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1.
Nanomedicine ; 23: 102104, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672600

RESUMO

Curcumin, a primary active element of turmeric, has potent antioxidant and anti-inflammatory activity, but its low bioavailability is a major hurdle in its pharmaceutical applications. To enhance the therapeutic efficacy of curcumin, we exploited polymeric prodrug strategy. Here, we report rationally designed acid-activatable curcumin polymer (ACP), as a therapeutic prodrug of curcumin, in which curcumin was covalently incorporated in the backbone of amphiphilic polymer. ACP could self-assemble to form micelles that rapidly release curcumin under the acidic condition. The potential of ACP micelles as therapeutics for osteoarthritis was evaluated using a mouse model of monoidoacetic acid (MIA)-induced knee osteoarthritis. ACP micelles drastically protected the articular structures from arthritis through the suppression of tumor necrosis factor-alpha (TNF-α) and interleukin 1ß (IL-1ß). Given their pathological stimulus-responsiveness and potent antioxidant and anti-inflammatory activities, ACP micelles hold remarkable potential as a therapeutic agent for not only osteoarthritis but also various inflammatory diseases.


Assuntos
Anti-Inflamatórios , Curcumina , Nanopartículas , Osteoartrite do Joelho/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Curcumina/química , Curcumina/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Modelos Animais de Doenças , Concentração de Íons de Hidrogênio , Interleucina-1beta/imunologia , Camundongos , Micelas , Nanopartículas/química , Nanopartículas/uso terapêutico , Osteoartrite do Joelho/induzido quimicamente , Osteoartrite do Joelho/imunologia , Osteoartrite do Joelho/patologia , Células RAW 264.7 , Fator de Necrose Tumoral alfa/imunologia
2.
Pharmaceuticals (Basel) ; 17(4)2024 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-38675430

RESUMO

For many years, sustained-release drug delivery systems (SRDDS) have emerged as a featured topic in the pharmaceutical field. Particularly for chronic diseases, such as osteoarthritis, there is a lot of demand for SRDDS because of the long treatment period and repetitive medication administration. Thus, we developed an injectable PLGA-F127 microsphere (MS) that is capable of the in situ conversion to an implant. The microprecipitation method for PLGA-F127 MS was established, and the physicochemical stability of the products was confirmed. The microspheres were assembled into a single mass in 37 °C aqueous conditions and showed a remarkably delayed drug release profile. First, the release started with no significant initial burst and lagged for 60 days. After that, in the next 40 days, the remaining 75% of the drugs were constantly released until day 105. We expect that our PLGA-F127 MS could be employed to extend the release period of 2 months of medication to 4 months. This could be a valuable solution for developing novel SRDDS for local injections.

3.
ACS Appl Bio Mater ; 4(5): 4450-4461, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35006857

RESUMO

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) uses photosensitizers and light to kill cancer cells and has become a promising therapeutic modality because of advantages such as minimal invasiveness and high cancer selectivity. However, PTT or PDT as a single treatment modality has insufficient therapeutic efficacy. Moreover, oxygen consumption by PDT activates angiogenic factors and leads to cancer recurrence and progression. Therefore, the therapeutic outcomes of phototherapy would be maximized by employing photosensitizers for concurrent PTT and PDT and suppressing angiogenic factors. Therefore, integrating photosensitive agents and antiangiogenic agents in a single nanoplatform would be a promising strategy to maximize the therapeutic efficacy of phototherapy. In this study, we developed hyaluronic acid-coated fluorescent boronated polysaccharide (HA-FBM) nanoparticles as a combination therapeutic agent for phototherapy and antiangiogenic therapy. Upon a single near-infrared laser irradiation, HA-FBM nanoparticles generated heat and singlet oxygen simultaneously to kill cancer cells and also induced immunogenic cancer cell death. Beside their fundamental roles as photosensitizers, HA-FBM nanoparticles exerted antiangiogenic effects by suppressing the vascular endothelial growth factor (VEGF) and cancer cell migration. In a mouse xenograft model, intravenously injected HA-FBM nanoparticles targeted tumors by binding CD44-overexpressing cancer cells and suppressed angiogenic VEGF expression. Upon laser irradiation, HA-FBM nanoparticles remarkably eradicated tumors and increased anticancer immunity. Given their synergistic effects of phototherapy and antiangiogenic therapy from tumor-targeting HA-FBM nanoparticles, we believe that integrating the photosensitizers and antiangiogenic agents into a single nanoplatform presents an attractive strategy to maximize the anticancer therapeutic efficacy of phototherapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Peróxido de Hidrogênio/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Lasers , Teste de Materiais , Camundongos , Estrutura Molecular , Nanopartículas/química , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Imagem Óptica , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
J Control Release ; 304: 164-172, 2019 06 28.
Artigo em Francês | MEDLINE | ID: mdl-31082433

RESUMO

A blood clot (thrombus) is formed as a final product of the hemostatic process with two major components, a mesh of cross-linked fibrin and platelets activated by high concentration of hydrogen peroxide (H2O2). Thrombus formation impedes blood flow to brain and heart and is a principle cause of life-threatening diseases such as stroke and myocardial infarction. Aspirin has been widely used for the treatment and prevention of various cardiovascular diseases, but is unable to target a thrombus and scavenge a high level of H2O2. In this study, we report thrombus targeting aspirin polyconjugate particles (T-APP) as a near infrared imaging agent and on-demand therapeutic agent for thrombotic vascular diseases. T-APP were formulated from H2O2-activatable aspirin polyconjugate, fibrin-specific peptides and fluorescent IR780. In mouse models of tail bleeding and arterial thrombosis, T-APP targeted the thrombosed vessels rapidly with excellent specificity. T-APP also exerted highly strong antithrombotic activity in the thrombosed vessel by suppressing anti-inflammatory cytokines and inhibiting platelet activation. Based on the unique features such as specific thrombus targeting, H2O2 scavenging, and on-demand therapeutic actions, the rationally engineered T-APP have important ramifications on imaging and on-demand therapy of thrombotic disorders.


Assuntos
Aspirina/farmacologia , Fibrinolíticos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Trombose/tratamento farmacológico , Animais , Aspirina/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrinolíticos/administração & dosagem , Hemorragia/induzido quimicamente , Peróxido de Hidrogênio/metabolismo , Camundongos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Polímeros/química
5.
ACS Omega ; 4(6): 10070-10077, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31460099

RESUMO

A main challenge in the development of anticancer drugs that eradicate cancer cells specifically with minimal toxicity to normal cells is to identify the cancer-specific properties. Cancer cells sustain a higher level of reactive oxygen species, owing to metabolic and signaling aberrations and unrestrained growth. Cancer cells are also furnished with a powerful reducing environment, owing to the overproduction of antioxidants such as glutathione (GSH). Therefore, the altered redox balance is probably the most prevailing property of cancer cells distinct from normal cells, which could serve as a plausible therapeutic target. In this work, we developed a GSH-depleting pro-oxidant, benzoyloxy dibenzyl carbonate, termed B2C, which is capable of rapidly declining GSH and elevating oxidative stress to a threshold level above which cancer cells cannot survive. B2C was designed to release quinone methide (QM) that rapidly depletes GSH through esterase-mediated hydrolysis. B2C was able to rapidly deplete GSH and induce an overwhelming level of oxidative stress in cancer cells, leading to mitochondrial disruption, activation of procaspase-3 and PARP-1, and cleavage of Bcl-2. In the study of tumor xenograft models, intravenously injected B2C caused apoptotic cell death in tumors and significantly suppressed tumor growth. These findings provide a new insight into the design of more effective anticancer drugs, which exploit altered redox balance in cancer cells.

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