RESUMO
This study investigates the capability of methylmethacrylate-sulfopropylmethacrylate (MMA-SPM) nanoparticles (NPs) with grafted RMP-7 (RMP-7/MMA-SPM NPs) to deliver stavudine (D4T), delavirdine (DLV), and saquinavir (SQV) across the blood-brain barrier (BBB). The permeability coefficients of the three drugs across the BBB were evaluated by a co-culture model containing human brain-microvascular endothelial cells and human astrocytes. An increase in the concentration of ammonium persulfate (APS), the polymerization initiator, enhanced the particle size of drug-loaded RMP-7/MMA-SPM NPs. When the concentration of APS was 0.6%, the average particle diameter was smaller than 50 nm. These spherical drug carriers were uniform in size and displayed a dominant topography of discrete hillocks and deep pits in deposited film. Smaller RMP-7/MMA-SPM NPs yielded a larger drug loading efficiency. The order of drug in the loading efficiency and in the particle uptake was, respectively, D4T>DLV>SQV and D4T>SQV>DLV. Endocytosis of RMP-7/MMA-SPM NPs and tight junction mediation can improve the permeability of D4T, DLV, and SQV across the BBB.
Assuntos
Fármacos Anti-HIV/metabolismo , Bradicinina/análogos & derivados , Portadores de Fármacos/química , Infecções por HIV/tratamento farmacológico , Metacrilatos/química , Terapia de Alvo Molecular/métodos , Sulfato de Amônio/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Astrócitos/citologia , Astrócitos/metabolismo , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Bradicinina/química , Bradicinina/metabolismo , Células Cultivadas , Técnicas de Cocultura , Delavirdina/química , Delavirdina/metabolismo , Delavirdina/farmacologia , Portadores de Fármacos/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , HIV/efeitos dos fármacos , HIV/fisiologia , Infecções por HIV/sangue , Infecções por HIV/patologia , Humanos , Cinética , Metacrilatos/metabolismo , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Permeabilidade , Saquinavir/química , Saquinavir/metabolismo , Saquinavir/farmacologia , Estavudina/química , Estavudina/metabolismo , Estavudina/farmacologiaRESUMO
Cost and toxicity problems associated with highly active antiretroviral therapy (HAART) in HIV/AIDS treatment could be alleviated by using designed multiple ligands (DMLs). Dual inhibitors of HIV reverse transcriptase (RT) and integrase (IN) were rationally designed by introducing a diketoacid (DKA) functionality into the tolerant C-5 site of RT inhibitor delavirdine. The resulting compounds all demonstrate good activity against both RT and IN in enzymatic assays and HIV in cell-based assay, whereas their C-7 regioisomers are all inactive in these assays. Balanced activities were observed with C-3 halogenated inhibitors.