P may be impacted by FcRn expression. This study aimed to investigate the effects of FcRn on nab-P elimination and distribution to targeted tissues. Wild-type and FcRn-knockout (FcRn-KO) mice were treated with nab-P, mouse-specific nab-P (distribution experiments only), and solvent-based paclitaxel (pac-T). Blood and tissue samples were collected for distribution analyses. Organ, urine, and fecal samples were collected for elimination analyses. The nab-P tissue penetration in the pancreas, fat pad, and kidney of wild-type mice, as reflected by the ratio of tissue/plasma concentration, was significantly higher (ranging from 5 to 80 fold) than that of FcRn-KO mice. In contrast, the tissue penetration of pac-T in these organs of FcRn-KO mice was similar to that of wild-type mice. More importantly, the excretion of nab-P in feces of FcRn-KO mice (45-68%) was significantly higher than that of wild-type mice (26-46%) from 8 to 48 h post treatment. In comparison, the difference of excretion of pac-T in feces between FcRn-KO mice and wild-type mice was smaller than that of nab-P. Furthermore, greater tissue penetration and fecal excretion were observed with nab-P than pac-T in both FcRn-KO and wild-type mice. These findings suggest that FcRn enhances the tissue distribution and penetration of nab-P in the targeted organs, while FcRn prevents excretion of nab-P to feces in the intestinal lumen. The findings support the notion that albumin nanoparticle delivery alters drug distribution and elimination through an FcRn-mediated process to impact drug efficacy and toxicity.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Paclitaxel/metabolismo , Receptores Fc/metabolismo , Albuminas/química , Animais , Camundongos , Camundongos Knockout , Nanopartículas/química , Distribuição Tecidual
20.
J Pharm Biomed Anal ; 172: 26-32, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31022613

RESUMO

We have developed a high performance liquid chromatography mass spectrometry method for quantitating paclitaxel and its 6-alpha-OH and 3-para-OH metabolites in 0.1 mL human plasma. After MTBE liquid-liquid extraction, chromatographic separation was achieved with a Phenomenex synergy polar reverse phase (4 µm, 2 mm × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an ABI SCIEX 4000Q with electrospray, positive-mode ionization. The assay was linear from 10-10,000 ng/mL for paclitaxel and 1-1000 ng/mL for both metabolites and proved to be accurate (94.3-110.4%) and precise (<11.3%CV). Recovery from plasma was 59.3-91.3% and matrix effect was negligible (-3.5 to 6.2%). Plasma freeze thaw stability (90.2-107.0%), stability for 37 months at -80 °C (89.4-112.6%), and stability for 4 h at room temperature (87.7-100.0%) were all acceptable. This assay will be an essential tool to further define the metabolism and pharmacology of paclitaxel and metabolites in the clinical setting. The assay may be utilized for therapeutic drug monitoring of paclitaxel and may also reveal the CYP2C8 and CYP3A4 activity phenotype of patients.


Assuntos
Antineoplásicos Fitogênicos/sangue , Coleta de Amostras Sanguíneas/métodos , Monitoramento de Medicamentos/métodos , Paclitaxel/sangue , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Clínicos Fase I como Assunto , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Estabilidade de Medicamentos , Humanos , Paclitaxel/metabolismo , Paclitaxel/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
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