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1.
Thromb Haemost ; 120(5): 737-746, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369845

RESUMO

Long-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).


Assuntos
Fator IX/administração & dosagem , Hemofilia B/tratamento farmacológico , Hemostáticos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adolescente , Fatores Etários , Ásia , Criança , Pré-Escolar , Esquema de Medicação , Europa (Continente) , Fator IX/efeitos adversos , Fator IX/farmacocinética , Hemofilia B/sangue , Hemofilia B/diagnóstico , Hemorragia/sangue , Hemorragia/diagnóstico , Hemorragia/prevenção & controle , Hemostáticos/efeitos adversos , Hemostáticos/sangue , Hemostáticos/farmacocinética , Humanos , Lactente , América do Norte , Segurança do Paciente , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
2.
Sheng Wu Gong Cheng Xue Bao ; 36(4): 750-762, 2020 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-32347069

RESUMO

PEGylation is considered one of the most successful techniques to improve the characteristics of protein drugs including to increase the circulating half-life of proteins in blood and to decrease their immunogenicity and antigenicity. One known PEG modification method is to attach PEG to the free amino group, typically at lysine residues or at the N-terminal amino acid with no selectivity, resulting in a heterogeneous product mixture. This lack of selectivity can present problems when a therapeutic PEGylated protein is being developed, because predictability of activity and manufacturing reproducibility are needed for regulatory approval. Enzymatic PEGylation of proteins is one route to overcome this limitation. Transglutaminases (TGase) are enzyme candidates for site-specific PEGylation. We use human interferon alpha 2a (IFN α2a) as a test case, and predict that the potential modification residues are Gln101 by computational approach as it contains 12 potential PEGylation sites. IFN α2a was PEGylated by Y shaped PEG40k-NH2 mediated by microbial transglutaminase. Our results show that the microbial transglutaminase mediated PEGylation of IFN α2a was site-specific only at the site of Gln101 in IFN α2a, yielding the single mono-conjugate PEG-Gln101-IFN α2a with a mass of 59 374.66 Da. Circular dichroism studies showed that PEG-Gln101-IFN α2a preserved the same secondary structures as native IFN α2a. As expected, the bioactivity and pharmacokinetic profile in rats of PEG-Gln101-IFN α2a revealed a significant improvement to unmodified IFN α2a, and better than PEGASYS.


Assuntos
Antivirais , Interferon-alfa , Polietilenoglicóis , Transglutaminases , Animais , Humanos , Interferon alfa-2/metabolismo , Interferon-alfa/biossíntese , Interferon-alfa/farmacocinética , Polietilenoglicóis/farmacocinética , Estrutura Secundária de Proteína , Ratos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Reprodutibilidade dos Testes , Transglutaminases/metabolismo
3.
Mater Sci Eng C Mater Biol Appl ; 108: 110455, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924042

RESUMO

An amphiphilic biodegradable branched copolymer, mPEG-b-PLGA-g-OCol, was synthesized by grafting copolymer (methoxy polyethylene glycol)-b-Poly (l,d-lactic-co-glycolic acid) (mPEG-b-PLGA) on oligomeric collagen (OCol), to form a branched structure with mPEG-b-PLGA as side chain and OCol as backbone. mPEG-b-PLGA and mPEG-b-PLGA-g-OCol were both amphipathic and can self-assemble into micelles in aqueous solution. The mPEG-b-PLGA-g-OCol micelles showed pH-sensitive behaviors and the particle size below 100 nm in slightly acidic environment such as tumor tissue milieu interieur to perform passive targeting. Observed by SEM, when the solution pH increased from 5 to 9, the morphology of mPEG-b-PLGA-g-OCol micelles changed from small spheres to larger ones to rings. For biodegradable mPEG-b-PLGA-g-OCol, the micelles will gradually degrade in body. Further, doxorubicin (DOX) was effectively loaded in the micelles with drug loading and encapsulation efficiency of 3.48% and 25.8%, respectively. To evaluate antineoplastic effect of DOX-laden micelles in vitro, MTT test, flow cytometry and CLSM were performed and found that DOX-laden micelles exhibited higher cellular proliferation inhibition against HeLa cells. These features indicated that the mPEG-b-PLGA-g-OCol micelles were potential drug carrier for cancer therapy.


Assuntos
Plásticos Biodegradáveis , Portadores de Fármacos , Micelas , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacocinética , Plásticos Biodegradáveis/farmacologia , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Poliésteres/síntese química , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia
4.
Talanta ; 206: 120184, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514844

RESUMO

Gemcitabine is a small molecular antitumor compound used to treat many types of solid tumors. The clinical application of gemcitabine is limited by its short biological half-life, rapid metabolism and poor tumor tissue targeting. The covalent attachment of polyethylene glycol to gemcitabine is a promising technique to overcome these limitations. After PEGylation, PEGylated gemcitabine could be metabolized into gemcitabine and its metabolites in vivo. Due to the scale effect of PEGylated gemcitabine, the DMPK process of the original drug is greatly changed. Therefore, understanding the pharmacokinetic behavior of PEGylated gemcitabine, gemcitabine and the metabolite dFdU in vivo is really important to clarify the antitumoral activity of these compounds. It would also guide the development of other PEGylated drugs. Due to the complex structure and diverse physiochemical property of PEG, direct quantification analysis of PEGylated gemcitabine presented many challenges in terms of assay sensitivity, selectivity, and robustness. In this article, a data-independent acquisition method, MSALL-based approach using electrospray ionization (ESI) coupled quadrupole time of flight mass spectrometry (MS), was utilized for the determination of PEGylated gemcitabine in rat plasma. The technique consists of a Q1 mass window through all the precursor ions, fragmenting and recording all product ions. PEGylated gemcitabine underwent dissociation in collision cell to generate a series of PEG related ions at m/z 89.0604, 133.0868, 177.1129 of 2, 3, 4 repeating ethylene oxide subunits and PEGylated gemcitabine related ions at m/z 112.0514. PEGylated gemcitabine was detected by the high resolution extracted ions based on the specific compound. For gemcitabine and dFdU, the study used derivatization of these high polarity compounds with dansyl chloride to improve their chromatographic retention. This paper describes comparative pharmacokinetic study of PEGylated gemcitabine and gemcitabine in rats by LC-MS/MS coupled with pre-column derivatization and MSALL technique. The results show that PEGylation could reduce the drug clearance of the conjugated compounds and increase the drug plasma half-life. After administration of PEGylated gemcitabine, the exposure of the free gemcitabine in vivo is lower than administration of gemcitabine, which means that PEGylated gemcitabine possesses lower toxicity compared with gemcitabine.


Assuntos
Desoxicitidina/análogos & derivados , Polietilenoglicóis/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Feminino , Floxuridina/análogos & derivados , Floxuridina/sangue , Floxuridina/farmacocinética , Meia-Vida , Masculino , Polietilenoglicóis/análise , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
5.
J Nanobiotechnology ; 17(1): 117, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783863

RESUMO

BACKGROUND: Cancer cells always develop ways to resist and evade chemotherapy. To overcome this obstacle, herein, we introduce a programmatic release drug delivery system that imparts avoiding drug efflux and nuclear transport in synchrony via a simple nanostructured drug strategy. RESULTS: The programmatic liposome-based nanostructured drugs (LNSD) contained two modules: doxorubicin (DOX) loaded into tetrahedral DNA (TD, ~ 10 nm) to form small nanostructured DOX, and the nanostructured DOX was encapsulated into the pH-sensitive liposomes. In the in vitro and in vivo studies, LNSD shows multiple benefits for drug resistance tumor treatment: (1) not only enhanced the cellular DOX uptake, but also maintained DOX concentration in an optimum level in resistant tumor cells via nanostructure induced anti-efflux effect; (2) small nanostructured DOX efficiently entered into cell nuclear via size depended nuclear-transport for enhanced treatment; (3) improved the pharmacokinetics and biodistribution via reducing DOX leakage during circulation. CONCLUSIONS: The system developed in this study has the potential to provide new therapies for drug-resistant tumor.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Doxorrubicina/análogos & derivados , Nanoestruturas/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , DNA/química , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Lipossomos/química , Células MCF-7 , Camundongos , Nanoestruturas/ultraestrutura , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/uso terapêutico
6.
J Oleo Sci ; 68(12): 1261-1270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787674

RESUMO

PEGylated liposomes are one of the useful boron carriers for boron neutron capture therapy (BNCT). Recently, a method of adding PEG after liposome formation (post-insertion) was reported. In this study, we prepared polyborane-encapsulated PEGylated liposomes for BNCT with half the amount of DSPE-PEG of the conventional method using post-insertion technique (post-PEG liposomes), and their usefulness were evaluated in comparison with conventional PEGylated liposomes (pre-PEG liposomes). From the results of physicochemical property measurements, it was confirmed that particle size distributions, surface charge densities, and fixed aqueous layer thicknesses of these liposomes were equivalent. In vitro cytotoxicity and cell uptake tests were also carried out using B16 melanoma and RAW264.7 cells. Polyborane solution and bare liposomes were used for comparison. From the results of these tests, we confirmed that post-PEG liposomes and pre-PEG liposomes have the same influence of PEGylation. To evaluate biodistribution properties at 24 h post-administration, these liposomes and polyborane solution were injected into the tail veins of tumor-bearing mice. Boron concentration and tumor/blood ratios of PEGylated liposomes were 73.2-77.6 µg/g of tumor tissue and 5.5-5.8, respectively. From these results, it was found that by using post-insertion technique, liposomes for BNCT having same effect as the liposome prepared using the conventional method can be prepared with half amount of DSPE-PEG.


Assuntos
Boranos/química , Portadores de Fármacos/química , Lipossomos/química , Polietilenoglicóis/química , Polímeros/química , Animais , Boranos/síntese química , Boranos/farmacocinética , Terapia por Captura de Nêutron de Boro/métodos , Linhagem Celular Tumoral , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Lipossomos/síntese química , Lipossomos/farmacocinética , Masculino , Camundongos , Neoplasias/metabolismo , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoglicóis/farmacocinética , Polímeros/síntese química , Polímeros/farmacocinética , Células RAW 264.7 , Distribuição Tecidual
7.
Int J Nanomedicine ; 14: 9587-9602, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824153

RESUMO

Background: The functionalization of a nanoparticle surface with PEG (polyethylene glycol) is an approach most often used for extending nanomaterial circulation time, enhancing its delivery and retention in the target tissues, and decreasing systemic toxicity of nanocarriers and their cargos. However, because PEGylated nanomedicines were reported to induce immune response including production of anti-PEG antibodies, activation of the complement system as well as hypersensitivity reactions, hydrophilic polymers other than PEG are gaining interest as its replacement in nanomaterial functionalization. Here, we present the results of in vivo evaluation of polyelectrolyte nanocapsules with biodegradable, polyelectrolyte multilayer shells consisting of poly-l-lysine (PLL) and poly-l-glutamic (PGA) acid as a potential drug delivery system. We compared the effects of nanocapsules functionalized with two different "stealth" polymers as the external layer of tested nanocapsules was composed of PGA (PGA-terminated nanocapsules, NC-PGA) or the copolymer of poly-l-lysine and polyethylene glycol (PEG-terminated nanocapsules, NC-PEG). Methods: Nanocapsules pharmacokinetics, biodistribution and routes of eliminations were analysed postmortem by fluorescence intensity measurement. Toxicity of intravenously injected nanocapsules was evaluated with analyses of blood morphology and biochemistry and by histological tissue analysis. DNA integrity was determined by comet assay, cytokine profiling was performed using flow cytometer and detection of antibodies specific to PEG was performed by ELISA assay. Results: We found that NC-PGA and NC-PEG had similar pharmacokinetic and biodistribution profiles and both were eliminated by hepatobiliary and renal clearance. Biochemical and histopathological evaluation of long-term toxicity performed after a single as well as repeated intravenous injections of nanomaterials demonstrated that neither NC-PGA nor NC-PEG had any acute or chronic hemato-, hepato- or nephrotoxic effects. In contrast to NC-PGA, repeated administration of NC-PEG resulted in prolonged increased serum levels of a number of cytokines. Conclusion: Our results indicate that NC-PEG may cause undesirable activation of the immune system. Therefore, PGA compares favorably with PEG in equipping nanomaterials with stealth properties. Our research points to the importance of a thorough assessment of the potential influence of nanomaterials on the immune system.


Assuntos
Nanocápsulas/toxicidade , Polieletrólitos/farmacocinética , Polieletrólitos/toxicidade , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/toxicidade , Ácido Poliglutâmico/farmacocinética , Ácido Poliglutâmico/toxicidade , Animais , Citocinas/sangue , Sistemas de Liberação de Medicamentos , Feminino , Fluorescência , Camundongos Endogâmicos BALB C , Nanocápsulas/química , Especificidade de Órgãos/efeitos dos fármacos , Polieletrólitos/química , Polietilenoglicóis/química , Ácido Poliglutâmico/química , Rodaminas/química , Distribuição Tecidual , Regulação para Cima/efeitos dos fármacos
8.
Nanoscale ; 11(45): 22006-22018, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31710073

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Nanomedicine, however, offers new opportunities to facilitate drug delivery in PDAC. Our previous work has shown that poly(ethylene glycol)-functionalized nanodiamond (ND) mediated drug delivery offered a considerable improvement over free drug in PDAC. Inspired by this result and guided by molecular simulations, we opted for simultaneous loading of irinotecan and curcumin in ultra-small PEGylated NDs (ND-IRT + CUR). We observed that ND-IRT + CUR was more efficacious in killing AsPC-1 and PANC-1 cells than NDs with single drugs. Using NDs functionalized with a near-infrared (NIR) dye, we demonstrated the preferential localization of the NDs in tumors and metastatic lesions. We further demonstrate that ND-IRT + CUR is capable of producing pronounced anti-tumor effects in two different clinically relevant, immune-competent genetic models of PDAC. Cytokine profiling indicated that NDs with or without drugs downregulated the expression of IL-10, a key modulator of the tumor microenvironment. Thus, using a combination of in silico, in vitro, and in vivo approaches, we show for the first time the remarkable anti-tumor efficacy of PEGylated NDs carrying a dual payload of irinotecan plus curcumin. These results highlight the potential use of such nano-carriers in the treatment of patients with pancreatic cancer.


Assuntos
Curcumina , Portadores de Fármacos , Nanodiamantes , Neoplasias Pancreáticas , Animais , Linhagem Celular Tumoral , Curcumina/química , Curcumina/farmacocinética , Curcumina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Camundongos , Camundongos Mutantes , Nanodiamantes/química , Nanodiamantes/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Nanobiotechnology ; 17(1): 115, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711496
10.
Expert Opin Drug Metab Toxicol ; 15(10): 779-785, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593639

RESUMO

Introduction: Interferon (IFN) had both antiviral and immunomodulatory effects, and was one of the approved treatments for hepatitis B virus (HBV). Herein, we reviewed the pharmacokinetics and pharmacodynamics of pegylated IFN-α (PegIFN-α) for the treatment of HBV. Areas covered: The steady-state serum levels of PegIFN-α were reached within 5 to 8 weeks, and the week 48 mean trough concentrations were approximately 2-fold higher than week 1. There was also no difference of the pharmacokinetics in male or female, healthy volunteers or patients with hepatitis B or C infection. PegIFN-α did not affect the metabolism of the cytochrome P450 (CYP) isozymes, except inhibition of CYP1A2. There was also no pharmacokinetic interaction between PegIFN-α and HBV nucleot(s)ide analogues (NUCs). Forty-eight weeks of PegIFN-α achieved 32% of HBeAg seroconversion, 32-43% of HBV DNA suppression, 41-59% of ALT normalization, and 3% of HBsAg seroconversion rate with a post-treatment durable response up to 80% in the initial responders. Expert opinion: On-treatment HBsAg titer guided the treatment of HBV with PegIFN-α. The recommendation of PegIFN-α and NUC combination or switch remained controversial. New immunotherapeutic agents are now in development. Although, PegIFN-α should continue to play a role in the treatment of HBV.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , DNA Viral/efeitos dos fármacos , Interações Medicamentosas , Feminino , Antígenos E da Hepatite B/sangue , Humanos , Interferon alfa-2/farmacocinética , Interferon alfa-2/farmacologia , Interferon-alfa/farmacocinética , Interferon-alfa/farmacologia , Masculino , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia
11.
Int J Pharm ; 571: 118701, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31593806

RESUMO

Immature manufacturing and sub-optimal control of quality attributes hinder the effective translation of nanoformulations for cancer treatment, being partially responsible for the scarce number of products on the market. The effect of the method of preparation on the performance of complex formulations such as bio-responsive nanomedicines needs further understanding. In this study, we investigated the the influence of the method of preparation on the characteristics and bio-responsiveness of doxorubicin-loaded redox-sensitive nanoparticles (DOX-SS-NPs), formed by a biocompatible cholesterol-based amphiphilic block copolymer (PC5MA-SS-PEO). Two commonly used preparation techniques: (1) cosolvent removal and (2) an O/W emulsion method were compared and the in vitro and in vivo performance of promising formulations was assessed. Besides particle size distribution and drug loading, the response of the nanoparticles to reducing environments and subsequent release kinetics and cytotoxicity were also affected by the method of preparation. The investigation and understanding of this extensive influence, led to a DOX-SS-NPs formulation with significant in vivo efficacy and an improved safety profile when evaluated against free doxorubicin (DOX-HCl) and the commercial pegylated liposomal form (Doxil®). Our findings highlight the importance of formulation optimization and support the use of systematic approaches like Quality by Design to the development of bio-responsive nanomedicines for cancer treatment.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Células A549 , Animais , Antibióticos Antineoplásicos/farmacocinética , Colesterol/química , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Emulsões , Feminino , Humanos , Injeções Intravenosas , Masculino , Camundongos , Neoplasias/patologia , Oxirredução , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Polímeros/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Appl Oral Sci ; 27: e20180663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596368

RESUMO

OBJECTIVE: To investigate the use of polymethyl methacrylate (PMMA) electrospun fiber mats containing different amounts of polyethylene oxide (PEO) as a doxycycline delivery system and to test antibacterial activity against an oral pathogen. METHODOLOGY: PMMA powders or PEO (mol wt 200 Kd) (10,20,30% w/w/) were dissolved in N, N-dimethylformamide (DMF) to obtain a final polymer concentration of 15% in DMF (w/v). 2% Doxycycline monohydrate was added to the solutions and submitted to vortex mixing. The solution was transferred to a plastic syringe and fit into a nanofiber electrospinning unit. The parameters applied were: voltage at 17.2 kV; distance of 20 cm between the needle tip and the collector plate; target speed at 2 m/min; and transverse speed at 1cm/min. Syringe pump speed was 0.15 mm/min. The drug release analysis was performed by removing aliquots of the drug-containing solution (in PBS) at specific periods. Doxycycline release was quantified using RP-HPLC. Fiber mats from all groups had their antibacterial action tested against S. mutans based on inhibition halos formed around the specimens. The experiments were performed in triplicate. Gravimetric analysis at specific periods was performed to determine any polymer loss. Morphological characterization of the electrospun fibers was completed under an optical microscope followed by SEM analysis. RESULTS: The addition of PEO to the PMMA fibers did not affect the appearance and diameter of fibers. However, increasing the %PEO caused higher doxycycline release in the first 24 h. Fibers containing 30% PEO showed statistically significant higher release when compared with the other groups. Doxycycline released from the fibers containing 20% or 30% of PEO showed effective against S. mutans. CONCLUSION: The incorporation of PEO at 20% and 30% into PMMA fiber mat resulted in effective drug release systems, with detected antibacterial activity against S. mutans.


Assuntos
Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Nanofibras/química , Polietilenoglicóis/farmacocinética , Polimetil Metacrilato/farmacocinética , Análise de Variância , Antibacterianos/química , Cromatografia Líquida de Alta Pressão/métodos , Doxiciclina/química , Imersão , Microscopia Eletrônica de Varredura , Peso Molecular , Polietilenoglicóis/química , Polimetil Metacrilato/química , Reprodutibilidade dos Testes , Streptococcus mutans/efeitos dos fármacos , Fatores de Tempo , Água/química
13.
Int J Nanomedicine ; 14: 7489-7502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571860

RESUMO

Background: 3,5,4'-trimethoxy-trans-stilbene (BTM) is a methylated derivative of resveratrol. To improve the pharmaceutical properties of BTM, BTM loaded PEG-PE micelles (BTM@PEG-PE) were fabricated and its anti-cancer efficacy against colon cancer was evaluated. Methods: BTM@PEG-PE micelles were prepared by the solvent evaporation method and were characterized by nuclear magnetic resonance (NMR), size, zeta potential, polymer disperse index (PDI) and transmission electron microscopy (TEM). Cellular uptake, cell viability assay, caspase-3 activity assay and flow cytometry were performed to evaluate the cell internalization and anti-cancer efficacy of BTM@PEG-PE micelles in vitro. Pharmacokinetic profiles of BTM and BTM@PEG-PE micelles were compared and in vivo anti-cancer therapeutic efficacy and safety of BTM@PEG-PE micelles on CT26 xenograft mice were evaluated. Results: BTM was successfully embedded in the core of PEG-PE micelles, with a drug loading capacity of 5.62±0.80%. PEG-PE micelles facilitated BTM entering to the CT26 cells and BTM@PEG-PE micelles exerted enhanced anti-cancer efficacy against CT26 cells. BTM@PEG-PE micelles showed prolonged half-life and increased bioavailability. More importantly, BTM@PEG-PE micelles treatment suppressed tumor growth in tumor-bearing mice and prolonged survival with minimal damage to normal tissues. Conclusion: Altogether, the BTM@PEG-PE micelles might be a promising strategy to enhance the pharmacokinetic and pharmacodynamic potentials of BTM for colon cancer therapy.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Micelas , Fosfatidiletanolaminas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Disponibilidade Biológica , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias do Colo/patologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose , Feminino , Humanos , Camundongos Endogâmicos BALB C , Fosfatidiletanolaminas/efeitos adversos , Fosfatidiletanolaminas/farmacocinética , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Polímeros/química , Ratos Sprague-Dawley , Resultado do Tratamento
14.
Biol Pharm Bull ; 42(10): 1679-1688, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582656

RESUMO

Targeted drug delivery system (DDS) is required for RNA interference (RNAi) therapy to increase the therapeutic effect and to reduce the adverse effect. Especially in transthyretin (TTR)-related amyloidosis, hepatocyte specific delivery is desired because TTR mainly expresses in hepatocyte. Herein, we report on a hepatocyte-specific small interfering RNA (siRNA) delivery system using polyethylene glycol (PEG)-modified lactosylated dendrimer (generation 3; G3) conjugates with α-cyclodextrin (PEG-LαCs (G3)) for TTR-related amyloidosis therapy, and investigated the in vitro and in vivo gene silencing effect of PEG-LαCs (G3)/siRNA polyplexes. PEG-LαC (G3, average degree of substitution of PEG (DSP) 2)/TTR siRNA (siTTR) polyplex exhibited the asialoglycoprotein receptor (ASGPR)-mediated cellular uptake, high endosomal escaping ability and localization of the siRNA in cytoplasm, resulting in significant TTR silencing in HepG2 cells. In vivo studies showed that PEG-LαC (G3, DSP2)/siTTR polyplex led to a significant TTR silencing effect in liver after systemic administration to mice. Furthermore, safety evaluation revealed that PEG-LαC (G3, DSP2)/siTTR polyplex had no significant toxicity both in vitro and in vivo. These findings suggest the utility of PEG-LαC (G3, DSP2) as a promising hepatocyte-specific siRNA delivery system both in vitro and in vivo, and as a therapeutic approach for TTR-related amyloidosis.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Ciclodextrinas/administração & dosagem , Dendrímeros/administração & dosagem , Hepatócitos/metabolismo , Polietilenoglicóis/administração & dosagem , Pré-Albumina/genética , RNA Interferente Pequeno/administração & dosagem , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Animais , Dendrímeros/farmacocinética , Células Hep G2 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Polietilenoglicóis/farmacocinética , Pré-Albumina/metabolismo , RNA Interferente Pequeno/farmacocinética
15.
Eur J Pharm Sci ; 139: 105063, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31487537

RESUMO

The development of so-called Proticles opens attractive possibilities for new drug delivery systems. Proticles are nanoparticles (NPs), which are formed by self-assembly of negatively charged oligonucleotides in combination with the positively charged peptide protamine. Polyethylene glycol (PEG) is a widely known pharmaceutical agent to stop particle growth and prolong circulation half-life of drug delivery systems. Therefore, two different NP formulations - one PEGylated and one non-PEGylated - were used in this work to gain information about the biological stability and half-life in circulation of Proticles. Thus, this study presents data of in vitro stability and in vivo pharmacokinetics of both, non-PEGylated and PEGylated Proticles radiolabeled with 111InCl3. The study demonstrated that successful radiolabeling of both Proticle-formulations was performed resulting in high radiochemical yields (> 85 %). Furthermore, the influence of PEGylation on the in vitro stability of 111In-radiolabeled NPs was investigated. No significant difference due to PEGylation was found. Unlike in vitro results, non-PEGylated 111In-Proticles seemed to degrade faster in vivo than PEGylated 111In-proticles, resulting in significantly higher blood values (111In-PEG-proticles: 0.23 ±â€¯0.01 % ID/g 1 h p.i.; 111In-proticles: 0.06 ±â€¯0.01 % ID/g 1 h p.i.; p < 0.05). Visualized by SPECT imaging urinary excretion represented the major pathway of elimination for both NP-formulations. In conclusion, this study provides data indicating a positive influence of PEG-derivatization on the biodistribution and pharmacokinetics of Proticles. These results form the basis for further developments as drug delivery and active drug targeting devices.


Assuntos
Nanopartículas , Oligonucleotídeos/farmacocinética , Polietilenoglicóis/farmacocinética , Protaminas/farmacocinética , Animais , Sistemas de Liberação de Medicamentos , Feminino , Meia-Vida , Nanopartículas/química , Oligonucleotídeos/química , Polietilenoglicóis/química , Protaminas/química , Ratos Endogâmicos Lew , Distribuição Tecidual
16.
Anal Bioanal Chem ; 411(27): 7087-7094, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471684

RESUMO

Accurate measurement and understanding of therapeutic uptake and metabolism is key in the drug development process. This work examines the amount of doxorubicin that can penetrate into spheroids after being encapsulated in a liposomal configuration in comparison with free drug. Through a process known as serial trypsinization, three distinct cellular populations of a spheroid were successfully separated and a small molecule extraction was used to isolate the chemotherapeutic. Doxorubicin showed a time-dependent permeability into spheroids with the most drug accumulating in the core at 24 h of treatment. Entrapment of the chemotherapeutic delayed the permeability of the drug and resulted in reduced amounts quantified at the earlier time points. These findings validate the claim that liposomal therapeutics have the ability to alter the pharmacokinetics and pharmacodynamics profiles of a drug while also demonstrating the combined power of mass spectrometry and three-dimensional cell cultures to evaluate drug penetration and metabolism. Graphical abstract.


Assuntos
Antibióticos Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Esferoides Celulares/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/metabolismo , Doxorrubicina/farmacocinética , Células HCT116 , Humanos , Espectrometria de Massas , Polietilenoglicóis/metabolismo , Polietilenoglicóis/farmacocinética , Tripsina/metabolismo
17.
Int J Biol Macromol ; 141: 161-170, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31479675

RESUMO

Core-shell-corona chitosan-based micelles were designed for the tumor intracellular pH-triggered doxorubicin (DOX) delivery, via a facile in-situ micellization in an aqueous solution of DOX and polyethylene glycol (PEG) and poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) dual-modified chitosan (PEG-g-CS-g-PDPA). The effect of the PDPA modification on the diameter, drug loading-capacity (DLC) and pH-triggered drug release was investigated for the three different polymerization degrees of PDPA (25, 32, and 42) with a similar modification degree of ~22%. The optimized ones, the core-shell-corona DOX/PEG-g-CS-g-PDPA32 micelles possessed a mean hydrodynamic diameter (Dh) of 211 nm and DLC of 54%, showing an excellent pH-triggered drug release with negligible premature drug leakage in 60 h. Such results indicated that grafting polycation could efficiently improve the performance of the chitosan-based drug delivery system (DDS) for tumor chemotherapy.


Assuntos
Quitosana , Doxorrubicina , Micelas , Neoplasias/tratamento farmacológico , Coroa de Proteína/química , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Células Hep G2 , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacocinética , Ácidos Polimetacrílicos/farmacologia
18.
Mater Sci Eng C Mater Biol Appl ; 105: 110060, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546370

RESUMO

The paper focuses on the preparation of polyacrylate based biomaterials designed as patches for dermal/transdermal drug delivery using materials obtained by the high internal phase emulsion (HIPE) technique. In particular, butyl acrylate and glycidyl methacrylate were selected, respectively, as backbone and functional monomer while two different crosslinkers, bifunctional or trifunctional, were used to form the covalent network. The influence of PEG on the main properties of the materials was also investigated. The obtained materials show a characteristic and interconnected internal structure as confirmed by SEM studies. By an industrial point of view, an interesting feature of this system is that it can be shaped as needed, in any form and thickness. The physiochemically characterized materials showed a tailorable curcumin (model of hydrophobic drugs) drug release, effective mechanical properties and cell viability and resulted neither pro nor anti-angiogenic as demonstrated in vivo by the chick embryo choriallantoic membrane (CAM) assay. Based on these results, the obtained polyHIPEs could be proposed as devices for dermal/transdermal drug delivery and/or for the direct application on wounded skin.


Assuntos
Resinas Acrílicas , Materiais Biocompatíveis , Polietilenoglicóis , Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/farmacologia , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/farmacologia , Embrião de Galinha , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Emulsões , Humanos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia
19.
Eur J Pharm Sci ; 139: 105043, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415903

RESUMO

Amorphous solid dispersion stands out among different formulation strategies for the improvement of dissolution rate and bioavailability via generating supersaturated drug solution, which provides a higher solubility than the crystalline counterpart, leading to a promoted intestinal absorption. Soluplus (SOL), termed as the fourth generation of solid dispersion carrier, presented a preferable effect on supersaturation maintaining and bioavailability enhancement for poorly water soluble drugs. However, some binary drug/SOL systems still suffer from insufficient dissolution and unsatisfied in vivo absorption. Thus, taking Lacidipine (LCDP) as a model drug, the aim of this study was to explore a ternary amorphous solid dispersion consisted of SOL and a surfactant to further increasing the dissolution rate and in vivo absorption. First of all, various surfactants were screened via equilibrium solubility enhancement and sodium dodecyl sulfate (SDS) was selected as the most effective candidate. Thereafter, the influence of SOL/SDS and drug/carrier weight ratio on the supersaturation maintaining was investigated. The supersaturated drug solutions were spray dried and the in vitro release, pharmacokinetic behavior as well as physical stability were investigated. It was found that although combination use of SOL and SDS did not present remarkable advantage in supersaturation maintenance in liquid state, 6-7 times higher dissolution rate under non-sink condition was noticed at SOL/SDS ratio 3:1 after spray drying, for LCDP/SOL/SDS based formulation compared to that of the binary LCDP/SOL system, which was maintained even after 92.5% humidity and 60 °C accelerated stability test. Moreover, compared to the LCDP/SOL formulation, approximately 3.3 and 3.7-fold increase in C max and AUC0-∞ was achieved with LCDP/SOL/SDS based formulation. In conclusion, the presented SDS could not only be regarded as solubility enhancer but also dissolution or bioavailability promoter, highlighting its potential application in ternary supersaturable amorphous solid dispersion for further increasing the dissolution and in vivo absorption of poorly water soluble drugs.


Assuntos
Di-Hidropiridinas/administração & dosagem , Portadores de Fármacos/administração & dosagem , Excipientes/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polivinil/administração & dosagem , Dodecilsulfato de Sódio/administração & dosagem , Tensoativos/administração & dosagem , Animais , Disponibilidade Biológica , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Excipientes/química , Excipientes/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polivinil/química , Polivinil/farmacocinética , Ratos Sprague-Dawley , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/farmacocinética , Tensoativos/química , Tensoativos/farmacocinética
20.
Pharmacol Res Perspect ; 7(5): e00503, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31417680

RESUMO

A pharmacokinetics (PK)/pharmacodynamics (PD) study (EudraCT number 2015-002966-21) was conducted to investigate the biosimilarity of Pelmeg® (pegfilgrastim), a biosimilar to EU-authorized Neulasta®, which is used in the clinic for prevention of chemotherapy-induced neutropenia. The single-dose, randomized, double-blind, two-way crossover study comprised 171 healthy male subjects, receiving Pelmeg and Neulasta (6 mg as subcutaneous injection) in a sequential manner. Primary PK endpoints were the area under the concentration curve from time zero to last measurable concentration (AUC0-last) and the maximum concentration (C max). The primary PD endpoint was the area under the effect curve (AUEC0-last) for absolute neutrophil count (ANC). Safety and immunogenicity were also assessed. Comparability was demonstrated for both PK endpoints, with geometric mean ratios (test/reference) for AUC0-last and C max of 95.2% and 92.8%, respectively. The corresponding confidence intervals (CIs; 94.3%) were [86.6%;104.7%] for AUC0-last and [84.4%;102.2%] for C max, both being within the equivalence margin of 80.0% to 125.0%. Likewise, PD comparability was demonstrated, with the geometric mean ratio (test/reference) of AUEC0-last of 100.2%, with a corresponding CI (95%) of 98.7%-101.8%. No clinically meaningful differences were observed for safety and immunogenicity between Pelmeg and Neulasta. Pelmeg was found to be highly similar to the reference product.


Assuntos
Medicamentos Biossimilares/administração & dosagem , Filgrastim/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Área Sob a Curva , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacocinética , Estudos Cross-Over , Método Duplo-Cego , Filgrastim/efeitos adversos , Filgrastim/farmacocinética , Voluntários Saudáveis , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Equivalência Terapêutica , Adulto Jovem
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