RESUMEN
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.
Asunto(s)
Portadores de Fármacos/química , Ensayos Analíticos de Alto Rendimiento/métodos , Nanopartículas/química , Sorafenib/farmacología , Terbinafina/farmacología , Animales , Candida albicans/efectos de los fármacos , Simulación por Computador , Portadores de Fármacos/síntesis química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Dispersión Dinámica de Luz , Excipientes/química , Femenino , Ácido Glicirrínico/química , Humanos , Aprendizaje Automático , Ratones Endogámicos , Absorción Cutánea , Sorafenib/química , Sorafenib/farmacocinética , Ácido Taurocólico/química , Terbinafina/química , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
There are major structural differences between plant and mammalian N-linked glycans, with those from plants being immunogenic in most laboratory mammals and eliciting glycan-specific IgE and IgG antibodies in humans, when delivered parenterally. However, because humans are constantly exposed to plant glycoproteins in the diet, glycosylated plant-made pharmaceuticals (PMPs) should be acceptable for topical and oral administration. To exploit fully the potential that plants offer for the production of therapeutic proteins for parenteral administration, it might be necessary to inhibit plant-specific post-translational modifications to obtain "humanized" non-immunogenic N-glycans on PMPs. The benefits that could accrue are lower manufacturing costs, relative to mammalian cell culture, and a reduced risk of transmission of mammalian pathogens.