RESUMO
Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib-glycyrrhizin and terbinafine-taurocholic acid both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug-loading capacities for a wide range of therapeutics.
Assuntos
Portadores de Fármacos/química , Ensaios de Triagem em Larga Escala/métodos , Nanopartículas/química , Sorafenibe/farmacologia , Terbinafina/farmacologia , Animais , Candida albicans/efeitos dos fármacos , Simulação por Computador , Portadores de Fármacos/síntese química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Difusão Dinâmica da Luz , Excipientes/química , Feminino , Ácido Glicirrízico/química , Humanos , Aprendizado de Máquina , Camundongos Endogâmicos , Absorção Cutânea , Sorafenibe/química , Sorafenibe/farmacocinética , Ácido Taurocólico/química , Terbinafina/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
For recombinant production of squalene, which is a triterpenoid compound with increasing industrial applications, in microorganisms generally recognized as safe, we screened Saccharomyces cerevisiae strains to determine their suitability. A strong strain dependence was observed in squalene productivity among Saccharomyces cerevisiae strains upon overexpression of genes important for isoprenoid biosynthesis. In particular, a high level of squalene production (400 ± 45 mg/L) was obtained in shake flasks with the Y2805 strain overexpressing genes encoding a bacterial farnesyl diphosphate synthase (ispA) and a truncated form of hydroxyl-3-methylglutaryl-CoA reductase (tHMG1). Partial inhibition of squalene epoxidase by terbinafine further increased squalene production by up to 1.9-fold (756 ± 36 mg/L). Furthermore, squalene production of 2011 ± 75 or 1026 ± 37 mg/L was obtained from 5-L fed-batch fermentations in the presence or absence of terbinafine supplementation, respectively. These results suggest that the Y2805 strain has potential as a new alternative source of squalene production.