Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a case study with the anticancer agent SNX-2112

Abstract

Introduction SNX-2112 is a promising anticancer agent but has poor solubility in both water and oil. In the study reported here, we aimed to develop a nanocrystal formulation for SNX-2112 and to determine the pharmacokinetic behaviors of the prepared nanocrystals. Methods Nanocrystals of SNX-2112 were prepared using the wet-media milling technique and characterized by particle size, differential scanning calorimetry, drug release, etc. Physiologically based pharmacokinetic (PBPK) modeling was undertaken to evaluate the drug’s disposition in rats following administration of drug cosolvent or nanocrystals. Results The optimized SNX-2112 nanocrystals (with poloxamer 188 as the stabilizer) were 203 nm in size with a zeta potential of −11.6 mV. In addition, the nanocrystals showed a comparable release profile to the control (drug cosolvent). Further, the rat PBPK model incorporating the parameters of particulate uptake (into the liver and spleen) and of in vivo drug release was well fitted to the experimental data following administration of the drug nanocrystals. The results reveal that the nanocrystals rapidly released drug molecules in vivo, accounting for their cosolvent-like pharmacokinetic behaviors. Due to particulate uptake, drug accumulation in the liver and spleen was significant at the initial time points (within 1 hour). Conclusion The nanocrystals should be a good choice for the systemic delivery of the poorly soluble drug SNX-2112. Also, our study contributes to an improved understanding of the in vivo fate of nanocrystals.

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“…The surface potential of GO prior to and following the loading of FA and SNX-2112 was then investigated (Figure D). The potential of GO increased after loading of FA, whereas the surface electronegativity of GFS decreased because of the introduction of SNX-2112 that had a negative zeta potential …”

Physiologically Based Pharmacokinetic Modeling of Nanoparticles

“…Another dual PBPK model was developed by Dong et al to characterize the distribution and in vivo drug release of a nanocrystal formulation of the anticancer agent SNX-2112 (203 nm, −11.6 mV) in rats after IV administration. 22 A two-step strategy was employed. First, a generic perfusion-limited PBPK model was developed for the non-particulate drug using the PK data of a cosolvent formulation (a small molecule formulation) in rats.…”

“…When combined with pharmacodynamic (PD) models relating exposure at target tissues to pharmacological effects, PBPK modeling can be used to predict efficacy and toxicity. 16 PBPK models have been applied for many types of nanoparticles, including carbon nanoparticles, 19 polymeric nanoparticles, 20,21 , nanocrystals, 22–26 silver nanoparticles, 27–29 liposomes, 30,31 gold/dendrimer composite nanoparticles, 32 and others. 33…”

Current Approaches and Techniques in Physiologically Based Pharmacokinetic (PBPK) Modelling of Nanomaterials

“…Phagocytosed NMs are exposed to various enzymes, reactive oxygen species (ROS) and acidic environments. With some exceptions, such as PBPK models for TiO 2 NPs [19] and the anticancer agent SNX-2112 [26], recent PBPK models generally included phagocytosis by the MPS system, while older PBPK models did not [6,10,25]. Those examples of models that included the MPS [8,11,17,22,24,34,56,75] divided each of the selected compartments/organs into sub-compartments of blood, tissue and phagocytic cells of the MPS.…”

“…These additional factors have been included in the development of various PBPK models for inorganic NMs such as quantum dots (QDs) [6][7][8], carbon based NMs [9], metal based NMs including silver (Ag) [10][11][12], gold (Au) [13][14][15][16], metal oxides such as titanium dioxide (TiO 2 ) [17][18][19][20], cerium dioxide (CeO 2 ) [16,21,22] and zinc oxide (ZnO) [23]. PBPK models have also been developed for polymeric NMs such as polyacrylamide (PAA) [24], poly(lactic-co-glycolic) acid (PLGA) [25], the anticancer agent SNX-2112 [26] and other polymers [27,28]. Differences exist in the approaches and techniques for developing these PBPK models.…”