Evaluation of the interplay between biomimetic high-density lipoproteins for drug delivery and the biological system

Abstract

In the past decades, nanomedicine has shown potential to revolutionize conventional medicines. Yet, the potential remains to be fully exploited, as only relatively few of the studied nanomedicines have reached the clinic. To harness the full potential of nanoparticle-based nanomedicines, many researchers stress that fundamental insight into the interplay between the nanoparticles and the biological system is essential. Furthermore, biomimicking nanoparticles have been proposed as promising drug delivery vehicles due to their high biocompatibility, biodegradability, and their possibility to utilize biological interactions. One of these biomimicking nanoparticles is the biomimetic high-density lipoproteins (b-HDL), which are nanosized particles that mimic the endogenous HDL. They consist of lipids and a stabilizing apolipoprotein-based scaffold. The endogenous HDL are natural lipid transporters, and several of the receptors that can recognize and mediate uptake of HDL cargo are expressed on various cells, including both cancer cells and immune cells. This has inspired many researchers to apply b-HDL for drug delivery. To aid the advancement of the b-HDL drug delivery field, this PhD project has been concerned with fundamental characterization of the interplay between b-HDL and the biological system. We show that the b-HDL lipids can desorb from the b-HDL to endogenous lipoproteins in biological environments via an enzyme-independent mechanism only requiring direct interaction with the lipoproteins. Importantly, it is possible to minimize this spontaneous lipid desorption through b-HDL design. We also found that part of the b-HDL can be taken up by circulating leukocytes in human whole blood with a preference towards monocytes, which is likely due to their expression of scavenger receptor class B type I (SR-BI), an important HDL receptor. Still, the majority of b-HDL will likely circulate for an extended period of time. We show through a systematic review that irrespective of the particular design of apolipoprotein A-I-based b-HDL, the b-HDL lipids primarily accumulate in the liver and tumor, whereas the b-HDL scaffold primarily accumulate in the kidneys, liver and tumor. This highlights that the b-HDL components can have different biological fates. We confirmed the relatively high tumor accumulation of b-HDL through in vivo studies. Furthermore, we show that b-HDL can penetrate tumors well and that b-HDL cargo can be internalized efficiently into SR-BI expressing cells through a SR-BI dependent mechanism. This PhD thesis shed light on the dynamic nature of the b-HDL, and present methods that can be widely applied to study the interplay between nanoparticles and the biological system. The insight gained from the project lay groundwork for advancement of the b-HDL drug delivery platform towards clinical translation.