RESUMO
Photodynamic therapy (PDT) is strongly O2 dependent. Therefore, its therapeutic effects are seriously hindered in hypoxic tumors. Red blood cells are responsible for delivering O2 in the blood. In this manuscript, biomimetic red blood cells (BRBCs) were exploited using a layer-by-layer assembly method, using Fe3O4@CuO, oxyhemoglobin (OxyHb), a photosensitizer and a photo-cross linked acrylate modified hyaluronic acid (HA) gel shell. The Fe3O4@CuO core has very high OxyHb loading efficiency (the adsorption capacity of Fe3O4@CuO for OxyHb is derived to be 0.99 mg mg-1) to ensure a sufficient O2 supply. OxyHb was protected well by the HA shell in order to avoid O2 release during the delivery process in blood before arrival at the tumor tissue. The HA shell protection can be eliminated in position at the tumor to trigger O2 release through hyaluronidase (HAase) triggered HA degradation. Furthermore, Fe3O4 in the nanosystem can provide magnetic field assisted tumor targeting and magnetic resonance imaging of the tumor. Therefore, this work presents a highly efficient all-in-one biomimetic nanomedicine approach to overcome hypoxia and achieve tumor targeting theranostics.
Assuntos
Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Oxiemoglobinas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Proliferação de Células/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Ácido Hialurônico/química , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanomedicina , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oxigênio/metabolismo , Oxiemoglobinas/síntese química , Oxiemoglobinas/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/químicaRESUMO
The propensity of site-specific carboxymethylation and propylation of Val-1(α) of Hb to attenuate the reductive hexaPEGylation-induced dissociation of tetramers has been investigated. Only reductive propylation of Val-1(α), which increases the stability of oxy Hb, attenuates the reductive hexaPEGylation-induced dissociation. Increasing the stability of the oxy conformation of Hb by chemical or genetic approaches is a strategy to generate PEGylated Hbs with native-like tetramer stability using direct PEGylation platforms. This new approach and EAF-PEGylation are the only two alternate PEGylation strategies available to design stable second-generation vasoinactive uncrosslinked PEGylated Hbs with native-like tetramer stability.
Assuntos
Aldeídos/química , Cromatografia Líquida de Alta Pressão/métodos , Glioxilatos/química , Oxigênio/química , Oxiemoglobinas/química , Valina/química , Regulação Alostérica , Cromatografia em Gel/métodos , Oxigênio/metabolismo , Oxiemoglobinas/síntese química , Oxiemoglobinas/metabolismo , Polietilenoglicóis/química , Polímeros/química , Estabilidade Proteica , Estrutura Quaternária de Proteína , Valina/metabolismoRESUMO
The mode of hemoglobin oxidation by ferricytochrome c and nitrite was investigated by using isoelectric focus electrophoresis on Ampholine plate gel. It was found that two intermediate hemoglobins, (alpha 2 + beta 3 +)2 and (alpha 3 + beta 2 +)2 valency hybrids, were produced during the reactions, though the modes of these reactions were quite different from each other. The changes in oxyhemoglobin, (alpha 2 + beta 3 +)2, (alpha 3 + beta 2 +)2 and methemoglobin during the oxidation of hemoglobin by ferricytochrome c well fit first order kinetics. On the other hand, the changes in these hemoglobin derivatives during nitrite oxidation of hemoglobin did not fit first order kinetics, but instead were appropriate for the chain reaction models proposed by us. Since we found that superoxide anion may be involved in the reaction of hemoglobin with nitrite, a plausible reaction process was proposed. The differences in the reaction mechanism of hemoglobin oxidation by ferricytochrome c and by nitrite are discussed.
