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1.
Int J Nanomedicine ; 15: 5491-5501, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848385

RESUMO

Purpose: Currently, the treatment of brain metastases from non-small cell lung cancer (NSCLC) is rather difficult in the clinic. A combination of small molecule-targeted drug and chemo-drug is a promising therapeutic strategy for the treatment of NSCLC brain metastases. But the efficacy of this combination therapy is not satisfactory due to the blood-brain barrier (BBB). Therefore, it is urgent to develop a drug delivery system to enhance the synergistic therapeutic effects of small molecule-targeted drug and chemo-drug for the treatment of NSCLC brain metastases. Methods: T7 peptide installed and osimertinib (AZD9291) loaded intracellular glutathione (GSH) responsive doxorubicin prodrug self-assembly nanocarriers (T7-DSNPs/9291) have been developed as a targeted co-delivery system to enhance the combined therapeutic effect on brain metastases from NSCLC. In vitro cell experiments, including intracellular uptake assay, in vitro BBB transportation, and MTT assay were used to demonstrate the efficacy of T7-DSNPs/9291 in NSCLC brain metastasis in vitro. Real-time fluorescence imaging analysis, magnetic resonance imaging analysis, and Kaplan-Meier survival curves were used to study the effect of T7-DSNPs/9291 on an animal model in vivo. Results: T7-DSNPs/9291 could significantly enhance BBB penetration of AZD9291 and doxorubicin via transferrin receptor-mediated transcytosis. Moreover, T7-DSNPs/9291 showed significant anti-NSCLC brain metastasis effect and prolonged median survival of an intracranial NSCLC brain metastasis animal model. Conclusion: T7-DSNPs/9291 is a potential drug delivery system for the combined therapy of brain metastasis from NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Portadores de Fármacos/administração & dosagem , Neoplasias Pulmonares/patologia , Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Colágeno Tipo IV/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Fragmentos de Peptídeos/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Receptores da Transferrina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 40(8): 4655-4661, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727789

RESUMO

In recent years, therapeutic drug monitoring (TDM) of intravenous administration of 5-fluorouracil (5-FU) has resulted in reduced toxicity and improved efficacy. Prodrugs of 5-FU were developed to reduce toxicity, extend the duration of action, and increase tumour selectivity of 5-FU. These drugs are important in daily practice because of their ease of administration. Dose adjustment of 5-FU prodrugs by TDM is expected to reduce its toxicity and improve its efficacy. This review focuses on data from a recent study of personalized treatment using TDM of 5-FU and its prodrugs.


Assuntos
Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Monitoramento de Medicamentos/métodos , Humanos , Neoplasias/tratamento farmacológico
3.
In Vivo ; 34(3 Suppl): 1567-1588, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-532631

RESUMO

BACKGROUND: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever. MATERIALS AND METHODS: The authors carried out a search in PubMed, ClinicalTrials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2. RESULTS: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2. CONCLUSION: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2.


Assuntos
Acetilcisteína/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Colchicina/uso terapêutico , Cobre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Colchicina/administração & dosagem , Colchicina/farmacologia , Cobre/administração & dosagem , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Inflamação , Óxido Nítrico/administração & dosagem , Óxido Nítrico/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ribonucleosídeos/administração & dosagem , Ribonucleosídeos/farmacologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
4.
In Vivo ; 34(3 Suppl): 1567-1588, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503814

RESUMO

BACKGROUND: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever. MATERIALS AND METHODS: The authors carried out a search in PubMed, ClinicalTrials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2. RESULTS: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2. CONCLUSION: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2.


Assuntos
Acetilcisteína/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Colchicina/uso terapêutico , Cobre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Colchicina/administração & dosagem , Colchicina/farmacologia , Cobre/administração & dosagem , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Inflamação , Óxido Nítrico/administração & dosagem , Óxido Nítrico/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ribonucleosídeos/administração & dosagem , Ribonucleosídeos/farmacologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
5.
PLoS Comput Biol ; 16(5): e1007926, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32463836

RESUMO

Tumour hypoxia is a well-studied phenomenon with implications in cancer progression, treatment resistance, and patient survival. While a clear adverse prognosticator, hypoxia is also a theoretically ideal target for guided drug delivery. This idea has lead to the development of hypoxia-activated prodrugs (HAPs): a class of chemotherapeutics which remain inactive in the body until metabolized within hypoxic regions. In theory, these drugs have the potential for increased tumour selectivity and have therefore been the focus of numerous preclinical studies. Unfortunately, HAPs have had mixed results in clinical trials, necessitating further study in order to harness their therapeutic potential. One possible avenue for the improvement of HAPs is through the selective application of anti angiogenic agents (AAs) to improve drug delivery. Such techniques have been used in combination with other conventional chemotherapeutics to great effect in many studies. A further benefit is theoretically achieved through nanocell administration of the combination, though this idea has not been the subject of any experimental or mathematical studies to date. In the following, a mathematical model is outlined and used to compare the predicted efficacies of separate vs. nanocell administration for AAs and HAPs in tumours. The model is experimentally motivated, both in mathematical form and parameter values. Preliminary results of the model are highlighted throughout which qualitatively agree with existing experimental evidence. The novel prediction of our model is an improvement in the efficacy of AA/HAP combination therapies when administered through nanocells as opposed to separately. While this study specifically models treatment on glioblastoma, similar analyses could be performed for other vascularized tumours, making the results potentially applicable to a range of tumour types.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Hipóxia Celular , Sistemas de Liberação de Medicamentos , Nanotecnologia , Pró-Fármacos/administração & dosagem , Simulação por Computador , Humanos
6.
Am J Physiol Cell Physiol ; 319(1): C129-C135, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32374677

RESUMO

The purpose of this study was to evaluate a new pharmacological strategy using a first-generation succinate prodrug, NV118, in peripheral blood mononuclear cells (PBMCs) obtained from subjects with carbon monoxide (CO) poisoning and healthy controls. We obtained human blood cells from subjects with CO poisoning and healthy control subjects. Intact PBMCs from subjects in the CO and Control group were analyzed with high-resolution respirometry measured in pmol O2 per second per 10-6 PBMCs. In addition to obtaining baseline respiration, NV118 (100 µM) was injected, and the same parameters of respiration were obtained for comparison in PBMCs. We measured mitochondrial dynamics with microscopy with the same conditions. We enrolled 37 patients (17 in the CO group and 20 in the Control group for comparison) in the study. PMBCs obtained from subjects in the CO group had overall significantly lower respiration compared with the Control group (P < 0.0001). There was a significant increase in respiration with NV118, specifically with an increase in maximum respiration and respiration from complex II and complex IV (P < 0.0001). The mitochondria in PBMCs demonstrated an overall increase in net movement compared with the Control group. Our results of this study suggest that the therapeutic compound, NV118, increases respiration at complex II and IV as well as restoration of mitochondrial movement in PBMCs obtained from subjects with CO poisoning. Mitochondrial-directed therapy offers a potential future strategy with further exploration in vivo.


Assuntos
Intoxicação por Monóxido de Carbono/metabolismo , Permeabilidade da Membrana Celular/fisiologia , Leucócitos Mononucleares/metabolismo , Mitocôndrias/metabolismo , Pró-Fármacos/metabolismo , Ácido Succínico/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Respiração Celular/fisiologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Ácido Succínico/administração & dosagem
7.
J Pharmacol Exp Ther ; 374(1): 1-5, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32269168

RESUMO

Stimulant abuse is a persistent public health problem with no Food and Drug Administration-approved pharmacotherapy. Although monoamine-releasing drugs such as d-amphetamine can decrease cocaine self-administration in human and animal laboratory studies, their potential for abuse limits clinical utility. "Abuse-deterrent" formulations of monoamine releasers, such as prodrugs, hold greater clinical promise if their abuse potential is, as theorized, lower than that of cocaine. In these studies, we determined the reinforcing strength of phendimetrazine (PDM), a prodrug for the amphetamine-like monoamine releaser phenmetrazine; both drugs have been shown to decrease cocaine self-administration in laboratory animals. To date, no study has directly compared PDM (Schedule III) with cocaine (Schedule II) under progressive-ratio (PR) schedules of reinforcement, which are better suited than fixed-ratio schedules to directly compare reinforcing strength of drugs. Dose-response curves for cocaine (saline, 0.001-0.3 mg/kg per injection) and PDM (0.1-1.0 mg/kg per injection) were generated in six cocaine-experienced male rhesus monkeys during 4-hour sessions with a 20-minute limited hold (LH). Under these conditions, the maximum number of injections was not significantly different between cocaine and PDM. The reinforcing strength of doses situated on the peaks of the cocaine and PDM dose-effect curves were redetermined with a 60-minute LH. The mean number of injections increased for both drugs, but not for saline. Cocaine presentations resulted in significantly higher peak injections than PDM with a 60-minute LH, which is consistent with the lower scheduling of PDM. These results support PDM as Schedule III and highlight the importance of schedule parameters when comparing reinforcing strength of drugs using a PR schedule of reinforcement. SIGNIFICANCE STATEMENT: One strategy for reducing cocaine use is to identify a treatment that substitutes for cocaine but has lower abuse potential. In a rhesus monkey model of drug abuse, this study compared the reinforcing strength of cocaine and phendimetrazine, a drug that has been shown to decrease cocaine use in some studies.


Assuntos
Morfolinas/administração & dosagem , Morfolinas/farmacologia , Reforço Psicológico , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Macaca mulatta , Masculino , Morfolinas/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Autoadministração
8.
Yakugaku Zasshi ; 140(3): 369-376, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115554

RESUMO

The first-pass hydrolysis of oral ester-type prodrugs in the liver and intestine is mediated mainly by hCE1 and hCE2 of the respective predominant carboxylesterase (CES) isozymes. In order to provide high blood concentrations of the parent drugs, it is preferable that prodrugs are absorbed as an intact ester in the intestine, then rapidly converted to active parent drugs by hCE1 in the liver. In the present study, we designed a prodrug of fexofenadine (FXD) as a model parent drug that is resistant to hCE2 but hydrolyzed by hCE1, utilizing the differences in catalytic characteristics of hCE1 and hCE2. In order to precisely predict the intestinal absorption of an FXD prodrug candidate, we developed a novel high-throughput system by modifying Caco-2 cells. Further, we evaluated species differences and aging effects in the intestinal and hepatic hydrolysis of prodrugs to improve the estimation of in vivo first-pass hydrolysis of ester-type prodrugs. Consequently, it was possible to design a hepatotropic prodrug utilizing the differences in tissue distribution and substrate specificity of CESs. In addition, we successfully established three useful in vitro systems for predicting the intestinal absorption of hCE1 substrate using Caco-2 cells. However, some factors involved in estimating the bioavailability of prodrugs in human, such as changes in recognition of drug transporters by esterification, and species differences of the first-pass hydrolysis, should be comprehensively considered in prodrug development.


Assuntos
Ésteres/metabolismo , Pró-Fármacos/metabolismo , Administração Oral , Disponibilidade Biológica , Hidrolases de Éster Carboxílico/fisiologia , Ésteres/administração & dosagem , Humanos , Hidrólise , Absorção Intestinal , Isoenzimas/fisiologia , Fígado/metabolismo , Pró-Fármacos/administração & dosagem , Especificidade da Espécie
9.
Proc Natl Acad Sci U S A ; 117(13): 7021-7029, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32179677

RESUMO

Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.


Assuntos
Antineoplásicos/administração & dosagem , Metaloporfirinas/administração & dosagem , Oxaliplatina/administração & dosagem , Células A549 , Animais , Antineoplásicos/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HCT116 , Humanos , Metaloporfirinas/farmacocinética , Camundongos Nus , Oxaliplatina/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Distribuição Tecidual , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
AAPS PharmSciTech ; 21(3): 98, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32128656

RESUMO

Oseltamivir is a neuraminidase inhibitor widely used to treat and prevent influenza A and B infections, although its safety and pharmacokinetics have not been evaluated in patients with severe hepatic impairment. A physiologically based pharmacokinetic (PBPK) model of the prodrug oseltamivir and its active metabolite, oseltamivir carboxylate (OC), was established and validated to simulate their disposition in adults and predict the exposure in patients with Child-Pugh C cirrhosis (CP-C). The simulated results from PBPK modeling and the observed data after oral administration of various oseltamivir regimens were consistent according to the fold error values of less than 2. Furthermore, the clinical observations published in the literature were comparable with our pharmacokinetic predictions. In patients with CP-C, the oseltamivir Cmax was approximately 2-fold increased, and its AUC was approximately 6-fold higher compared with those in normal subjects. In contrast, the AUC of OC in CP-C patients did not differ significantly from that in normal subjects, whereas its Cmax was reduced by approximately 30% in the patients. Examination of drug exposure in different health conditions indicated that the oseltamivir exposure was significantly increased in conditions with elevated cirrhosis severity, which might be associated with a higher risk of adverse drug effects, e.g., neuropsychiatric adverse events (NPAEs). In conclusion, the pharmacokinetics of oseltamivir and OC were correctly predicted by PBPK modeling. The model further predicted that the pharmacokinetics of oseltamivir might be altered in liver cirrhosis, depending on the degree of severity.


Assuntos
Antivirais/farmacocinética , Simulação por Computador , Cirrose Hepática/metabolismo , Modelos Biológicos , Oseltamivir/análogos & derivados , Oseltamivir/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Cirrose Hepática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Oseltamivir/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Adulto Jovem
11.
Nat Commun ; 11(1): 661, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005826

RESUMO

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rß). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/agonistas , Interleucina-2/imunologia , Ipilimumab/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
12.
Proc Natl Acad Sci U S A ; 117(9): 4518-4526, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071209

RESUMO

The inception and development of supramolecular chemistry have provided a vast library of supramolecular structures and materials for improved practice of medicine. In the context of therapeutic delivery, while supramolecular nanostructures offer a wide variety of morphologies as drug carriers for optimized targeting and controlled release, concerns are often raised as to how their morphological stability and structural integrity impact their in vivo performance. After intravenous (i.v.) administration, the intrinsic reversible and dynamic feature of supramolecular assemblies may lead them to dissociate upon plasma dilution to a concentration below their critical micellization concentration (CMC). As such, CMC represents an important characteristic for supramolecular biomaterials design, but its pharmaceutical role remains elusive. Here, we report the design of a series of self-assembling prodrugs (SAPDs) that spontaneously associate in aqueous solution into supramolecular polymers (SPs) with varying CMCs. Two hydrophobic camptothecin (CPT) molecules were conjugated onto oligoethylene-glycol (OEG)-decorated segments with various OEG repeat numbers (2, 4, 6, 8). Our studies show that the lower the CMC, the lower the maximum tolerated dose (MTD) in rodents. When administrated at the same dosage of 10 mg/kg (CPT equivalent), SAPD 1, the one with the lowest CMC, shows the best efficacy in tumor suppression. These observations can be explained by the circulation and dissociation of SAPD SPs and the difference in molecular and supramolecular distribution between excretion and organ uptake. We believe these findings offer important insight into the role of supramolecular stability in determining their therapeutic index and in vivo efficacy.


Assuntos
Portadores de Fármacos/química , Micelas , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Portadores de Fármacos/toxicidade , Feminino , Células HT29 , Humanos , Dose Máxima Tolerável , Camundongos , Camundongos Nus , Polietilenoglicóis/química , Polimerização , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-Dawley
13.
Molecules ; 25(3)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32012733

RESUMO

The aim of this study was to develop a prodrug of ubiquinol-10 (UqH-10), the active form of ubiquinone-10 (Uq-10), for oral delivery. Bioavailability of UqH-10 is hampered by its high susceptibility to oxidation and water-insolubility. We prepared three novel N,N-dimethylglycine ester derivatives of UqH-10, including a 1-monoester (UqH-1-DMG), 4-monoester (UqH-4-DMG), and 1,4-bis-ester (UqH-DMG), and assessed their physicochemical properties in vitro and in vivo. UqH-DMG spontaneously formed an aqueous micelle solution comprising 20 nm particles at 36.5 °C. Cationic UqH-DMG formed nano-sized (5 nm) mixed-micelles with taurocholic acid. Reconversion of the derivatives to UqH-10 was accelerated in human liver microsomes. The oral bioavailability of UqH-10 after administration of UqH-derivatives or Uq-10 was determined in fasted and postprandial rats secreting normal and high levels of bile, respectively. In fasted rats, plasma UqH-10 after UqH-derivatives administration reached Cmax at 2-3 h and after Uq-10 administration, it remained low. The AUC0-24h of UqH-10 after UqH-derivatives administration was 2-3-fold higher than that after Uq-10 administration. In postprandial rats, the Tmax of UqH-10 after UqH-derivatives administration was an hour earlier than after Uq-10 administration. In conclusion, cationic UqH-derivatives are convenient prodrugs that enhance UqH-10 bioavailability by forming nanosized mixed-micelles with intestinal bile acids.


Assuntos
Ânions/química , Ácidos e Sais Biliares/química , Cátions/química , Absorção Intestinal/efeitos dos fármacos , Micelas , Pró-Fármacos/administração & dosagem , Ubiquinona/administração & dosagem , Administração Oral , Animais , Ânions/metabolismo , Ácidos e Sais Biliares/metabolismo , Disponibilidade Biológica , Transporte Biológico , Masculino , Nanopartículas , Oxirredução , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Ratos , Ratos Sprague-Dawley , Ubiquinona/química , Ubiquinona/metabolismo
14.
Colloids Surf B Biointerfaces ; 185: 110608, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707225

RESUMO

Drug content and releasing rate are the main determining factors for the drug delivery systems (DDSs). Here, doxorubicin dimer (D-DOXcar) was synthesized as drug-drug conjugate prodrug with high drug content of 86%, via an acid-triggered hydrolysable carbamate linker. The prodrug nanoparticles (D-DOXcar-NP) with different diameters were prepared as drug self-delivery system (DSDS) for intracellular pH-triggered slow release. They showed size- and concentration-dependent pH-triggered slow DOX release. For the D-DOXcar-sNP with smaller diameter, the cumulative release ratio reached 25.6% at pH 5.0 within 60 h. The MTT results demonstrated that the proposed DSDS showed similar tumor inhibition regardless of carboxylesterases, and an enhanced anti-tumor efficacy on the HepG2 cells in comparison with the free DOX.


Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Pró-Fármacos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Células Hep G2 , Humanos , Hidrodinâmica , Concentração de Íons de Hidrogênio , Células MCF-7 , Nanopartículas/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espectroscopia de Prótons por Ressonância Magnética
15.
Mater Sci Eng C Mater Biol Appl ; 107: 110356, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761247

RESUMO

Chemotherapeutic agents with different anticancer mechanisms could enhance therapeutic effect in cancer therapy by their combined application. In this study, redox-sensitive prodrug nanoparticles based on Xyl-SS-Cur conjugate were developed for co-delivery of curcumin and 5-FU in cancer therapy. The Xyl-SS-Cur conjugate was synthesized via covalent conjugation of curcumin to xylan through a disulphide (-S-S-) linkage. The Xyl-SS-Cur conjugate could self-assemble in aqueous medium into nanoparticles and the lipophilic 5-fluorouracil-stearic acid (5-FUSA) prodrug was encapsulated into the hydrophobic core of Xyl-SS-Cur NPs through dialysis membrane method. The obtained Xyl-SS-Cur/5-FUSA NPs had an appropriate size (∼217 ±â€¯2.52 nm), high drug loading of curcumin (∼ 31.4 wt%) and 5-FUSA (∼ 11.8 wt%) and high stability. The interaction of Xyl-SS-Cur/5-FUSA NPs with blood components was investigated by hemolysis study. The cytotoxicity study demonstrated that Xyl-SS-Cur/5-FUSA NPs induced higher cytotoxicity than free drugs against the Human colorectal cancer cells (HT-29, HCT-15). These results indicate that Xyl-SS-Cur/5-FUSA NPs can serve as a promising drug delivery system in cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Curcumina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Curcumina/química , Curcumina/farmacologia , Dissulfetos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Células HT29 , Hemólise/efeitos dos fármacos , Humanos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Oxirredução , Tamanho da Partícula , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Espectroscopia de Infravermelho com Transformada de Fourier , Ácidos Esteáricos/química , Xilanos/química
16.
Artigo em Espanhol | IBECS | ID: ibc-191008

RESUMO

La infección por el virus SARS-CoV-2, denominada COVID-19 (COronaVIrus Disease 19), fue detectada inicialmente en China en diciembre 2019, y posteriormente se ha diseminado rápidamente por todo el mundo, hasta el punto de que el 11 de marzo la OMS declaró que el brote podría definirse como pandemia. La COVID-19 presenta un cuadro que oscila desde episodios leves pseudogripales a otros graves e incluso potencialmente mortales debido, sobre todo, a insuficiencia respiratoria aguda. Es frecuente el ingreso de estos pacientes en nuestros Servicios de Medicina Intensiva en relación con un Síndrome de Distrés Respiratorio Agudo (SDRA). La falta de un tratamiento con evidencia científica ha llevado al empleo de diferentes pautas terapéuticas, en muchas ocasiones, con modificaciones rápidas de los protocolos. Recientes revisiones en revistas de prestigio han destacado la falta de terapias probadas y la necesidad de ensayo clínicos que permitan establecer pautas de tratamiento claras y objetivas. Este documento tiene por objeto ofrecer una actualización de la terapia que se está aplicando en la actualidad, y una ayuda en la asistencia diaria, sin pretender sustituir los protocolos adoptados en cada centro


Infection by the SARS-CoV-2 virus, known as COVID-19 (Corona VIrus Disease-19) was initially detected in China in December 2019, and has subsequently spread rapidly throughout the world, to the point that on March 11 the World Health Organization (WHO) reported that the outbreak could be defined as a pandemic. COVID-19 disease ranges from mild flu-like episodes to other serious and even life-threatening conditions, mainly due to acute respiratory failure. These patients are frequently admitted to our Intensive Care Units in relation to acute respiratory distress syndrome (ARDS). The lack of a treatment based on scientific evidence has led to the use of different management guidelines, in many cases with rapid changes in the applied protocols. Recent reviews in reputed journals have unders cored the lack of proven therapies and the need for clinical trials to establish clear and objective treatment guidelines. The present study provides an update on the currently applied treatment, and intends to offer help in relation to daily care, without seeking to replace the protocols adopted in each individual center


Assuntos
Humanos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Antivirais/administração & dosagem , Pró-Fármacos/administração & dosagem , Hidroxicloroquina/administração & dosagem , Azitromicina/administração & dosagem , Interferon beta-1b/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Fatores Imunológicos
17.
ACS Appl Mater Interfaces ; 12(3): 3327-3340, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31872760

RESUMO

Effective new therapies for pancreatic ductal adenocarcinoma (PDAC) are desperately needed as the prognosis of PDAC patients is dismal and treatment remains a major challenge. Gemcitabine (GEM) is commonly used to treat PDAC; however, the clinical use of GEM has been greatly compromised by its low delivery efficacy and drug resistance. Here, we describe a very simple yet cost-effective approach that synergistically combines drug reconstitution, supramolecular nanoassembly, and tumor-specific targeting to address the multiple challenges posed by the delivery of the chemotherapeutic drug GEM. Using our developed PUFAylation technology, the GEM prodrug was able to spontaneously self-assemble into colloidal stable nanoparticles with sub-100 nm size on covalent attachment of hydrophobic linoleic acid via amide linkage. The prodrug nanoassemblies could be further refined by PEGylation and PDAC-specific peptide ligand for preclinical studies. In vitro cell-based assays showed that not only were GEM nanoparticles superior to free GEM but also the decoration with PDAC-homing peptide facilitated the intracellular uptake of nanoparticles and thereby augmented the cytotoxic activity. In two separate xenograft models of human PDAC, one of which was a patient-derived xenograft model, the administration of targeted nanoparticles resulted in marked inhibition of tumor progression as well as alleviated systemic toxicity. Together, these data unequivocally confirm that the hydrophilic and rapidly metabolized drug GEM can be feasibly transformed into a pharmacologically efficient nanomedicine through exploiting the PUFAylation technology. This strategy could also potentially be applied to rescue many other therapeutics that show unfavorable outcomes in the preclinical studies because of pharmacologic obstacles.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Nanopartículas/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Pró-Fármacos/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Pró-Fármacos/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Pharm Res ; 37(1): 4, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823030

RESUMO

PURPOSE: The discovery of nano drug delivery system has rendered a great hope for improving cancer therapy. However, there are some inevitable obstacles that constrain its development, such as the physical and biological barriers, the toxicity of carrier materials and the physiological toxicity of drugs. Here, we report a polymeric prodrug micelle (PPM) with pH/redox dual-sensitivity, which was prepared using methoxy poly (ethylene glycol) (mPEG) with favorable biosafety to improve cancer therapy. METHOD: The tumor microenvironment stimuli-responsive PPMs were prepared and characterized in vitro and in vivo. RESULTS: Our data displayed that the PPMs with excellent biocompatibility exhibited the stimuli-responsive drug release behavior under the microenvironment of cancer cells, superior cellular internalization and lower cytotoxicity. A new method to control drug release behavior was proposed by comparing the release behavior of PPMs formed by PEG of different molecular weight. Furthermore, the fabricated PPMs exhibited the "oral-like" blood concentration curve, improved biodistribution, reduced tissue toxicity and excellent antitumor efficiency in vivo. Consistently, these results indicated that PPMs improved chemotherapeutic efficiency and reduced side effects of the model drug doxorubicin (DOX). CONCLUSION: The prepared pH/redox dual-sensitive PPM enhanced the chemotherapy effect on the tumor site while reducing the physiological toxicity of DOX. Graphical Abstract.


Assuntos
Portadores de Fármacos/química , Micelas , Polietilenoglicóis/química , Pró-Fármacos/química , Microambiente Tumoral , Células A549 , Animais , Antineoplásicos/administração & dosagem , Preparações de Ação Retardada , Doxorrubicina/administração & dosagem , Humanos , Masculino , Camundongos Endogâmicos BALB C , Pró-Fármacos/administração & dosagem , Ratos Sprague-Dawley
19.
Drug Deliv ; 26(1): 1280-1291, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31793355

RESUMO

To obtain a high-efficiency drug and gene co-delivery system to HNE-1 tumor therapy, a polymeric prodrug (PAAs-MTX) with chemotherapeutic sensibilization was synthesized consisting of a GSH-response hyperbranched poly(amido amine) (PAAs) and an antitumor drug of methotrexate (MTX). Then, the targeting molecule to HNE-1 cells, transferrin (Tf), was conjugated to form the Tf-PAAs-MTX. This polymeric prodrug could deliver MMP-9 shRNA plasmid (pMMP-9) again to form the drug and gene co-delivery system of Tf-PAAs-MTX/pMMP-9. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency to HNE-1 cells. Besides that, Tf-PAAs-MTX also showed the chemotherapeutic sensibilization effect, the formulation containing PAAs segments showed much higher cytotoxicity than that of free MTX. Benefiting from the sensibilization effect and MTX/pMMP-9 co-delivery strategy, this Tf-PAAs-MTX/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. Moreover, its biocompatibility, especially the blood compatibility was analyzed. This polymeric prodrug provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization and targeting into one single platform, which showed a promising application in nasopharyngeal carcinoma therapy.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Técnicas de Transferência de Genes , Metaloproteinase 9 da Matriz/administração & dosagem , Metotrexato/administração & dosagem , Carcinoma Nasofaríngeo/terapia , Plasmídeos/administração & dosagem , Poliaminas/química , Pró-Fármacos/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Células 3T3 , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Terapia Combinada , Metaloproteinase 9 da Matriz/genética , Metotrexato/uso terapêutico , Camundongos , Camundongos Nus , Plasmídeos/genética , Pró-Fármacos/uso terapêutico , RNA Interferente Pequeno/genética , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Nanomedicine ; 14: 8805-8818, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806973

RESUMO

Purpose: The objective of the present study was to develop a liposomal drug delivery system based on combretastatin A4 (CA4) prodrugs modified with varying alkyl chains and investigate the in vitro drug conversion from prodrug and in vivo antitumor effect. Methods: The prodrug of CA4 was synthesized with stearyl chloride (18-carbon chain), palmitoyl chloride (16-carbon chain), myristoyl chloride (14-carbon chain), decanoyl chloride (10-carbon chain), and hexanoyl chloride (6-carbon chain) at the 3'-position of the CA4. Subsequently, it was encapsulated with liposomes through the thin-film evaporation method. Furthermore, the characteristics of prodrug-liposome were evaluated using in vitro drug release, conversion, and cytotoxicity assays, as well as in vivo pharmacokinetic, antitumor, and biodistribution studies. Results: The liposome system with loaded CA4 derivatives was successfully developed with nano-size and electronegative particles. The rate of in vitro drug release and conversion was reduced as the fatty acid carbon chain lengthened. On the contrary, in vivo antitumor effects were improved with the enlargement of the fatty acid carbon chain. The results of the in vivo pharmacokinetic and tissue distribution studies indicated that the reduced rate of CA4 release with a long carbon chain could prolong the circulation time and increase the drug concentration in the tumor tissue. Conclusion: These results suggested that the release or hydrolysis of the parent drug from the prodrug was closely related with the in vitro and in vivo properties. The slow drug release of CA4 modified with longer acyl chain could prolong the circulation time and increase the concentration of the drug in the tumor tissue. These effects play a critical role in increasing the antitumor efficacy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/administração & dosagem , Pró-Fármacos/química , Estilbenos/administração & dosagem , Acilação , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Lipossomos/química , Células MCF-7 , Masculino , Camundongos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologia , Ratos Sprague-Dawley , Estilbenos/química , Estilbenos/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
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