(165g) Mouse Obesity Increases Peg-Based Micelle Liver Uptake and Decreases Lipid Nanoparticle Liver Uptake through the Modified Activity of Kupffer Cells and Lsecs

Understanding the mammalian response to nanoparticles (NPs) in an obesity environment is an unmet crucial need in nanomedicine since more than two-thirds of adults in the U.S. are overweight to obese. Thus, patients that will be treated with nanoparticles (NPs) will have non-alcoholic fatty liver disease (NAFLD) and chronic inflammation. Yet, NP pharmacokinetics (PKs) and toxicity (TOX) are determined in lean rodents with healthy livers and low inflammation. Thus, we have little understanding of how NPs will behave in a metabolically realistic environment. To bridge this knowledge gap, we determined the PK and TOX of PEG-based cylindrical nanoparticles (CNPs) and lipid-based nanoparticles (LNPs) as a function of diet- and genetic-induced obesity in ob/ob and wild-type mice. In PK studies, CNPs localized to fatty livers in ob/ob mice on a high-fat diet (HFD) more quickly than to healthy livers in ob/ob mice on a restricted low-fat diet (LFD). The PKs of LNP liver signal are greatly affected by mouse weight. LNP liver signal peaks 6 hours post-injection in lean mice, 24 hours post-injection in heavy mice, and 48 hours post-injection in obese mice. We next aimed to determine the reasons for these observations. In lean mice, most NPs rapidly localize to Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs) after intravenous injection. But the distribution of NPs between these liver cells is unknown in both lean and obese mice. In lean mice, clodronate liposome-induced-depletion of KCs decreased both CNP and LNP liver localization, with a much stronger reduction in CNP localization. MCT-induced depletion of LSECs increased CNP liver localization and decreased LNP liver localization. This suggests that CNPs interact more strongly with KCs than LSECs and that LNPs interact with both KCs and LSECs. These experiments were not possible in obese mice because of lethality. To determine why CNP localization to fatty livers is higher than to lean livers, we focused on the expression of SR-BI, which binds CNPs and causes CNP cellular uptake. SR-BI liver expression was increased in ob/ob mice fed a HFD. SR-BI was also increased in RAW 264.7 murine macrophages cultured in HFD conditions in vitro. On the other hand, in vitro experiments showed that SR-BI does not appear to be important for CNP uptake by LSECs. Also, oleic acid (a model fatty acid) decreased the uptake up of CNPs by LSECs in vitro by 100-fold. Conversely, oleic acid increased the uptake up of CNPs by macrophages in vitro. To determine if obesity-driven inflammation played an additional role in CNP and LNP liver localization, we administered the leaky-gut endotoxin lipopolysaccharide (LPS) to wild-type mice on a LFD. LPS triggers inflammation in obese mammals. LPS increased the liver localization of CNPs but decreased the liver localization of LNPs. Therefore, LPS-induced inflammation plays a role in the increased CNP localization to the liver. CNPs and LNPs reduced most cytokine and chemokine levels that were elevated in obese ob/ob mice. Interestingly, CNPs and LNPs greatly increased IL-5 levels which promotes the survival, differentiation, and chemotaxis of eosinophils.