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1.
Life Sci ; 264: 118674, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33129876

RESUMO

AIMS: Arginine depleting enzymes are found effective to treat arginine-auxotrophic cancers and therapy-resistant malignancies, alone or in combination with cytotoxic agents or immune checkpoint inhibitors. We aim to select and validate a long-lasting, safe and effective PEGylated and cobalt-chelated arginase conjugated at the selective cysteine residue as a therapeutic agent against cancers. MAIN METHODS: Exploring pharmacokinetic and pharmacodynamic properties of the three arginase conjugates with different PEG modality (20 kDa linear as A20L, 20 kDa branched as A20Y, and 40 kDa branched as A40Y) by cell-based and animal studies. KEY FINDINGS: Arginase conjugates showed comparable systemic half-lives, about 20 h in rats and mice. The extended half-life of PEGylated arginase was concurrent with the integrity of conjugates of which PEG and protein moieties remain attached in bloodstream for 72 h after drug administration. Arginase modified with a linear 20 kDa PEG (A20L) was chosen as the lead candidate (PT01). In vitro assays confirmed the very potent cytotoxicity of PT01 against cancer cell lines of breast, prostate, and pancreas origin. In MIA PaCa-2 pancreatic and PC-3 prostate tumor xenograft models, weekly infusion of the PT01 at 5 and 10 mg/kg induced significant tumor growth inhibition of 44-67%. All mice experienced dose-dependent but rapidly reversible weight loss following each weekly dose, suggesting tolerable toxicity. SIGNIFICANCE: These non-clinical data support PT01 as the lead candidate for clinical development that may benefit cancer patients by providing an alternative cytotoxic mechanism.


Assuntos
Antineoplásicos/síntese química , Arginase/síntese química , Arginina/deficiência , Engenharia Química/métodos , Desenho de Fármacos , Polietilenoglicóis/síntese química , Animais , Antineoplásicos/administração & dosagem , Arginase/administração & dosagem , Arginina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/administração & dosagem , Isoenzimas/síntese química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/administração & dosagem , Estrutura Secundária de Proteína , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
Int J Nanomedicine ; 15: 6167-6182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922000

RESUMO

Background: Among the novel cancer treatment strategies, combination therapy is a cornerstone of cancer therapy. Materials and Methods: Here, combination therapy with targeted polymer, magnetic hyperthermia and chemotherapy was presented as an effective therapeutic technique. The DOX-loaded PLA-PEG-FA magnetic nanoparticles (nanocarrier) were prepared via a double emulsion method. The nanocarriers were characterized by particle size, zeta potential, morphology, saturation magnetizations and heat generation capacity, and the encapsulation efficiency, drug content and in-vitro drug release for various weight ratios of PLA:DOX. Then, cytotoxicity, cellular uptake and apoptosis level of nanocarrier-treated cells for HeLa and CT26 cells were investigated by MTT assay, flow cytometry, and apoptosis detection kit. Results and Conclusions: The synthesized nanoparticles were spherical in shape, had low aggregation and considerable magnetic properties. Meanwhile, the drug content and encapsulation efficiency of nanoparticles can be achieved by varying the weight ratios of PLA:DOX. The saturation magnetizations of nanocarriers in the maximum applied magnetic field were 59/447 emu/g and 28/224 emu/g, respectively. Heat generation capacity of MNPs and nanocarriers were evaluated in the external AC magnetic field by a hyperthermia device. The highest temperature, 44.2°C, was measured in the nanocarriers suspension at w/w ratio 10:1 (polymer:DOX weight ratio) after exposed to the magnetic field for 60 minutes. The encapsulation efficiency improved with increasing polymer concentration, since the highest DOX encapsulation efficiency was related to the nanocarriers' suspension at w/w ratio 50:1 (79.6 ± 6.4%). However, the highest DOX loading efficiency was measured in the nanocarriers' suspension at w/w ratio 10:1 (5.14 ± 0.6%). The uptake efficiency and apoptosis level of nanocarrier-treated cells were higher than those of nanocarriers (folic acid free) and free DOX-treated cells in both cell lines. Therefore, this targeted nanocarrier may offer a promising nanosystem for cancer-combined chemotherapy and hyperthermia.


Assuntos
Doxorrubicina/farmacologia , Ácido Fólico/farmacologia , Hipertermia Induzida , Nanopartículas de Magnetita/química , Neoplasias/terapia , Polietilenoglicóis/química , Animais , Apoptose/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Células HeLa , Humanos , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Tamanho da Partícula , Polietilenoglicóis/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
3.
Int J Nanomedicine ; 15: 4151-4169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606670

RESUMO

Purpose: Focused ultrasound (FUS) is a noninvasive method to produce thermal and mechanical destruction along with an immune-stimulatory effect against cancer. However, FUS ablation alone appears insufficient to generate consistent antitumor immunity. In this study, a multifunctional nanoparticle was designed to boost FUS-induced immune effects and achieve systemic, long-lasting antitumor immunity, along with imaging and thermal enhancement. Materials and Methods: PEGylated PLGA nanoparticles encapsulating astragalus polysaccharides (APS) and gold nanorods (AuNRs) were constructed by a simple double emulsion method, characterized, and tested for cytotoxicity. The abilities of PA imaging and thermal-synergetic ablation efficiency were analyzed in vitro and in vivo. The immune-synergistic effect on dendritic cell (DC) differentiation in vitro and the immune response in vivo were also evaluated. Results: The obtained APS/AuNR/PLGA-PEG nanoparticles have an average diameter of 255.00±0.1717 nm and an APS-loading efficiency of 54.89±2.07%, demonstrating their PA imaging capability and high biocompatibility both in vitro and in vivo. In addition, the as-prepared nanoparticles achieved a higher necrosis cell rate and induced apoptosis rate in an in vitro cell suspension assay, greater necrosis area and decreased energy efficiency factor (EEF) in an in vivo rabbit liver assay, and remarkable thermal-synergic performance. In particular, the nanoparticles upregulated the expression of MHC-II, CD80 and CD86 on cocultured DCs in vitro, followed by declining phagocytic function and enhanced interleukin (IL)-12 and interferon (INF)-γ production. Furthermore, they boosted the production of tumor necrosis factor (TNF)-α, IFN-γ, IL-4, IL-10, and IgG1 (P< 0.001) but not IgG2a. Immune promotion peaked on day 3 after FUS in vivo. Conclusion: The multifunctional APS/AuNR/PLGA-PEG nanoparticles can serve as an excellent synergistic agent for FUS therapy, facilitating real-time imaging, promoting thermal ablation effects, and boosting FUS-induced immune effects, which have the potential to be used for further clinical FUS treatment.


Assuntos
Astrágalo (Planta)/química , Neoplasias da Mama/terapia , Ouro/química , Nanopartículas Multifuncionais/química , Nanotubos/química , Polissacarídeos/química , Terapia por Ultrassom , Animais , Antígenos CD/metabolismo , Apoptose , Morte Celular , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/metabolismo , Células Dendríticas/citologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunoglobulina G/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos BALB C , Fagocitose , Técnicas Fotoacústicas , Poliésteres/síntese química , Poliésteres/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Coelhos , Nanomedicina Teranóstica , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Cardiovasc Drugs Ther ; 34(5): 651-657, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32444994

RESUMO

BACKGROUND: The high surgical risk in redo cardiac surgery is largely attributed to adhesions around the epicardium and the great vessels. BAX602 is an adhesion prevention reagent composed of two synthetic polyethylene glycols. Spraying BAX602 over the epicardium and the great vessels reportedly contributes to adhesion prevention after pediatric cardiac surgery. The present study aims to evaluate the safety and effectiveness of BAX602 spray in patients undergoing extracorporeal ventricular assist device implantation surgery to treat refractory congestive heart failure. METHODS AND DESIGN: This investigator-initiated, multicenter, pivotal, two-arm, open-label, randomized trial will include a total of 30 patients. The primary outcome measure is the severity of adhesions, which will be evaluated during re-sternotomy surgery performed 2-12 weeks after the primary extracorporeal ventricular assist device implantation surgery. The adhesion severity will be evaluated at five predefined sites using a four-grade adhesion evaluation score (0 = no adhesion; 1 = filmy and avascular adhesion; 2 = dense/vascular adhesion; 3 = cohesive adhesion). This measure will be summarized in two ways to evaluate the effect of BAX602: (1) the total score of the severity of adhesions at all five sites (ranging from 0 to 15), and (2) the total number of sites with dense/vascular or cohesive adhesions (ranging from 0 to 5). ETHICS AND DISSEMINATION: The study findings will be disseminated at regional, national, and international conferences and through peer-reviewed scientific journals. TRIAL REGISTRATION: The trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000038998) on 6 January 2020.


Assuntos
Cardiopatias/prevenção & controle , Insuficiência Cardíaca/terapia , Coração Auxiliar , Polietilenoglicóis/administração & dosagem , Implantação de Prótese/instrumentação , Função Ventricular Esquerda , Adolescente , Adulto , Aerossóis , Idoso , Feminino , Cardiopatias/etiologia , Cardiopatias/patologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/síntese química , Desenho de Prótese , Implantação de Prótese/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores de Tempo , Aderências Teciduais , Resultado do Tratamento , Adulto Jovem
5.
AAPS PharmSciTech ; 21(4): 121, 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32337630

RESUMO

Multidrug resistance is the major problem in cancer treatment nowadays. Compounds from plants are the new targets to solve this problem. Quercetin (QCT), quercetrin (QTR), and rutin (RUT) are potential anticancer flavonoids but their poor water solubility leads to less efficacy. In this study, the polymeric micelles of benzoylated methoxy-poly (ethylene glycol)-b-oligo(ε-caprolactone) or mPEG-b-OCL-Bz loading with the flavonoids were prepared to solve these problems. The flavonoid-loaded micelles showed an average size of 13-20 nm and maximum loading capacity of 35% (w/w). The release of QCT (21%, 3 h) was lower than that of QTR (51%, 3 h) and RUT (58%, 3 h). QCT (free and micelle forms) exhibited significantly higher cytotoxicity against P-glycoprotein-overexpressing leukemia (K562/ADR) cells than QTR and RUT (p < 0.05). The results demonstrated that QCT-loaded micelles effectively reversed cytotoxicity of both doxorubicin (multidrug resistant reversing (δ) values up to 0.71) and daunorubicin (δ values up to 0.74) on K562/ADR cells. It was found that QCT-loaded micelles as well as empty polymeric micelles inhibited P-gp efflux of tetrahydropyranyl Adriamycin. Besides, mitochondrial membrane potential was decreased by QCT (in its free form and micellar formation). Our results suggested that the combination effects of polymeric micelles (inhibiting P-gp efflux) and QCT (interfering mitochondrial membrane potential) might be critical factors contributing to the reversing multidrug resistance of K562/ADR cells by QCT-loaded micelles. We concluded that QCT-loaded mPEG-b-OCL-Bz micelles are the attractive systems for overcoming multidrug-resistant cancer cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/síntese química , Antineoplásicos/síntese química , Flavonoides/síntese química , Micelas , Polietilenoglicóis/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Flavonoides/farmacologia , Humanos , Células K562 , Polietilenoglicóis/farmacologia , Polímeros/síntese química , Polímeros/farmacologia , Solubilidade
6.
AAPS PharmSciTech ; 21(4): 124, 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32342227

RESUMO

To achieve improved drug delivery efficiency to hepatocellular carcinoma (HCC), biodegradable poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NP), surface-modified with SP94 peptide, were designed for the efficient delivery of cryptotanshinone to the tumor for the treatment of HCC. Cryptotanshinone NP and SP94-NP were prepared by using nanoprecipitation. The physicochemical and pharmaceutical properties of the NP and SP94-NP were characterized, and the release kinetics suggested that both NP and SP94-NP provided continuous, slow release of cryptotanshinone for 48 h. The in vitro cellular experiment demonstrated that SP94-NP significantly enhanced the cellular uptake of cryptotanshinone and induced high cytotoxicity and cellular apoptosis of hepatocellular carcinoma (HepG2) cells. The in vivo detecting results of targeting effect using the Cy5.5 probe evidenced that SP94-NP showed an accumulation in tumor more efficiently than that of unconjugated ones. Meanwhile, SP94-NP exhibited the smallest tumor size than other groups and showed no toxicity to body. The results of this study provide a promising nanoplatform for the targeting of HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Fenantrenos/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/metabolismo , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/metabolismo , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/metabolismo , Fenantrenos/síntese química , Fenantrenos/metabolismo , Poliésteres/síntese química , Poliésteres/metabolismo , Polietilenoglicóis/síntese química , Polietilenoglicóis/metabolismo
7.
Mater Sci Eng C Mater Biol Appl ; 111: 110811, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279824

RESUMO

Implants of poly(ether ether ketone) (PEEK) are gaining importance in surgical bone reconstruction of the skull. As with any implant material, PEEK is susceptible to bacterial contamination and occasionally PEEK implants were removed from patients because of infection. To address this problem, a combination of anti-fouling and bactericidal polymers is grafted onto PEEK. The originality is that anti-fouling (modified poly(ethylene glycol)) and bactericidal (quaternized poly(dimethylaminoethyl acrylate)) moieties are simultaneously and covalently grafted onto PEEK via UV photoinsertion. The functionalized PEEK surfaces are evaluated by water contact angle measurements, FTIR, XPS and AFM. Grafting of anti-fouling and bactericidal polymers significantly reduces Staphylococcus aureus adhesion on PEEK surfaces without exhibiting cytotoxicity in vitro. This study demonstrates that grafting combinations of anti-fouling and bactericidal polymers synergistically prevents bacterial adhesion on PEEK implants. This approach shows clinical relevance as grafting is rapid, does not modify PEEK properties and can be conducted on pre-formed implants.


Assuntos
Antibacterianos/farmacologia , Incrustação Biológica , Cetonas/farmacologia , Luz , Polietilenoglicóis/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Cetonas/síntese química , Cetonas/química , Testes de Sensibilidade Microbiana , Espectroscopia Fotoeletrônica , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Espectroscopia de Prótons por Ressonância Magnética , Staphylococcus aureus/efeitos dos fármacos , Propriedades de Superfície
8.
Int J Nanomedicine ; 15: 1499-1515, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189965

RESUMO

Purpose: Some chemotherapeutics have been shown to induce both the release of damage-associated molecular patterns (DAMPs) and the production of type I interferon (IFN-I), leading to immunogenic cell death (ICD). However, the standard chemotherapy drug for glioma, temozolomide (TMZ), cannot induce ICD as it cannot activate IFN-I signaling. Moreover, inefficient delivery of immunostimulants across the blood-brain barrier (BBB) is the main obstacle to overcome in order to induce local immune responses in the brain. Methods: A new oligonucleotide nanoformulation (Au@PP)/poly(I:C)) was constructed by coating gold nanoparticles (AuNPs) with methoxypolyethylene glycol (mPEG)-detachable (d)-polyethyleneimine (PEI) (Au@PP) followed by inducing the formation of electrostatic interactions with polyinosinic-polycytidylic acid (poly(I:C)). Intracranial GL261 tumor-bearing C57BL/6 mice were used to explore the therapeutic outcomes of Au@PP/poly(I:C) plus TMZ in vivo. The anti-tumor immune response in the brain induced by this treatment was analyzed by RNA sequencing and immunohistochemical analyses. Results: Au@PP/poly(I:C) induced IFN-I production after endocytosis into glioma cells in vitro. Additionally, Au@PP/poly(I:C) was efficiently accumulated in the glioma tissue after intranasal administration, which allowed the nanoformulation to enter the brain while bypassing the BBB. Furthermore, Au@PP/poly(I:C) plus TMZ significantly improved the overall survival of the tumor-bearing mice compared with group TMZ only. RNA sequencing and immunohistochemical analyses revealed efficient immune response activation and T lymphocyte infiltration in the Au@PP/poly(I:C) plus TMZ group. Conclusion: This study demonstrates that intranasal administration of Au@PP/poly(I:C) combined with TMZ induces ICD, thereby stimulating an in situ immune response to inhibit glioma growth.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Glioma/tratamento farmacológico , Glioma/imunologia , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/uso terapêutico , Administração Intranasal , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Feminino , Ouro/uso terapêutico , Humanos , Interferon Tipo I/metabolismo , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/síntese química , Poli I-C/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoimina/síntese química , Polietilenoimina/química , Análise de Sobrevida , Linfócitos T/efeitos dos fármacos , Temozolomida/farmacologia , Temozolomida/uso terapêutico
9.
Nat Chem ; 12(4): 381-390, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32152477

RESUMO

Stimuli-responsive biomaterials that contain logic gates hold great potential for detecting and responding to pathological markers as part of clinical therapies. However, a major barrier is the lack of a generalized system that can be used to easily assemble different ligand-responsive units to form programmable nanodevices for advanced biocomputation. Here we develop a programmable polymer library by including responsive units in building blocks with similar structure and reactivity. Using these polymers, we have developed a series of smart nanocarriers with hierarchical structures containing logic gates linked to self-immolative motifs. Designed with disease biomarkers as inputs, our logic devices showed site-specific release of multiple therapeutics (including kinase inhibitors, drugs and short interfering RNA) in vitro and in vivo. We expect that this 'plug and play' platform will be expanded towards smart biomaterial engineering for therapeutic delivery, precision medicine, tissue engineering and stem cell therapy.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Polietilenoglicóis/química , Polietilenoimina/química , Anilidas/química , Anilidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/química , Cisplatino/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Feminino , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Lógica , Camundongos Nus , Nanopartículas/metabolismo , Polietilenoglicóis/síntese química , Polietilenoglicóis/metabolismo , Polietilenoimina/síntese química , Polietilenoimina/metabolismo , Estudo de Prova de Conceito , Piridinas/química , Piridinas/farmacologia , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Eur J Pharm Biopharm ; 150: 77-86, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32151729

RESUMO

AIM: It was the aim of this study to synthesize a phosphorylated emulsifier possessing a PEG-linker for establishment of a potent zeta potential changing system in self-emulsifying drug delivery systems (SEDDS). METHODS: N,N'-Bis(polyoxyethylene)oleylamine (POA) was phosphorylated utilizing pyrophosphoric acid. Successful synthesis of POA bisphosphate (POAP) was confirmed by NMR and HR CS MAS. After incorporation of 1% POAP into SEDDS (Kolliphor RH 40, Capmul PG-8, Labrafac Lipophile WL 1349, Labrafac PG; 30/20/20/30, v/v), according emulsions were incubated with intestinal alkaline phosphatase (IAP) and the zeta potential was measured. Additionally, the amount of released phosphate upon incubation with IAP or on Caco-2 cells was quantified by malachite green assay. Finally, cell viability studies on Caco-2 cells were performed and mucus permeation properties with and without IAP preincubation were assessed. RESULTS: POAP was synthesized as brown viscous liquid with a yield of 36% and could be incorporated into SEDDS. By incubation with IAP a zeta potential shift from -15.1 to 6.5 mV was observed. A corresponding phosphate release in presence of isolated IAP as well as on Caco-2 cells was found. Assessment of the cytotoxic potential revealed no significant alteration in the safety profile of SEDDS by incorporation of POAP. Mucus permeation studies exposed a 2-fold higher permeation of fluorescein diacetate (FDA) having been embedded in SEDDS loaded with POAP in comparison to blank formulation and 3-fold higher permeability than for emulsions having been preincubated with phosphatase. CONCLUSION: The novel phosphorylated surfactant exhibiting a PEG-linker facilitated a potent zeta potential change of SEDDS.


Assuntos
Difosfatos/síntese química , Portadores de Fármacos , Emulsificantes/síntese química , Polietilenoglicóis/síntese química , Fosfatase Alcalina/metabolismo , Células CACO-2 , Composição de Medicamentos , Emulsões , Proteínas Ligadas por GPI/metabolismo , Humanos , Absorção Intestinal , Mucosa Intestinal/enzimologia , Permeabilidade , Fosfatos/metabolismo , Fosforilação , Propriedades de Superfície
11.
Colloids Surf B Biointerfaces ; 189: 110857, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32066087

RESUMO

Hydrophobic modification PEO-PPO copolymer BP123 was synthesized, with two aromatic rings in the centre linked to PEO-PPO blocks, and the identical PEO and PPO block numbers were possessed with commercial copolymer P123. The influence of three common pharmaceutical excipient salts sodium chloride (NaCl), sodium citrate (NaCA) and sodium benzoate (NaBZ) on self-assembly behaviors of BP123 and P123 was investigated via cloud point, surface tension, pyrene fluorescence and dynamic light scattering. Solubilization for hydrophobic drug simvastatin (SV) and in vitro drug release behavior were assessed accordingly. In the presence of NaCl or NaCA, cloud point and critical micellization concentration (CMC) decreased, micelles became more hydrophobic, micellar size and drug solubilization increased, drug release rate slowed, and the impact of NaCA was more significant than NaCl. Oppositely, cloud point and CMC increased with the addition of NaBZ. NaBZ could participate in the formation of micelles by hydrophobic aromatic ring, which greatly raised solubilization of SV. Moreover, a different performance occurred when NaBZ was added to BP123 or P123, due to the hydrophobic benzene rings in BP123, which prominently enhanced the interaction with hydrophobic drug, leading to obvious delay of drug release for BP123. This work is conducive to turning copolymer property in diverse pharmaceutical applications and in drug delivery systems as drug carriers.


Assuntos
Hipolipemiantes/química , Polietilenoglicóis/química , Propilenoglicóis/química , Sinvastatina/química , Benzoato de Sódio/química , Cloreto de Sódio/química , Citrato de Sódio/química , Portadores de Fármacos/química , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Polietilenoglicóis/síntese química , Propilenoglicóis/síntese química , Solubilidade
12.
Carbohydr Polym ; 233: 115832, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32059885

RESUMO

In the present study, a type of bioconjugate was synthesized by post modification of alginate by conjugating temperature-responsive poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide) and O-phosphorylethanolamine as phosphorylation functional groups. Freely flowing bioconjugate sols at low temperature can transform to stable viscoelastic gels at the physiological temperature (37 °C). Subcutaneous administration of temperature-responsive bioconjugate sols into the dorsal region of Sprague-Dawley rats formed in situ hydrogel. in situ formation of bioconjugate gels in stimulated body fluids at 37 °C showed nucleation and hydroxyapatite mineral growth. Furthermore, hydroxyapatite growth was also found in in vivo gels, which suggested the potential of alginate-based bioconjugate gels as a scaffold for bone engineering. Bone morphogenetic protein 2 (BMP-2)-loaded bioconjugate formed stable gel in vivo, and demonstrated sustained release. BMP-2-loaded bioconjugates exhibited in situ biomineralization in vivo. These results imply that the in situ formation of injectable biomimetic materials has potential for bone tissue engineering applications.


Assuntos
Alginatos/farmacologia , Materiais Biocompatíveis/farmacologia , Biomineralização/efeitos dos fármacos , Hidrogéis/farmacologia , Poliésteres/farmacologia , Polietilenoglicóis/farmacologia , Alginatos/síntese química , Alginatos/toxicidade , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/toxicidade , Proteína Morfogenética Óssea 2/farmacologia , Sistemas de Liberação de Medicamentos , Durapatita/metabolismo , Etanolaminas/química , Células HEK293 , Humanos , Hidrogéis/síntese química , Hidrogéis/toxicidade , Masculino , Transição de Fase , Poliésteres/síntese química , Poliésteres/toxicidade , Polietilenoglicóis/síntese química , Polietilenoglicóis/toxicidade , Ratos Sprague-Dawley , Engenharia Tecidual/métodos
13.
Colloids Surf B Biointerfaces ; 189: 110830, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045844

RESUMO

The stability of polymeric micelles is a key property for anticancer drug delivery. In this study, a novel amphiphilic triblock copolymer, methoxy poly(ethylene glycol)-b-poly(allyl glycidyl ether)-b-poly(ε-caprolactone) (mPEG-b-PAGE-b-PCL), with different hydrophobic lengths was designed and synthesized using the combination of two successive ring-opening polymerizations. The products were characterized using 1H NMR and gel permeation chromatography (GPC). The triblock copolymers could self-assemble into micelles to encapsulate doxorubicin (DOX). The diameter of the DOX-loaded micelles increased from 63 to 92 nm with increasing PCL block length in the copolymer composition. The interface of the mPEG-b-PAGE-b-PCL micelles was crosslinked by a thiol-ene reaction with 1,4-butanedithiol. The stability, drug release and in vitro cytotoxicity of the DOX-loaded micelles were studied. The results showed that the DOX-loaded micelles could be effectively endocytosed by cancer cells and have good antitumor efficacy. In addition, the crosslinked micelles (CLMs) had better tumor accumulation than the noncrosslinked micelles (NCLMs) after intravenous injection using the lipophilic dye DiR.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Reagentes para Ligações Cruzadas/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Poliésteres/química , Polietilenoglicóis/química , Animais , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tamanho da Partícula , Poliésteres/síntese química , Polietilenoglicóis/síntese química , Propriedades de Superfície , Distribuição Tecidual , Células Tumorais Cultivadas
15.
Chem Commun (Camb) ; 56(7): 1085-1088, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894779

RESUMO

We report an elastase-responsive, H2S-releasing hydrogel prepared by covalently crosslinking a mixture of carboxymethylcellulose and poly(ethylene glycol) with an elastase-degradable peptide functionalized with an H2S-releasing S-aroylthiooxime (SATO) unit. Addition of elastase triggered a gel-to-sol transition, which exposed SATOs, leading to more and longer H2S release compared to untriggered gels.


Assuntos
Carboximetilcelulose Sódica/farmacologia , Hidrogéis/farmacologia , Sulfeto de Hidrogênio/metabolismo , Elastase de Leucócito/metabolismo , Polietilenoglicóis/farmacologia , Animais , Carboximetilcelulose Sódica/síntese química , Carboximetilcelulose Sódica/metabolismo , Linhagem Celular , Doxorrubicina/toxicidade , Humanos , Hidrogéis/síntese química , Hidrogéis/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oximas/síntese química , Oximas/metabolismo , Oximas/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/metabolismo , Substâncias Protetoras/síntese química , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Ratos
16.
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
17.
Nanotechnology ; 31(16): 165102, 2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-31899896

RESUMO

The non-specific biodistribution of traditional chemotherapeutic drugs against tumors is the key factor that causes systemic toxicity and hinders their clinical application. In this study, a reduction-sensitive polymer conjugate micelle was manufactured to achieve tumor-specific targeting, reduce toxic side-effects and improve anti-tumor activity of a natural anti-cancer drug, hydroxycamptothecin (HCPT). Therefore, HCPT was conjugated with methoxy-poly(ethylene glycol)-poly(ß-benzyl-L-aspartate) (mPEG-PBLA) by a disulfide bond or succinate bond for the first time to obtain the mPEG-PBLA-SS-HCPT (PPSH) and mPEG-PBLA-CC-HCPT (PPCH) that would form micelles after high-speed agitation and dialysis. The PPSH micelles showed an average particle size of 126.3 nm, a low polydispersity index of 0.209, and a negative surface charge of -21.1 mV zeta potential. Transmission electron microscopy showed the PPSH micelles to have spherical morphology. PPSH had a low critical micelle concentration of 1.29 µg ml-1 with high dilution stability, storage stability and reproducibility. Moreover, the particle size of the PPSH micelles had no significant change after incubation with rat plasma for 72 h, probably resulting in high long circulation in the blood. The PPSH micelles showed significant reduction sensitivity to glutathione. Their sizes increased by 403.2 nm after 24 h post-incubation, and 87.6% drug release was achieved 48 h post-incubation with 40 mM glutathione solutions. The PPSH micelles showed stronger inhibition of HepG2 cells in vitro and growth of H-22 tumor in vivo than the PPCH and HCPT solutions after intravenous injection. The accumulation of PPSH micelles in the tumor tissue contributed to the high anti-tumor effect with little side-effect on the normal tissues. The reduction-sensitive PPSH micelles were a promising carrier of HCPT and other poorly soluble anti-cancer drugs.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos , Espaço Intracelular/química , Micelas , Peptídeos/química , Polietilenoglicóis/química , Animais , Camptotecina/sangue , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/farmacologia , Morte Celular/efeitos dos fármacos , Dissulfetos/química , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Oxirredução , Tamanho da Partícula , Peptídeos/síntese química , Polietilenoglicóis/síntese química , Ratos Sprague-Dawley , Succinatos/química , Distribuição Tecidual
18.
AAPS PharmSciTech ; 21(3): 78, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970547

RESUMO

Protein drugs were considered to be the first choice to treat many human diseases, but their clinical application was usually limited by their short half-life and lack of validated targeted therapy. Here, a series of folate-functionalized poly(ethylene glycol)-b-(poly(2-aminoethyl-L-glutamate)-g-poly(L-glutamic acid))s (FA-PEG-b-(PELG-g-PLGA)s) were designed as tumor-targeted carriers for cationic protein delivery. Compared with traditional copolymers consisting of PEG and linear charged hydrophilic blocks, FA-PEG-b-(PELG-g-PLGA) with brush-like polyelectrolyte segments were beneficial to improving their electrostatic interactions with loading protein molecules, thus increasing drug-loading stability and protecting encapsulated proteins from degradation. The designed polymer brushes could efficiently encapsulate cytochrome C (CytC), a cationic model protein, to form polyion complex (PIC) micelles with an average particle size of approximately 200 nm. An in vitro drug release study showed that the drug-loading stability of the formed PIC micelles was largely improved. The functionalization of the block copolymer carriers with a targeting folate group enhanced the tumor cell growth inhibition and total apoptotic rates induced by CytC. Our results shed light on the unique advantages of brush-like polymer carriers in delivering cationic proteins, and the poly(L-glutamic acid)-based linear-brush diblock copolymers could be applied as a versatile delivery platform for molecular targeting in cancer therapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Ácido Glutâmico/síntese química , Poliésteres/síntese química , Polietilenoglicóis/síntese química , Proteínas/síntese química , Animais , Cátions , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/metabolismo , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Células NIH 3T3 , Tamanho da Partícula , Poliésteres/administração & dosagem , Poliésteres/metabolismo , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/metabolismo , Polímeros/administração & dosagem , Polímeros/síntese química , Polímeros/metabolismo , Proteínas/administração & dosagem , Proteínas/metabolismo
19.
Colloids Surf B Biointerfaces ; 188: 110806, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31978698

RESUMO

The fabrication of a functional small-diameter vascular graft with good biocompatibility, in particular hemocompatibility, has become an urgent clinical necessity. We fabricated a native bilayer, small-diameter vascular graft using PEGylated chitosan (PEG-CS) and poly (L-lactic acid-co-ε-caprolactone; PLCL). To stabilize the inner layer, a PEG-CS blend with PLCL at ratio of 1:6 was casted on a round metal bar by a drip feed, and the outer layer, a PLCL blend with water-soluble PEG that acted as a sacrificial part to enhance pore size, was fabricated by electrospinning. The results showed excellent hemocompatibility and strong mechanical properties. In vitro, the degradation of the graft was evaluated by measuring the graft structure, mass loss rate, and changes in molecular weight. The results indicated that the graft had adequate support for the regeneration of blood vessels before collapse. An in vivo study was performed in a canine femoral artery model for up to 24 weeks, which demonstrated that the PEGylated bilayer grafts possessed excellent structural integrity, high compatibility with blood, good endothelial cell (EC) and smooth muscle cell (SMC) growth, and high expression levels of angiogenesis-related proteins, features that are highly similar to autologous blood vessels. Moreover, the results showed almost negligible calcification within 24 weeks. These findings confirm that the bilayer graft mimics native cells, thereby effectively improving vascular remodeling.


Assuntos
Prótese Vascular , Quitosana/química , Artéria Femoral/química , Bicamadas Lipídicas/síntese química , Polietilenoglicóis/síntese química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Quitosana/metabolismo , Cães , Artéria Femoral/metabolismo , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Modelos Biológicos , Tamanho da Partícula , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Propriedades de Superfície , Engenharia Tecidual
20.
Mater Sci Eng C Mater Biol Appl ; 108: 110358, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923953

RESUMO

In the field of drug delivery, the controlled release of drugs is continuously one of the highly prioritized research domains. Stimuli-responsive polymers are being investigated as drug delivery vehicles that modulate pharmaceutical effect via tumor specific mechanisms. In this work, a biocompatible graft copolymer (denoted as PSNC-g-mPEG/TPE) was constructed, which comprised a triple-responsive polycarbonate backbone coupled with fluorescent TPE and hydrophilic methoxypoly(ethylene glycol) (mPEG) segments. This multifunctional amphiphilic copolymer was able to self-assemble in aqueous solutions and acted as a drug delivery vehicle that releases cargo in response to multiple biological stimuli (ROS, pH and enzymes). And the results of confocal laser scanning microscopy (CLSM) suggested that these micelles could be rapidly internalized by cells and achieve more effective drug release in cancer cells. Furthermore, the cytotoxicity assays proved the safety of this material. It is anticipated that this strategy has enormous potential in constructing novel anticancer therapeutics.


Assuntos
Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Corantes Fluorescentes/síntese química , Polímeros/química , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Endocitose , Corantes Fluorescentes/química , Humanos , Camundongos , Micelas , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , Espectrometria de Fluorescência , Estilbenos/síntese química , Estilbenos/química , Suínos
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