Abstract
Nanomedicine rests at the nexus of medicine, bioengineering, and biology with great potential for improving health through innovation and development of new drugs and devices. Carbon nanotubes are an example of a fibrillar nanomaterial poised to translate into medical practice. The leading candidate material in this class is ammonium-functionalized carbon nanotubes (fCNT) that exhibits unexpected pharmacological behavior in vivo with important biotechnology applications. Here, we provide a multi-organ evaluation of the distribution, uptake and processing of fCNT in nonhuman primates using quantitative whole body positron emission tomography (PET), compartmental modeling of pharmacokinetic data, serum biomarkers and ex vivo pathology investigation. Kidney and liver are the two major organ systems that accumulate and excrete [86Y]fCNT in nonhuman primates and accumulation is cell specific as described by compartmental modeling analyses of the quantitative PET data. A serial two-compartment model explains renal processing of tracer-labeled fCNT; hepatic data fits a parallel two-compartment model. These modeling data also reveal significant elimination of the injected activity (>99.8%) from the primate within 3 days (t1/2 = 11.9 hours). These favorable results in nonhuman primates provide important insight to the fate of fCNT in vivo and pave the way to further engineering design considerations for sophisticated nanomedicines to aid late stage development and clinical use in man.
Highlights
Nanomaterial medicines, which exist at the interface between matter and life, continue to hold great promise to deliver improvements in patient care
The input function was derived from the dynamic positron emission tomography (PET) images by calculating the mean radioactivity concentration within a volumes of interest (VOI) placed over the heart
CryoTEM images of functionalized carbon nanotubes (fCNT) in water (100 μg/L) revealed the fibrillar nature of this material in solution (Fig 1B). fCNT was functionalized with the metal-ion chelate 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) in order to tracer radiolabel with the positron-emitting yttrium-86 (86Y; t1/2 = 14.7 h)
Summary
Nanomaterial medicines, which exist at the interface between matter and life, continue to hold great promise to deliver improvements in patient care. Rodents are widely used to investigate novel materials, larger models that more closely parallel human physiology are required to predict translational success and move a field forward. Ammonium-functionalized carbon nanotubes have been investigated in rodent models with description of rapid renal clearance and biocompatibility by several different groups that strongly suggest that this embodiment of a water-soluble cylindrical graphene offers a number of distinct advantages for drug delivery [4,5,6,7,8,9,10,11,12,13,14]. Our data in nonhuman primates reveals that this fibrillar nanocarbon derivative is safe, biocompatible and favorably predicts a pharmacology suitable for translation to man
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