Tissue Uptake Mechanisms Involved in the Clearance of Non‐Protein Nanoparticles that Mimic LDL Composition: A Study with Knockout and Transgenic Mice

Abstract

Lipid core nanoparticles (LDE) resembling LDL behave similarly to native LDL when injected in animals or subjects. In contact with plasma, LDE acquires apolipoproteins (apo) E, A-I and C and bind to LDL receptors. LDE can be used to explore LDL metabolism or as a vehicle of drugs directed against tumoral or atherosclerotic sites. The aim was to investigate in knockout (KO) and transgenic mice the plasma clearance and tissue uptake of LDE labeled with H-cholesteryl ether. LDE clearance was lower in LDLR KO and apoE KO mice than in wild type (WT) mice (p< 0.05). However, infusion of human apoE3 into the apoE KO mice increased LDE clearance. LDE clearance was higher in apoA-I KO than in WT. In apoA-I transgenic mice, LDE clearance was lower than in apoA-I KO and than in apoA-I KO infusion with human HDL. Infusion of human HDL into the apoA-I KO mice resulted in higher LDE clearance than in the apoA-I transgenic mice (p < 0.05). In apoA-I KO and apoA-I KO infused human HDL, the liver uptake was greater than in WT animals and apoA-I transgenic animals (p < 0.05). LDE clearance was lower in apoE/A-I KO than in WT. Infusion of human HDL increased LDE clearance in those double KO mice. No difference among the groups in LDE uptake by the tissues occurred. In conclusion, results support LDLR and apoE as the key players for LDE clearance, apoA-I also influences those processes.

Aerobic physical exercise enhances nanoparticle efficacy in prostate cancer treatment

“…In this regard, it had been also showed that in athletes the removal of LDE from the circulation was vefold greater than in sedentary (Vinagre et al 2007). Experiments with LDL KO mice submitted to training showed that LDL receptor overexpression also occurred, which can account for the higher LDE removal (Daminelli et al 2017). In this setting, the present study has two primary objectives: to test the antitumoral action of the taxane LDE-docetaxel in an animal model of prostate cancer and, secondly, to verify whether physical exercise increases the antitumoral action of LDE-docetaxel.…”