Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles

There are very few drug delivery systems that target key organs via the oral route, as oral delivery advances normally address gastrointestinal drug dissolution, permeation, and stability. Here we introduce a nanomedicine in which nanoparticles, while also protecting the drug from gastric degradation, are taken up by the gastrointestinal epithelia and transported to the lung, liver, and spleen, thus selectively enhancing drug bioavailability in these target organs and diminishing kidney exposure (relevant to nephrotoxic drugs). Our work demonstrates, for the first time, that oral particle uptake and translocation to specific organs may be used to achieve a beneficial therapeutic response. We have illustrated this using amphotericin B, a nephrotoxic drug encapsulated within <i>N</i>-palmitoyl-<i>N</i>-methyl-<i>N</i>,<i>N</i>-dimethyl-<i>N</i>,<i>N</i>,<i>N</i>-trimethyl-6-<i>O</i>-glycol chitosan (GCPQ) nanoparticles, and have evidenced our approach in three separate disease states (visceral leishmaniasis, candidiasis, and aspergillosis) using industry standard models of the disease in small animals. The oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral liposomal AmB (AmBisome). Our work thus paves the way for others to use nanoparticles to achieve a specific targeted delivery of drug to key organs via the oral route. This is especially important for drugs with a narrow therapeutic index

Oral Particle Uptake and Organ Targeting Drives the Activity of Amphotericin B Nanoparticles

There are very few drug delivery systems that target key organs via the oral route, as oral delivery advances normally address gastrointestinal drug dissolution, permeation, and stability. Here we introduce a nanomedicine in which nanoparticles, while also protecting the drug from gastric degradation, are taken up by the gastrointestinal epithelia and transported to the lung, liver, and spleen, thus selectively enhancing drug bioavailability in these target organs and diminishing kidney exposure (relevant to nephrotoxic drugs). Our work demonstrates, for the first time, that oral particle uptake and translocation to specific organs may be used to achieve a beneficial therapeutic response. We have illustrated this using amphotericin B, a nephrotoxic drug encapsulated within <i>N</i>-palmitoyl-<i>N</i>-methyl-<i>N</i>,<i>N</i>-dimethyl-<i>N</i>,<i>N</i>,<i>N</i>-trimethyl-6-<i>O</i>-glycol chitosan (GCPQ) nanoparticles, and have evidenced our approach in three separate disease states (visceral leishmaniasis, candidiasis, and aspergillosis) using industry standard models of the disease in small animals. The oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral liposomal AmB (AmBisome). Our work thus paves the way for others to use nanoparticles to achieve a specific targeted delivery of drug to key organs via the oral route. This is especially important for drugs with a narrow therapeutic index

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.

The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p  FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels