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1.
Chem Biodivers ; 17(2): e1900631, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31967396

RESUMO

A mixture of taxols was prepared from 10-deacetyl-7-xylosyltaxanes by three-step reactions: redox, acetylation, and deacetylation. The mixture was separated by column chromatography on silica gel to afford Taxol, Taxol B (Cephalomannine) and Taxol C. The mixture of Taxol B and Taxol C was converted to Docetaxel by Schwartz's reagent. The structures of Taxol and Docetaxel were characterized by HPLC, 1 H-NMR, 13 C-NMR and MS. This synthetic process has expanded the source of biomass for the chemical semi-synthesis of Taxol and Docetaxel, reduced the production costs, and increased the biomass resource of taxanes.


Assuntos
Docetaxel/química , Paclitaxel/química , Taxoides/química , Acetilação , Cromatografia Líquida de Alta Pressão , Docetaxel/síntese química , Espectroscopia de Ressonância Magnética , Oxirredução , Paclitaxel/síntese química
2.
Biomed Res Int ; 2019: 3079895, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31380416

RESUMO

Breast and colon cancers are leading causes of cancer-related deaths globally. Plants are a potential source of natural products that may be used for the treatment of cancer. Ferula hermonis (FH) is reported to have diverse therapeutic effects. However, there are few reports on the in vitro anticancer potential of FH extract. Our results showed that the Ferula hermonis root hexane extract (FHRH) can induce dose-dependent cytotoxic effects in breast and colon cancer cells with MTT IC50 values of 18.2 and 25 µg/ml, respectively. The FHRH extract induced apoptosis in both breast and colon cancer cells; this was confirmed by light and nuclear staining, q-PCR, and caspase 3/7 activation. This study also demonstrated the antitumor activity of FHRH in 9,10-dimethylbenz[α]anthracene DMBA-induced rodent mammary tumor model. The GC/MS analysis revealed the presence of 3,5-Dimethylbenzenemethanol, Alpha-Bisabolol, Alpha-pinene, Beta-pinene, and Baccatin III that have various pharmacological potentials. Overall, the present study suggests that FHRH extract possesses anticancer potential which is mediated through apoptotic effects in MDA-MB-231 and LoVo cells. The present study also considered a basis for further investigations into the potential use of FHRH extract as an anticancer therapy for breast and colon cancers.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Ferula/química , Extratos Vegetais/farmacologia , Alcaloides/química , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Feminino , Humanos , Camundongos , Extratos Vegetais/química , Raízes de Plantas/química , Taxoides/química
3.
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
4.
Biomed Pharmacother ; 116: 109001, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146114

RESUMO

Renal cell carcinoma (RCC) has always been considered resistant to chemotherapy. IR-780 is a near-infrared fluorescent (NIRF) dye that can be efficiently taken up by RCC cells. Cabazitaxel is a cytotoxic drug that interferes with mitosis by acting on tubulin. We chemically fused IR-780 and cabazitaxel into a new drug, Caba-780, which is expected to increase the sensitivity of RCC to chemotherapy. Infrared spectrum, nuclear magnetic resonance spectra, high-resolution mass spectra, and IR spectra were used for detecting structural characterization of the new synthetic drug Caba-780. The RCC cells lines ACHN and 786-O, as well as the non-cancerous human embryonic kidney cell line HEK293, were used to assess the cytotoxicity and tumor-efficient uptake of Caba-780 in vitro. The xenograft tumor-bearing mice and C57 mice were used to estimate the tumor-efficient imaging of Caba-780 as well as the safety and efficacy of its anti-tumor effects in vivo. The new synthetic drug Caba-780 retains the NIRF properties of IR-780. In vitro, Caba-780 was efficiently absorbed by the RCC cell lines ACHN and 786-O, and had an inhibitory effect on their growth, clonogenicity migration, and invasion. At the same time, Caba-780 retained the anti-tumor effect of cabazitaxel, which can inhibit the growth of tumor cells and promote apoptosis by inhibiting mitosis. In vivo experiments showed that Caba-780 can be taken up and imaged in tumor tissue, whereby it inhibits tumor growth. The novel fused molecule Caba-780 has application prospects in the diagnosis and treatment of RCC and makes RCC chemotherapy possible.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Indóis/uso terapêutico , Raios Infravermelhos , Neoplasias Renais/tratamento farmacológico , Taxoides/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Neoplasias Renais/patologia , Camundongos , Invasividade Neoplásica , Transportadores de Ânions Orgânicos/metabolismo , Frações Subcelulares/metabolismo , Taxoides/síntese química , Taxoides/química , Taxoides/farmacologia , Testes de Toxicidade Aguda
5.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052317

RESUMO

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and ß-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, ß-elemene liposome and cabazitaxel-ß-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and ß-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and ß-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and ß-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and ß-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that ß-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Lipossomos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Taxoides/administração & dosagem , Taxoides/farmacocinética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Lipossomos/química , Camundongos , Estrutura Molecular , Paclitaxel/farmacologia , Tamanho da Partícula , Sesquiterpenos/química , Taxoides/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Commun ; 10(1): 1033, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833575

RESUMO

Taxanes are a family of natural products with a broad spectrum of anticancer activity. This activity is mediated by interaction with the taxane site of beta-tubulin, leading to microtubule stabilization and cell death. Although widely used in the treatment of breast cancer and other malignancies, existing taxane-based therapies including paclitaxel and the second-generation docetaxel are currently limited by severe adverse effects and dose-limiting toxicity. To discover taxane site modulators, we employ a computational binding site similarity screen of > 14,000 drug-like pockets from PDB, revealing an unexpected similarity between the estrogen receptor and the beta-tubulin taxane binding pocket. Evaluation of nine selective estrogen receptor modulators (SERMs) via cellular and biochemical assays confirms taxane site interaction, microtubule stabilization, and cell proliferation inhibition. Our study demonstrates that SERMs can modulate microtubule assembly and raises the possibility of an estrogen receptor-independent mechanism for inhibiting cell proliferation.


Assuntos
Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Taxoides/química , Taxoides/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Tubulina (Proteína)/química , Antineoplásicos/farmacologia , Sítios de Ligação , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Ligantes , Proteínas dos Microtúbulos/efeitos dos fármacos , Modelos Moleculares , Paclitaxel/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Microambiente Tumoral
7.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897704

RESUMO

It has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent taxane-site ligands, including cyclostreptin, to gain further insight into this mechanism. The crystal structure of cyclostreptin-bound tubulin reveals covalent binding to ßHis229, but no stabilization of the M-loop. The capacity of cyclostreptin to induce microtubule assembly compared to other covalent taxane-site agents demonstrates that the induction of tubulin assembly is not strictly dependent on M-loop stabilization. We further demonstrate that most covalent taxane-site ligands are able to partially overcome drug resistance mediated by ßIII-tubulin (ßIII) overexpression in HeLa cells, and compare their activities to pironetin, an interfacial covalent inhibitor of tubulin assembly that displays invariant growth inhibition in these cells. Our findings suggest a relationship between a diminished interaction of taxane-site ligands with ßIII-tubulin and ßIII tubulin-mediated drug resistance. This supports the idea that overexpression of ßIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands.


Assuntos
Microtúbulos/química , Compostos Policíclicos/química , Tubulina (Proteína)/química , Resistencia a Medicamentos Antineoplásicos , Ácido Edético/química , Células HeLa , Humanos , Espectrometria de Massas , Taxoides/química
8.
Nat Prod Res ; 33(24): 3478-3484, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29897250

RESUMO

Four C-13, C-14 side chain modified 9(R)-hydroxy-1-deoxy-taxane analogues 15, 16, 19 and 22 were semi-synthesized from 1-deoxybaccatin VI. The in vitro antitumor activity of these compounds was evaluated against A549 and A2780 cell lines. The preliminary SAR analysis showed that introduction of oxygen-containing group on C-14 could improve the cytotoxic activities.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Células A549 , Hidrocarbonetos Aromáticos com Pontes/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade , Taxoides/química
9.
Carbohydr Polym ; 203: 302-309, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30318217

RESUMO

The malignant gliomas are most destructive brain tumor having low drug response. The thermosensitive hydrogel from pluronic F127 (PF127) and N,N,N-trimethyl chitosan (TMC) is developed as a drug delivery system for anticancer drug docetaxel (DTX) to the glioblastoma multiforme. The influence of TMC on morphology, physico-chemical, mechanical, and release properties of PF127 based thermosensitive hydrogel is investigated here. The hydrogels shows porous network as shown by scanning electron microscopy and TMC addition hindered close packing of PF127 layers in the gel system leaving more pores on the surface. TEM images demonstrate micelle formation by PF127-TMC with diameters of about 50 nm. MTT assay result shows that DTX loaded PF127-TMC hydrogel is more capable of killing U87MG cell than free DTX and DTX loaded PF-127. Hydrogels retain sustained release of DTX under different pH conditions more than one month. Furthermore, in vivo experiments are carried out by creating xenograft tumor model on the head of BALB/c nude mice for checking tumor suppression by PF127-TMC/DTX hydrogel. Overall, the hydrogels shows sustained release of DTX on different pH with tumor suppression suggests that it can be used for treating tumor.


Assuntos
Antineoplásicos/uso terapêutico , Quitosana/química , Glioblastoma/tratamento farmacológico , Hidrogéis/química , Poloxâmero/química , Taxoides/uso terapêutico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Quitosana/síntese química , Docetaxel , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Hidrogéis/síntese química , Concentração de Íons de Hidrogênio , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Taxoides/química
10.
Nanotechnology ; 30(5): 055601, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30511654

RESUMO

Novel type of multifunctional polymeric micelles (PMs) designated as HM-PMss/CTX micelles were developed in the present study for tumor-targeted and glutathione (GSH)-responsive delivery of cabazitaxel (CTX). The surface of the vehicles was modified with piloting molecules (HM-3 peptide), which targets α v ß 3 integrin overexpressed on cancer cells, and the micelle core was cross-linked by GSH-disintegrable disulfide linkages for controlled drug release. HM-PMss/CTX micelles were prepared using a mixture of two functionalized amphiphilic block copolymers and found to physically encapsulate CTX with excellent entrapment efficiency (93.94 ± 4.19%), drug-loading capacity (8.39 ± 2.28%), and a narrow size distribution. In vitro release profiles showed that CTX remained stably entrapped in the micelles in a release medium without GSH or with GSH of low concentration, while undergoing a rapid release in a highly reductive environment. Cellular uptake experiments showed that the conjugation of the targeting peptide, containing an arginine-glycine-aspartate sequence, enhanced the cellular uptake of HM-PMss/CTX micelles via α v ß 3 integrin-mediated endocytosis. In vitro cell viability measurements revealed that blank micelles were biocompatible, while HM-PMss/CTX micelles, owing to their tumor-targeting ability and GSH sensitivity, effectively inhibited the proliferation of MDA-MB-231 breast cancer cells. These results indicate that HM-PMss/CTX micelles could be a promising platform for future intelligent drug delivery in cancer therapy.


Assuntos
Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Glutationa/metabolismo , Neoplasias/tratamento farmacológico , Taxoides/química , Taxoides/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Micelas
11.
Mol Med Rep ; 19(1): 490-498, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30483775

RESUMO

The present study investigated the feasibility of improving the tumor­targeting efficacy and decreasing the toxicity of liposomal cabazitaxel (Cab) with aptamer modification. The process involved preparing aptamer (TLS1c)­modified liposomes and studying the behavior of the liposomes in vitro and in vivo. TLS1c as an aptamer, which has high specificity for BNL 1ME A.7R.1 (MEAR) cells, was conjugated with Cab liposomes (Cab/lipo) to enhance MEAR tumor tissue targeting. Confocal laser scanning microscopy and flow cytometry analyses demonstrated that the fluorescence of the liposomes modified with the aptamer was notably stronger compared with that of the unmodified liposomes. Furthermore, the biodistribution data of the modified liposomes tested in tumor­bearing mice revealed high specificity of biotinylated TLS1c­modified Cab/lipo (BioTL­Cab/lipo) for tumor tissues. Furthermore, the modified liposomes demonstrated decreased cytotoxicity and simultaneously retained potent inhibition against tumor growth. It is likely that the specific binding of the aptamer (TLS1c) to the targeted cells (MEAR) facilitates the binding of the liposomes to the targeted cells. Therefore, BioTL­Cab/lipo may be considered as a promising delivery system to improve cell targeting and reduce drug toxicity in the treatment of cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/química , Lipossomos/química , Neoplasias/tratamento farmacológico , Taxoides/química , Taxoides/farmacologia , Animais , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/metabolismo , Taxoides/metabolismo , Distribuição Tecidual
12.
Bioconjug Chem ; 29(11): 3550-3560, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30403467

RESUMO

A family of five water-soluble Gd3+:1,4,7,10-tetraazacyclododecane-1,4,7-tetraacetic acid-modified polyrotaxane (PR) magnetic resonance contrast agents bearing mixtures of 2-hydroxypropyl-ß-cyclodextrin and 4-sulfobutylether-ß-cyclodextrin macrocycles threaded onto Pluronic cores were developed as long circulating magnetic resonance contrast agents. Short diethylene glycol diamine spacers were utilized for linking the macrocyclic chelator to the PR scaffold prior to Gd3+ chelation. The PR products were characterized by 1H NMR, gel permeation chromatography/multiangle light scattering, dynamic light scattering, and analytical ultracentrifugation. Nuclear magnetic relaxation dispersion and molar relaxivity measurements at 23 °C revealed that all the PR contrast agents displayed high spin-spin T1 relaxation and spin-lattice T2 relaxation rates relative to a DOTAREM control. When injected at 0.05 mmol Gd/kg body weight in BALB/c mice, the PR contrast agents increased the T1-weighted MR image intensities with longer circulation times in the blood pool than DOTAREM. Excretion of the agents occurred predominantly via the renal or biliary routes depending on the polyrotaxane structure, with the longest circulating L81 Pluronic-based agent showing the highest liver uptake. Proteomic analysis of PR bearing different ß-cyclodextrin moieties indicated that lipoproteins were the predominant component associated with these materials after serum exposure, comprising as much as 40% of the total protein corona. We infer from these findings that Gd(III)-modified PR contrast agents are promising long-circulating candidates for blood pool analysis by MRI.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Quelantes/química , Meios de Contraste/química , Compostos Heterocíclicos com 1 Anel/química , Imagem por Ressonância Magnética/métodos , Taxoides/química , Animais , Quelantes/farmacocinética , Meios de Contraste/farmacocinética , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 1 Anel/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Poloxâmero/química , Poloxâmero/farmacocinética , Coroa de Proteína/análise , Espectroscopia de Prótons por Ressonância Magnética , Taxoides/sangue , Taxoides/farmacocinética
13.
Anticancer Res ; 38(11): 6209-6215, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30396939

RESUMO

BACKGROUND/AIM: More than half of prostate cancer patients use, in addition to conventional therapies, some kind of complementary medicine, including flavonoid-rich products. However, knowledge about the co-effects of flavonoids with cytotoxic chemotherapies is still rather poor. Therefore, this study was undertaken to assess the cytotoxic activity of flavonoids and their interactions with taxanes in human advanced prostate cancer cells. MATERIALS AND METHODS: Cytotoxicity of different flavonoids and their effects on the efficacy of docetaxel and cabazitaxel were studied in the human metastatic prostate cancer cell line PPC-1, using MTT colorimetric assay. RESULTS: Both taxanes suppressed the viability of PPC-1 cells with IC50 values in the nanomolar range. Tested flavonoids exerted cytotoxic activity only at high micromolar concentrations or revealed no remarkable effect on cell survival. Simultaneous treatment of cells with taxanes and flavonoids baicalein, chrysin, luteolin, fisetin, quercetin, genistein or daidzein did not lead to any change in chemotherapy-induced cytotoxicity. However, simultaneous exposure of cells to hesperetin and taxanes resulted in 9.8- and 13.1-fold reduction in cytotoxicity of docetaxel and cabazitaxel, respectively. CONCLUSION: Flavonoid hesperetin remarkably suppressed the cytotoxic efficacy of taxanes in prostate cancer cells. Therefore, caution is required from prostate cancer patients who take hesperetin-containing oral supplements.


Assuntos
Suplementos Nutricionais/efeitos adversos , Hesperidina/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Taxoides/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Antagonismo de Drogas , Hesperidina/química , Humanos , Masculino , Taxoides/química
14.
Proc Natl Acad Sci U S A ; 115(48): E11406-E11414, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30429313

RESUMO

Drug receptor site occupancy is a central pharmacology parameter that quantitatively relates the biochemistry of drug binding to the biology of drug action. Taxanes and epothilones bind to overlapping sites in microtubules (MTs) and stabilize them. They are used to treat cancer and are under investigation for neurodegeneration. In cells, they cause concentration-dependent inhibition of MT dynamics and perturbation of mitosis, but the degree of site occupancy required to trigger different effects has not been measured. We report a live cell assay for taxane-site occupancy, and relationships between site occupancy and biological effects across four drugs and two cell lines. By normalizing to site occupancy, we were able to quantitatively compare drug activities and cell sensitivities independent of differences in drug affinity and uptake/efflux kinetics. Across all drugs and cells tested, we found that inhibition of MT dynamics, postmitotic micronucleation, and mitotic arrest required successively higher site occupancy. We also found interesting differences between cells and drugs, for example, insensitivity of the spindle assembly checkpoint to site occupancy. By extending our assay to a mouse xenograft tumor model, we estimated the initial site occupancy required for paclitaxel to completely prevent tumor growth as 80%. The most important cellular action of taxanes for cancer treatment may be formation of micronuclei, which occurs over a broad range of site occupancies.


Assuntos
Antineoplásicos/metabolismo , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Taxoides/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Transporte Biológico , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Epotilonas/química , Epotilonas/metabolismo , Epotilonas/farmacologia , Humanos , Cinética , Microscopia , Microtúbulos/química , Microtúbulos/metabolismo , Taxoides/química , Taxoides/farmacologia
15.
Eur J Pharm Sci ; 124: 288-294, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30193858

RESUMO

Enteric polymers have been found with absorption promotion effect on nanoparticles. To study the role of enteric polymers played in the process of oral nanoparticle delivery, Eudragit L100-55 (EU) and sodium alginate (SA) were selected as model enteric polymers and larotaxel (LTX) as model drug. Suspensions composed of LTX-loaded nanoparticles, HPMC and different enteric polymers (EU and SA) were prepared (NP@EU, NP@SA). And aspects like precipitate morphology upon contact with acid, nanoparticle encapsulation capability, in vitro drug release, intestinal residence and in vivo oral bioavailability were studied. It was found that precipitates formed by EU could encapsulate more NP in acidic environment than those of SA (>95% of EU vs. approximately 70% of SA), and this difference in NP encapsulation was found correlated with the morphology of the precipitates formed: precipitates of EU appeared as three dimensional granules with dense inner structure, while SA precipitated into film-like porous structures. Results of pharmacokinetic study indicated that both EU and SA were capable in improving LTX absorption with absolute bioavailability of 77.1% and 42.5%, respectively. And the better absorption promoting effect of NP@EU was correlated with its longer intestinal residence shown by the results of ex vivo imaging study. In conclusion, both EU and SA could improve the oral bioavailability of LTX-loaded NP, and NP encapsulation capability and intestinal residence time are considered as key factors affecting the degree of absorption promotion.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Taxoides/administração & dosagem , Resinas Acrílicas/administração & dosagem , Resinas Acrílicas/química , Administração Oral , Alginatos/administração & dosagem , Alginatos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Absorção Intestinal , Masculino , Nanopartículas/química , Ratos Sprague-Dawley , Taxoides/química , Taxoides/farmacocinética
16.
J Labelled Comp Radiopharm ; 61(12): 895-902, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30101475

RESUMO

Radiolabelled azidophenyl analogues can make powerful photoaffinity probes for the identification of molecular targets. We describe our efforts to prepare tritiated azidophenyl analogues of the taxols cabazitaxel and docetaxel. Late-stage tritiation by isotope exchange with diiodo precursors resulted in reduction of the azide moiety, which could only be overcome by addition of high excess of a sacrificial azide. Iodine-deuterium exchange experiments on a model system established that deiodination with concomitant azide reduction is a general problem when performing such isotope-exchange reactions on azide-containing aryl iodides.


Assuntos
Azidas/química , Docetaxel/química , Iodo/química , Marcadores de Fotoafinidade/química , Taxoides/química , Trítio/química , Marcação por Isótopo , Modelos Moleculares , Conformação Molecular
17.
Biomed Res Int ; 2018: 8746729, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30065947

RESUMO

This study was conducted to evaluate the ability of Raman spectroscopy (RS) to control antineoplastic preparations used for chemotherapy in order to ensure its physical and chemical qualities. Three taxane drugs: cabazitaxel (CBX), docetaxel (DCX) and paclitaxel (PCX) at therapeutic concentration ranges were analyzed using a handheld spectrometer at 785 nm. Qualitative and quantitative models were developed and optimized using a calibration set (n=75 per drug) by partial least square discriminant analysis and regression and validated using a test set (n=27 per drug). All samples were correctly assigned with an accuracy of 100%. Despite optimization, quantitative analysis showed limited performances at the lowest concentrations. The root mean square error of predictions ranged from 0.012 mg/mL for CBX to 0.048 mg/mL for DCX with a minimal coefficient of determination of 0.9598. The linearity range was validated from 0.175 to 0.30 mg/mL for CBX, from 0.40 to 1.00 mg/mL for DCX and from 0.57 to 1.20 mg/mL for PCX. Despite some limitations, this study confirms the potential of RS to control these drugs and also provides substantial advantages to secure the activity for healthcare workers. As a result of its rapidity and the uncomplicated use of a handheld instrument, RS appears to be a promising method to augment security of the medication preparation process in hospitals.


Assuntos
Antineoplásicos/química , Análise Espectral Raman , Taxoides/química , Antineoplásicos/normas , Calibragem , Análise Discriminante , Humanos , Taxoides/normas
18.
Biomed Pharmacother ; 106: 1461-1468, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30119220

RESUMO

In the present study, docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) nanoparticles were successfully prepared and coated with chitosan (CS). The prepared nanoparticles (NPs) were evaluated for their particle size, zeta potential, particle morphology, drug entrapment efficiency (EE%), and in vitro drug release profile. The anticancer activity of DTX-loaded NPs was assessed in human HT29 colon cancer cell line utilizing MTT assay. The pharmacokinetics of DTX-loaded NPs was monitored in Wistar rats in comparison to DTX solution. The prepared NPs exhibited particle sizes in the range 177.1 ± 8.2-287.6 ± 14.3 nm. CS decorated NPs exhibited a significant increase in particle size and a switch of zeta potential from negative to positive. In addition, high EE% values were obtained for CS coated PCL NPs and PLGA NPs as 67.1 and 76.2%, respectively. Moreover, lowering the rate of DTX in vitro release was achieved within 48 h by using CS coated NPs. Furthermore, a tremendous increase in DTX cytotoxicity was observed by CS-decorated PLGA NPs compared to all other NPs including DTX-free-NPs and pure DTX. The in vivo study revealed significant enhancement in DTX bioavailability from CS-decorated PLGA NPs with more than 4-fold increase in AUC compared to DTX solution. In conclusion, CS-decorated PLGA NPs are a considerable DTX-delivery carrier with magnificent antitumor efficacy.


Assuntos
Antineoplásicos/administração & dosagem , Quitosana/química , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos , Ácido Láctico/química , Nanopartículas , Poliésteres/química , Ácido Poliglicólico/química , Taxoides/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Preparações de Ação Retardada , Docetaxel , Composição de Medicamentos , Liberação Controlada de Fármacos , Difusão Dinâmica da Luz , Células HT29 , Humanos , Injeções Intraperitoneais , Masculino , Microscopia Eletrônica de Varredura , Nanotecnologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Wistar , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Taxoides/química , Taxoides/farmacocinética , Tecnologia Farmacêutica/métodos
19.
Int J Pharm ; 548(1): 357-374, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-29981409

RESUMO

The present study investigates effect of linkers [zero length (without linker), short length linker (glycine and lysine) and long length linker (PEG1000, PEG2000 and PEG3500)] on pharmacokinetics and toxicity of docetaxel (DTX) and gemcitabine (GEM) bio-conjugates. Conjugates were synthesized via carbodiimide chemistry and characterized by 1H NMR and FTIR. Conjugation of DTX and GEM via linkers showed diverse physiochemical and plasma stability profile. Cellular uptake mechanism in MCF-7 and MDA-MB-231 cell lines revealed clathrin mediated internalization of bio-conjugates developed by using long length linkers, leading to higher cytotoxicity compared with free drug congeners. DTX-PEG3500-GEM and DTX-PEG2000-GEM demonstrated 4.21 and 3.81-fold higher AUC(0-∞) of GEM in comparison with GEM alone. DTX-PEG2000-GEM and DTX-PEG3500-GEM exhibited reduced hepato-, nephro- and haemolytic toxicity as evident via histopathology, biochemical markers and SEM analysis of RBCs. Conclusively, PEG2000 and PEG3500 significantly improved pharmacokinetics without any sign of toxicity and hence can be explored further for the development of dual-drug conjugates for better therapeutic efficacy.


Assuntos
Antineoplásicos , Desoxicitidina/análogos & derivados , Taxoides , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/química , Desoxicitidina/farmacologia , Docetaxel , Combinação de Medicamentos , Feminino , Hemólise/efeitos dos fármacos , Humanos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Ratos Sprague-Dawley , Taxoides/química , Taxoides/farmacologia
20.
Drug Deliv Transl Res ; 8(5): 1365-1379, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30019282

RESUMO

This paper aimed to develop a novel lipid microsphere delivering cabazitaxel (CTX) using phosphatidylcholine combined with DSPE-PEG2000 as emulsifier, and evaluate its stability, pharmacokinetics, antitumor efficacy, and toxicity. The pegylated cabazitaxel-loaded lipid microspheres (CTX-PLMs) were prepared by high-pressure homogenization methods; the biological samples were analyzed by the UPLC-MS/MS method. CTX-PLMs had a drug concentration of 1.2 mg/ml and a mean particle size of 180.0 ± 51.119 nm. CTX-PLMs showed a superior physical stability as it could remain nearly intact after 1-year storage. The AUC0-t of the CTX-PLMs was 1562.6 ± 520.1 µg h L-1 compared with the CTX-solution of 860.734 ± 312.4 µg h L-1. CTX-PLMs exhibited a strong antitumor efficacy against NCI-N87 and DU145 tumor models with tumor growth inhibition rates of 93.5 and 88.5%, respectively. The LD50 of CTX-PLMs in rats was 20.89 mg/kg. As for the long-term toxicity, the thymus, mesenteric lymph nodes, and bone marrow were the main toxic target organs and systemic toxicity induced by CTX-PLMs was alleviated relative to that of the CTX-solution. Safety assessment studies including hemolysis test, dermal sensitization test, systemic anaphylaxis, and vascular stimulation test indicated that CTX-PLMs is safe enough for intravenous administration. In a word, CTX-PLMs are a promising carrier for intravenous administration with satisfactory stability, stronger tumor inhibition, and superior safety profile.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Taxoides/administração & dosagem , Taxoides/farmacocinética , Administração Intravenosa , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Disponibilidade Biológica , Linhagem Celular Tumoral , Portadores de Fármacos/química , Estabilidade de Medicamentos , Feminino , Cobaias , Humanos , Dose Letal Mediana , Masculino , Camundongos , Camundongos Nus , Microesferas , Tamanho da Partícula , Ratos , Taxoides/efeitos adversos , Taxoides/química , Ensaios Antitumorais Modelo de Xenoenxerto
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