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1.
Int J Nanomedicine ; 14: 6691-6706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692515

RESUMO

Purpose: Amentoflavone, robustaflavone, 2'',3''-dihydro-3',3'''-biapigenin, 3',3'''-binaringenin and delicaflavone are five major active ingredients in the total biflavonoids extract from Selaginella doederleinii (TBESD) with favorable anticancer properties. However, the natural-derived potent antitumor agent of TBESD is undesirable due to its poor solubility. The present study was to develop and optimize a proliposomal formulation of TBESD (P-TBESD) to improve its solubility, oral bioavailability and efficacy. Materials and methods: P-TBESD containing a bile salt, a protective hydrophilic isomalto-oligosaccharides (IMOs) coating, were successfully prepared by thin film dispersion-sonication method. The physicochemical and pharmacokinetic properties of P-TBESD were characterized, and the antitumor effect was evaluated using the HT-29 xenograft-bearing mice models in rats. Results: Compared with TBESD, the relative bioavailability of amentoflavone, robustaflavone, 2'',3''-dihydro-3',3'''-biapigenin, 3',3'''-binaringenin and delicaflavone from P-TBESD were 669%, 523%, 761%, 955% and 191%, respectively. The results of pharmacodynamics demonstrated that both TBESD and P-TBESD groups afforded antitumor effect without systemic toxicity, and the antitumor effect of P-TBESD was significantly superior to that of raw TBESD, based on the tumor growth inhibition and histopathological examination. Conclusion: Hence, IMOs-modified proliposomes have promising potential for TBESD solving the problem of its poor solubility and oral bioavailability, which can serve as a practical oral preparation for TBESD in the future cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Biflavonoides/administração & dosagem , Lipossomos/administração & dosagem , Extratos Vegetais/administração & dosagem , Selaginellaceae/química , Administração Oral , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Biflavonoides/farmacocinética , Biflavonoides/farmacologia , Ácidos e Sais Biliares/química , Disponibilidade Biológica , Células HT29 , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oligossacarídeos/química , Extratos Vegetais/química , Ratos Sprague-Dawley , Solubilidade , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Molecules ; 24(19)2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31590459

RESUMO

There is robust epidemiological evidence for the beneficial effects of broccoli consumption on health, many of them clearly mediated by the isothiocyanate sulforaphane. Present in the plant as its precursor, glucoraphanin, sulforaphane is formed through the actions of myrosinase, a ß-thioglucosidase present in either the plant tissue or the mammalian microbiome. Since first isolated from broccoli and demonstrated to have cancer chemoprotective properties in rats in the early 1990s, over 3000 publications have described its efficacy in rodent disease models, underlying mechanisms of action or, to date, over 50 clinical trials examining pharmacokinetics, pharmacodynamics and disease mitigation. This review evaluates the current state of knowledge regarding the relationships between formulation (e.g., plants, sprouts, beverages, supplements), bioavailability and efficacy, and the doses of glucoraphanin and/or sulforaphane that have been used in pre-clinical and clinical studies. We pay special attention to the challenges for better integration of animal model and clinical studies, particularly with regard to selection of dose and route of administration. More effort is required to elucidate underlying mechanisms of action and to develop and validate biomarkers of pharmacodynamic action in humans. A sobering lesson is that changes in approach will be required to implement a public health paradigm for dispensing benefit across all spectrums of the global population.


Assuntos
Brassica/química , Isotiocianatos/química , Isotiocianatos/uso terapêutico , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/uso terapêutico , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Ensaios Clínicos como Assunto , Humanos , Isotiocianatos/farmacocinética , Estrutura Molecular , Extratos Vegetais/química
3.
Mater Sci Eng C Mater Biol Appl ; 105: 110099, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546395

RESUMO

Multi-modality strategies of albumin-mediated drug accumulation in tumor, boronate-based active tumor targeting and synergistic cancer therapy were combined together for effective treatment of breast cancer. Herein we report the development of albumin-shell oily-core nanocapsules (NCs), loaded with novel combination of hydrophobic drugs, exemestane (EXE) and hesperetin (HES), for targeted breast cancer therapy. This protein-lipid nanohybrid carrier was successfully fabricated using a simple protein-coating method based on the electrostatic adsorption of negatively charged albumin shell onto the oily core containing cationic surfactant. While EXE was directly encapsulated into the oily core, HES was pre-formulated in the form of phospholipid complex before solubilization in oily phase. In addition to albumin-mediated binding to albondin and SPARC, phenylboronic acid was chemically coupled to the albumin shell to confer additional tumor targeting. The targeted nanocarrier (TNC) demonstrated enhanced internalization into MCF-7 breast cancer cells resulting in synergistic cytotoxic activity with a combination index (CI) of 0.662 and dose reduction index (DRI) of 8.22 and 1.84 for EXE and HES, respectively. In vivo, TNC displayed superior anti-cancer activity in tumor-bearing mice compared to their non-targeted counterparts and the free drug combination. A significant reduction of both tumor volume (7-folds) and Ki67 expression (3-folds) was obtained by the targeted nanocarriers compared to positive control. Overall, the boronic-targeted albumin NCs offer a promising platform for hydrophobic drug combination against cancer therapy.


Assuntos
Androstadienos , Antineoplásicos Fitogênicos , Inibidores da Aromatase , Neoplasias da Mama , Hesperidina , Nanocápsulas , Albuminas/química , Albuminas/farmacocinética , Albuminas/farmacologia , Androstadienos/química , Androstadienos/farmacocinética , Androstadienos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Boro/química , Boro/farmacocinética , Boro/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Hesperidina/química , Hesperidina/farmacocinética , Hesperidina/farmacologia , Humanos , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Fosfolipídeos/farmacologia
4.
Biomater Sci ; 7(10): 4060-4074, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31475710

RESUMO

Combined photothermal-chemotherapy guided by multimodal imaging is a promising strategy for cancer diagnosis and treatment. Multifunctional nanoparticles, such as those comprising organic and inorganic compounds, have been extensively investigated for combined photothermal-chemotherapy; however, their application is still limited by their potential long-term toxicity and lack of contrast properties. To solve these problems, in this study, a new type of multifunctional nanoparticle for combined photothermal-chemotherapy guided by dual-modality imaging was prepared with endogenous melanin by multistep emulsification to enhance tumor ablation. The nanoparticles were coated with poly(lactide-co-glycolic acid) (PLGA) and loaded with paclitaxel (PTX), encapsulated melanin and perfluoropentane (PFP). The materials in the nanoparticles were endogenous, ensuring high stability, biocompatibility, and biosafety. Nanoparticles irradiated with a laser, which induced their phase transformation into microbubbles, exhibited high photothermal conversion efficiency, thereby achieving photoacoustic (PA)/ultrasound (US) dual-modality imaging to determine tumor location, boundary, and size and to monitor drug distribution. Furthermore, optical droplet vaporization (ODV) of the nanoparticles could trigger the release of PTX; thus, these nanoparticles are a useful drug carrier. In vivo and in vitro experiments revealed that a strong synergistic antitumor effect was achieved by combining the photothermal properties of the nanoparticles with a chemotherapy drug. Importantly, the cavitation, thermoelastic expansion, and sonoporation caused by the phase transformation of the nanoparticles could directly damage the tumors. These processes also promoted the release, penetration and absorption of the drug, further enhancing the effect of combined photothermal-chemotherapy on tumor suppression. Therefore, the multifunctional nanoparticles prepared in this study provide a new strategy of using endogenous materials for controlled near-infrared (NIR)-responsive drug release and combined photothermal-chemotherapy guided by multimodal imaging.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Fluorcarbonetos/administração & dosagem , Melaninas/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/terapia , Paclitaxel/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Preparações de Ação Retardada/administração & dosagem , Feminino , Fluorcarbonetos/farmacocinética , Células Endoteliais da Veia Umbilical Humana , Humanos , Melaninas/farmacocinética , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Paclitaxel/farmacocinética , Técnicas Fotoacústicas , Fototerapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Distribuição Tecidual , Ultrassonografia
5.
Curr Drug Deliv ; 16(7): 654-662, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31418659

RESUMO

BACKGROUND: Prolonged chemodrug delivery to the tumor site is a prerequisite to maintaining its localised therapeutic concentrations for effective treatment of malignant solid tumors. OBJECTIVE: The current study aims to develop implantable polymeric depots through conventional electrospinning for sustained drug delivery, specifically to the peritoneum. METHODS: Non-woven electrospun mats were fabricated by simple electrospinning of Polydioxanone solution loaded with the chemodrug, Paclitaxel. The implants were subjected to the analysis of morphology, mechanical properties, degradation and drug release in phosphate buffer and patient-derived peritoneal drain fluid samples. In vivo studies were conducted by surgical knotting of these implants to the peritoneal wall of healthy mice. RESULTS: Non-woven electrospun mats with a thickness of 0.65±0.07 mm, weighing ~ 20 mg were fabricated by electrospinning 15 w/v% polymer loaded with 10 w/w% drug. These implants possessing good mechanical integrity showed a drug entrapment efficiency of 87.82±2.54 %. In vitro drug release studies in phosphate buffer showed a sustained profile for ~4 weeks with a burst of 10 % of total drug content, whereas this amounted to >60% in patient samples. Mice implanted with these depots remained healthy during the study period. The biphasic drug release profile obtained in vivo showed a slow trend, with peritoneal lavage and tissues retaining good drug concentrations for a sustained period. CONCLUSION: The results indicate that non-woven electrospun mats developed from biodegradable Polydioxanone polymer can serve as ideal candidates for easily implantable drug depots to address the challenges of peritoneal metastasis in ovarian cancer.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanofibras/administração & dosagem , Paclitaxel/administração & dosagem , Polidioxanona/administração & dosagem , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Líquido Ascítico/química , Liberação Controlada de Fármacos , Feminino , Humanos , Injeções Intraperitoneais , Camundongos Endogâmicos BALB C , Nanofibras/química , Neoplasias Ovarianas , Paclitaxel/química , Paclitaxel/farmacocinética , Polidioxanona/química , Polidioxanona/farmacocinética
6.
J Microencapsul ; 36(6): 566-575, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31411510

RESUMO

Objective: To improve the water solubility and enhance the oral bioavailability of gambogenic acid (GNA). Methods: GNA-phospholipid complex (GNA-PLC) micelles were successfully prepared by anti-solvent method. Results: The encapsulation efficiency of GNA-PLC micelles can reach 99.33 % (w/w). The average particle size of the GNA-PLC micelles was 291.23 nm which was approximate agreed with the transmission electron microscopy (TEM). In vitro release profile showed the GNA-PLC and GNA-PLC micelles have significant sustained-release of GNA compared with crude GNA. Pharmacokinetic parameters indicated that the area under concentration-time curve (AUC0→t) of GNA in cases of GNA-PLC and GNA-PLC micelles are 2.04- and 3.92-fold higher than crude GNA, respectively. Conclusions: The better water solubility and higher bioavailability of GNA in GNA-PLC micelles with significant sustained-release of GNA endow the nanoparticle with great potential in GNA delivery system.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Preparações de Ação Retardada/química , Micelas , Fosfolipídeos/química , Xantenos/administração & dosagem , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Disponibilidade Biológica , Liberação Controlada de Fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Garcinia/química , Células Hep G2 , Humanos , Masculino , Ratos Sprague-Dawley , Solubilidade , Xantenos/química , Xantenos/farmacocinética
7.
Nanoscale ; 11(34): 15907-15916, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31414111

RESUMO

Small molecular prodrugs that self-assemble into nanoparticles have many advantages over commonly studied nanomedicines based upon nanoscale carriers such as liposomes, micelles and polymeric nanoparticles. These carrier-free nanodrugs exhibit favorable nanoproperties without the help of a nanocarrier, and they have many unique merits, such as a simple synthetic procedure, well-defined structure and high drug loading capacity. To date, most of these carrier-free nanodrugs have been spherical and very few nonspherical nanodrugs have been synthesized and studied. Herein, we report a camptothecin (CPT) prodrug that self-assembles into nanofibers. These carrier-free CPT nanofibers have a width of approximately one hundred nanometers and a length of several micrometers. The cellular uptake and tumor penetration behaviour of these nanofibers were observed by time-lapse video microscopy. These nanofibers can rapidly enter cancer cells by penetrating the cell membrane, gradually dissolve intracellularly and efficiently release the active drug. Coating the surface of these nanofibers with a pH-responsive PEG layer improves the stability of these nanofibers and shields their positive charge to minimize nonspecific interactions. These pH-responsive nanofibers are sheddable in the acidic tumor microenvironment and deliver carried cargoes deep into tumors. Our findings demonstrate that small molecular CPT prodrugs that form nanofibers are efficient for cancer drug delivery.


Assuntos
Antineoplásicos Fitogênicos , Camptotecina , Nanofibras , Neoplasias , Pró-Fármacos , Microambiente Tumoral , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/farmacologia , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Nanofibras/química , Nanofibras/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia
8.
Molecules ; 24(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426477

RESUMO

Ginsenoside Ro (Ro), a major saponin derived and isolated from Panax ginseng C.A. Meyer, exerts multiple biological activities. However, the anti-tumour efficacy of Ro remains unclear because of its poor in vitro effects. In this study, we confirmed that Ro has no anti-tumour activity in vitro. We explored the anti-tumour activity of Ro in vivo in B16F10 tumour-bearing mice. The results revealed that Ro considerably suppressed tumour growth with no significant side effects on immune organs and body weight. Zingibroside R1, chikusetsusaponin IVa, and calenduloside E, three metabolites of Ro, were detected in the plasma of Ro-treated tumour-bearing mice and showed excellent anti-tumour effects as well as anti-angiogenic activity. The results suggest that the metabolites play important roles in the anti-tumour efficacy of Ro in vivo. Additionally, the haemolysis test demonstrated that Ro has good biocompatibility. Taken together, the findings of this study demonstrate that Ro markedly suppresses the tumour growth of B16F10-transplanted tumours in vivo, and its anti-tumour effects are based on the biological activity of its metabolites. The anti-tumour efficacy of these metabolites is due, at least in part, to its anti-angiogenic activity.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ginsenosídeos/farmacologia , Melanoma Experimental/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Biotransformação , Ginsenosídeos/metabolismo , Ginsenosídeos/farmacocinética , Hemólise/efeitos dos fármacos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/farmacologia , Panax/química , Extratos Vegetais/química , Saponinas/metabolismo , Saponinas/farmacocinética , Neoplasias Cutâneas/patologia
9.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443458

RESUMO

Natural compounds, in recent years, have attracted significant attention for their use in the prevention and treatment of diverse chronic diseases as they are devoid of major toxicities. Boswellic acid (BA), a series of pentacyclic triterpene molecules, is isolated from the gum resin of Boswellia serrata and Boswellia carteri. It proved to be one such agent that has exhibited efficacy against various chronic diseases like arthritis, diabetes, asthma, cancer, inflammatory bowel disease, Parkinson's disease, Alzheimer's, etc. The molecular targets attributed to its wide range of biological activities include transcription factors, kinases, enzymes, receptors, growth factors, etc. The present review is an attempt to demonstrate the diverse pharmacological uses of BA, along with its underlying molecular mechanism of action against different ailments. Further, this review also discusses the roadblocks associated with the pharmacokinetics and bioavailability of this promising compound and strategies to overcome those limitations for developing it as an effective drug for the clinical management of chronic diseases.


Assuntos
Triterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Doença Crônica/tratamento farmacológico , Humanos , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Relação Estrutura-Atividade , Triterpenos/administração & dosagem , Triterpenos/química , Triterpenos/farmacocinética
10.
Colloids Surf B Biointerfaces ; 181: 872-878, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31382335

RESUMO

Fluorescence imaging is widely used to determine biodistribution of drugs in mice. However, the dye distribution may not be able to exactly reflect the true distribution of drug molecules. We synthesized PTX-Cy5.5 and mPEG-PLA-Cy5.5, and then prepared dye-loaded nanoparticles (NPs) (Cy5.5, DiR, PTX-Cy5.5, and mPEG-PLA-Cy5.5), dye and PTX co-loaded NPs, and PTX-loaded NPs, respectively. The particle sizes of resulting NPs were between 42.7 nm and 68.8 nm, and Zeta potential was between -0.86 mV and -8.49 mV. The biodistribution of fluorescent NPs (dye-loaded NPs and dye and PTX co-loaded NPs) on Bel-7402 tumor-bearing mice was studied via in vivo fluorescence imaging assays, results of which suggested that Cy5.5 loaded NPs and Cy5.5 conjugates (PTX-Cy5.5 and mPEG-PLA-Cy5.5) formulated NPs can reflect the tissue distribution of PTX whether it was incorporated or not. However, DiR failed to reflect true tissue distribution of PTX unless it was co-loaded with PTX. Based on these results, a guidance for the selection of dyes in drug distribution investigations and disease-targeted treatment was presented.


Assuntos
Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/farmacocinética , Corantes Fluorescentes/química , Imagem Óptica , Paclitaxel/análise , Paclitaxel/farmacocinética , Células A549 , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Corantes Fluorescentes/análise , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Conformação Molecular , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/patologia , Paclitaxel/química , Distribuição Tecidual
11.
J Pharm Biomed Anal ; 174: 728-733, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299453

RESUMO

Xiao-Ai-Ping injection (XAP) has been shown to be clinically effective in treatment of gastric carcinoma, liver cancer and lung cancer, when it was combined with anticancer drug paclitaxel (PTX). To analyze the effect of XAP on the pharmacokinetics of PTX, a liquid chromatography-tandem mass spectroscopy (LCMS/MS) assay method was developed and validated to quantify PTX simultaneously and its main metabolite 3'-p-hydroxypaclitaxel (C3'-OHP) in rat plasma. PTX and C3'-OHP were quantified using positive MRM mode. The analysis method was validated for specificity, recovery, carry-over, accuracy, precision, sample stability and dilution integrity under various storage conditions. The pharmacokinetic parameters were determined in rats after tail intravenous administration of 6 mg/mL PTX in the absence (control group) or presence of intraperitoneal administration of 10 mL/kg、20 mL/kg XAP (study groups). Compared to control group, the area under the plasma concentration-time curve (AUC) of PTX and C3'-OHP in study groups increased significantly following consecutive administration with XAP for 10 days. In conclusion, pretreatment with XAP enhanced the exposure of PTX and C3'-OHP. There would be herb-drug interaction happening between XAP and PTX in rats.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Interações Ervas-Drogas , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/farmacocinética , Calibragem , Cromatografia Líquida , Feminino , Modelos Lineares , Paclitaxel/sangue , Controle de Qualidade , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
12.
Drug Deliv ; 26(1): 673-679, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31266376

RESUMO

10-Hydroxycamptothecin (HCPT) liposomes surface modified with stearyl glycyrrhetinate (SG) were prepared by the film dispersion method. Characterization of the liposomes, including drug release in vitro, pharmacokinetics and tissue distribution, was done. HCPT in plasma and tissues was determined by high-performance liquid chromatography (HPLC). Compared with the conventional HCPT-liposomes and commercially available hydroxycamptothecin injection (HCPT Inject), pharmacokinetic parameters indicated that SG-HCPT-liposomes had better bioavailability. Regarding tissue distribution, the concentration of HCPT loaded by SG modified liposomes in the liver was higher than other tissues and the risk to the kidney was lower than HCPT-liposomes and HCPT Inject. These results support the hypothesis that the HCPT-liposomes modified with SG show enhanced liver-targeting through the glycyrrhetinic acid (GA) receptor to be an efficient drug carrier, which may help to improve therapeutic methods for hepatic diseases in the future.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/análogos & derivados , Portadores de Fármacos/química , Ácido Glicirretínico/análogos & derivados , Lipossomos/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Disponibilidade Biológica , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Portadores de Fármacos/farmacocinética , Feminino , Lipossomos/farmacocinética , Lipossomos/ultraestrutura , Camundongos , Tamanho da Partícula , Ratos , Distribuição Tecidual
13.
Pharm Biol ; 57(1): 437-448, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31280667

RESUMO

Context: Radix Tripterygium wilfordii Hook. f. (Celastraceae) (LGT) has outstanding curative efficacy; however, side effects include high toxicity, particularly hepatotoxicity and nephrotoxicity. Objective: To investigate detoxification mechanisms of LGT through processing separately with each of these medicinal herbs including Flower Lonicera japonica Thunb. (Caprifoliaceae) (JYH), Radix Paeonia lactiflora Pall. (Ranunculaceae) (BS), Herba Lysimachia christinae Hance (Primulaceae) (JQC), Radix et Rhizoma Glycyrrhiza uralensis Fisch. (Fabaceae) (GC) and Seed Phaseolus radiatus L. (Fabaceae) (LD) in S180-bearing mice by involving nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Materials and methods: LGT raw and processed products were orally administered at 60 mg/kg to KM male mice inoculated with S180 tumour cells for 14 consecutive days, and blood, tumour, liver and kidney were taken to observe the detoxifying effects and biological mechanisms. Results: Herbal-processing technology significantly weakened hepatotoxicity and nephrotoxicity evoked by LGT with ED50 of the converted triptolide in each processed-herb product for serum alanine transaminase, aspartate transaminase, creatinine and urea nitrogen of 9.3, 16.6, 2.5 and 4.2 µg/kg, for liver glutathione, glutathione S-transferase, catalase, tumour necrosis factor-α and interleukin-10 of 114.9, 67.8, 134.1, 7.7, 4171.6 µg/kg, and for kidney 21.9, 20.5, 145.0, 529.7, 19.4 µg/kg, respectively. Moreover, herbal-processing technology promoted the accumulation of Nrf2 into the nucleus, and upregulated mRNA expression of Nrf2 and heme oxygenase-1. Additionally, herbal-processing technology enhanced the tumour inhibition rate with ED50 12.2 µg/kg. Discussion and conclusions: Herbal-processing technology improves the safety and effectiveness of LGT in cancer treatment, and future research may be focused on the Nrf2-related molecules.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Sarcoma 180/tratamento farmacológico , Tripterygium/química , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/farmacocinética , Glutationa/metabolismo , Inativação Metabólica , Interleucina-10/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas/química , Sarcoma 180/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Nat Commun ; 10(1): 3211, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324811

RESUMO

Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Carbono/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Nanomedicina , Pró-Fármacos/farmacocinética , Selênio/química , Enxofre/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Dissulfetos/química , Portadores de Fármacos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Dinâmica Molecular , Nanopartículas/química , Oxirredução , Paclitaxel/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Microambiente Tumoral
15.
Discov Med ; 27(149): 177-188, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31361980

RESUMO

Genistein is an isoflavone derived from soy-rich products, which is known to exhibit several beneficial biological effects, such as anti-tumor activity, improvement of glucose metabolism, and reduction of the frequency of peri-menopausal hot flashes, and thus has potential for clinical application. Certain limitations and side effects, such as low bioavailability, biological estrogenic activity, and detrimental effects on thyroid function, have restricted its clinical applications to some extent. Recently, it has been reported that fermentation, use of micromicelles, and modification of its chemical structure can enhance the bioavailability of genistein. Moreover, the modification of its molecular structure may also eliminate its biological estrogenic activity and adverse effects on thyroid function. In this review, we summarize the clinical application prospects and limitations of genistein, as well as the plausible solutions to overcome its low bioavailability, phytoestrogenic activity, and adverse effects on thyroid function.


Assuntos
Antineoplásicos Fitogênicos , Estrogênios , Genisteína , Fogachos/tratamento farmacológico , Menopausa/metabolismo , Glândula Tireoide/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Estrogênios/farmacocinética , Estrogênios/uso terapêutico , Feminino , Genisteína/farmacocinética , Genisteína/uso terapêutico , Fogachos/metabolismo , Fogachos/patologia , Humanos , Micelas
16.
Biopharm Drug Dispos ; 40(8): 265-275, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292985

RESUMO

AR-67 is a lipophilic camptothecin analog currently under clinical investigation using a Cremophor EL based formulation. However, as potential toxicity limitations exist in the clinical use of Cremophor, an alternative cyclodextrin (SBE-ß-CD) based formulation has been proposed. Pharmacokinetic (PK) studies were conducted in mice and the SBE-ß-CD based formulation was compared with the Cremophor EL formulation. PK studies were conducted following intravenous or oral administration of AR-67 in either Cremophor or SBE-ß-CD formulation in mice. Noncompartmental analysis was used to determine the plasma and tissue drug distribution. A non-linear mixed effects (population) PK model was developed to fit both the oral and intravenous data and to estimate key PK parameters. The effect of formulation was explored as a covariate in the PK model. AR-67 in the SBE-ß-CD formulation had similar plasma PK and biodistribution to that in the Cremophor EL formulation. The proposed two-compartment model described the plasma PK of AR-67 in both formulations adequately. AR-67 in the SBE-ß-CD formulation exhibited dose linearity following both oral and intravenous administration. Our studies indicate that SBE-ß-CD is a viable alternative to Cremophor EL as a pharmaceutical excipient for formulating AR-67.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/análogos & derivados , Excipientes/química , Modelos Biológicos , Compostos de Organossilício/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Glicerol/análogos & derivados , Glicerol/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos de Organossilício/farmacocinética , Distribuição Tecidual , beta-Ciclodextrinas/química
17.
Drug Deliv ; 26(1): 724-731, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31293182

RESUMO

The aim of drug delivery is to increase therapeutic efficacy. Externally triggered drug delivery systems enable site-specific and time-controlled drug release. To achieve this goal, our strategy was based on ultrasound-triggered release of an anticancer agent from sonosensitive liposomes (SL). To realize the ultrasound-triggered drug release, a lipophilic sonosensitizer, hematoporphyrin monomethyl ether (HMME) was incorporated into the lipid bilayer of liposomes. Once irradiated by the ultrasound in tumor tissues, the sonodynamic effect generated by HMME could lead to an efficient disruption of the lipid bilayer in the SL. After encapsulating vincristine bitartrate (VIN) as the model drug, the ultrasound-triggered lipid bilayer breakdown can trigger the instant release of VIN, enabling ultrasound-controlled chemotherapy with great specificity. In the in vitro and in vivo studies, by integrating tumor-specific targeting and stimuli-responsive controlled release into one system, VIN-loaded SL showed excellent antitumor efficacy. The SL could potentially produce viable clinical strategies for improved targeting efficiency of VIN for the treatment of related cancer. More importantly, this report provides an example of controlled release by means of a novel class of ultrasound triggering system.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Lipossomos/química , Vincristina/administração & dosagem , Animais , Antineoplásicos Fitogênicos/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Hematoporfirinas/administração & dosagem , Humanos , Lipossomos/administração & dosagem , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Ultrassonografia , Vincristina/farmacocinética , Vincristina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Colloids Surf B Biointerfaces ; 182: 110337, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306829

RESUMO

This paper aims to improve the systemic circulation of paclitaxel (PTX) by modifying nanocrystals with DSPE-PEG 2000. PTX nanocrystals (PNCs) were prepared by an anti-solvent method and DSPE-PEG 2000 was inserted into PNCs by hybridization. The average size of DSPE-PEG-PNCs did not change obviously compared to the naked PNCs, but the negative charge increased after hybridization. The saturated attachment ratio of DSPE-PEG 2000 was 0.4%. In vitro release rate of DSPE-PEG-PNCs was significantly slower than that of PTX solution and the naked PNCs, which indicated that DSPE-PEG 2000 hindered the release of PTX. Moreover, pharmacokinetics results showed that DSPE-PEG-PNCs achieved a higher area-under-the-curve (AUC, 4.43 ±â€¯0.19 mg/L*h) and lower clearance rate (1.08 ±â€¯0.16 L/h/kg) compared to PNCs with an AUC of 2.48 ±â€¯0.18 mg/L*h and a clearance rate of 1.89 ±â€¯0.15 L/h/kg. Therefore, DSPE-PEG-PNCs could have a significant potential in clinical use by improving the systemic circulation of the drug.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Paclitaxel/farmacocinética , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Animais , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/química , Área Sob a Curva , Composição de Medicamentos/métodos , Humanos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Paclitaxel/sangue , Paclitaxel/química , Tamanho da Partícula , Ratos , Eletricidade Estática
19.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1145-1154, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31303583

RESUMO

Survivin (IAP proteins) is considered as a significant target for anticancer drug research owing to its upregulation in tumor cells to mediate resistance to apoptotic stimulus. The current study aimed to investigate phytochemicals as inhibitors of survivin with caspases to reactivate the functioning of caspases through molecular docking. The compounds namely 2(R), 4(R)-dihydroxypyrrolidine, 4-hydroxy-2-(4-methoxyphenyl)-1,1-dioxo-3,4-dihydrothieno[3,2-e]thiazine-6-sulfonamide, 2,3-Diketo-L-gulonic acid, (3-hydroxy-2-octadeca-9,12-dienoyloxypropyl) octadecanoate, 2-[[4-[[4-[(4-formamido-1-methylimidazole-2-carbonyl)amino]-1-methylimidazole-2-carbonyl]amino]-1-methylimidazole-2-carbonyl]amino]ethyl-dimethylazanium, Picolinic acid and (2-Hydroxy-5-nitrophenyl) dihydrogen phosphate successfully bind inside the pocket of survivin. ADMETsar was used to evaluate the anticancer potential of selected compounds. These compounds can be proposed as effective inhibitors, disrupting the survivin-caspases interaction and reactivating the caspases function of apoptosis. The study might facilitate the development of cost-effective and natural drugs against cancer. However, further validation is essential for confirmation of its drug efficacy and bio-compatibility.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Compostos Fitoquímicos/farmacologia , Survivina/antagonistas & inibidores , Survivina/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/toxicidade , Caspases/metabolismo , Simulação por Computador , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Compostos Fitoquímicos/farmacocinética , Compostos Fitoquímicos/toxicidade , Conformação Proteica , Survivina/metabolismo , Distribuição Tecidual
20.
Pharm Res ; 36(9): 127, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236836

RESUMO

PURPOSE: Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model. METHODS: PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling. RESULTS: A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg. CONCLUSIONS: The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.


Assuntos
Paclitaxel Ligado a Albumina/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias Peritoneais/tratamento farmacológico , Paclitaxel Ligado a Albumina/química , Paclitaxel Ligado a Albumina/farmacocinética , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Reagentes para Ligações Cruzadas/química , Portadores de Fármacos , Gelatina/química , Humanos , Iridoides/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Microesferas , Modelos Biológicos , Ensaios Antitumorais Modelo de Xenoenxerto
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