RESUMO
Implant-associated infections present severe and difficult-to-treat complications after surgery, related to implant biofilm colonization. Systemic administration of antibiotics cannot reach sufficient concentrations at the infected site and may be toxic. Here we describe how mussel-inspired dendritic material coated on a titanium surface can locally activate a prodrug of daptomycin (pro-dapto) to treat methicillin-resistant Staphylococcus aureus. The mechanism of the prodrug activation is based on bio-orthogonal click chemistry between a tetrazine (Tz) and trans-cyclooctene (TCO). The former is attached to the dendritic polymer, while the later converts daptomycin into a prodrug. Characterization of the material's properties revealed that it is hydrophobic, non-toxic, and stable for a prolonged period of time. We envision that the titanium coated dendritic material will be able to improve the treatment of implant-associated infections by concentrating systemically administered antibiotic prodrugs, thus converting them into active localized medicines.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes , Materiais Revestidos Biocompatíveis/farmacologia , Humanos , Polímeros , Infecções Estafilocócicas/tratamento farmacológico , Titânio/farmacologiaRESUMO
A systematic study of N(4) amino PEG-prodrugs of ara-C (1) was conducted and provided a series of disubstituted amides, as well as a carbamate derivative. These conjugates showed hydrolysis half lives in rat plasma from about 1 h to 3 days, but were stable for >24 h in phosphate buffer, pH 7.4. In an LX-1 solid lung tumor model some of the PEG prodrugs exhibited superior activity to ara-C when compared on a molar basis. One problematic issue that was identified in this investigation was the need to increase the loading of ara-C onto PEG in order to avoid highly viscous solutions.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Citarabina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antimetabólitos Antineoplásicos/química , Citarabina/química , Sistemas de Liberação de Medicamentos/estatística & dados numéricos , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Leucemia P388/tratamento farmacológico , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Polietilenoglicóis/química , Pró-Fármacos/química , Solventes/administração & dosagem , Solventes/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/estatística & dados numéricosRESUMO
The synthesis of branched PEG (40,000) acids has been achieved using aspartic acid (Asp) and AspAsp dendrons. Complete conjugation of these dendritic acids with cytosine arabinoside (ara-C) was achieved by the use of spacers that allowed a greater separation of the branches to accommodate several large ara-C molecules in proximity to each other. The tetrameric and octameric PEG-ara-C amide prodrugs were much more effective in the treatment of solid and ascites tumors compared to the native drug. The greater loading of the PEG backbone appears to have achieved a minimum threshold concentration for the therapeutic delivery of ara-C.