Lipoprotein Drug Delivery Vehicles for Cancer: Rationale and Reason

Abstract

Lipoproteins are a family of naturally occurring macromolecular complexes consisting amphiphilic apoproteins, phospholipids, and neutral lipids. The physiological role of mammalian plasma lipoproteins is to transport their apolar cargo (primarily cholesterol and triglyceride) to their respective destinations through a highly organized ligand-receptor recognition system. Current day synthetic nanoparticle delivery systems attempt to accomplish this task; however, many only manage to achieve limited results. In recent years, many research labs have employed the use of lipoprotein or lipoprotein-like carriers to transport imaging agents or drugs to tumors. The purpose of this review is to highlight the pharmacologic, clinical, and molecular evidence for utilizing lipoprotein-based formulations and discuss their scientific rationale. To accomplish this task, evidence of dynamic drug interactions with circulating plasma lipoproteins are presented. This is followed by epidemiologic and molecular data describing the association between cholesterol and cancer.

Keywords: cancer imaging; cancer therapy; cholesterol; lipoprotein; nanoparticle.

Figure 1

Frequency of publications on lipoproteins nanoparticles and cancer from 1998 to November 2019 in Pubmed using the search term “lipoprotein”, “nanoparticle”, ”cancer”. Exact search criteria: (“lipoproteins” or “lipoprotein”) and (“nanoparticles” or “nanoparticle”) and (“cancer” or “tumor”).

Figure 2

Typical Structure of Lipoproteins. Lipoprotein particles are made up of an apolipoprotein, a phospholipid monolayer with cholesterol particles intercalated in the membrane surrounding a lipophilic core consisting of TGs and cholesterol derivatives.

Figure 3

Four Quadrant System for Drug Classification. Biopharmaceutics Drug Disposition Classification System as proposed by Wu and Benet [37].

Figure 4

Hazard Ratios of Cholesterol-Cancer Association in Large Cohort Studies. Summary of hazard ratios in various large studies relating cancer and cholesterol. Note that majority of hazard ratio values are close to 1.

Figure 5

Total serum cholesterol levels observed by Miller et al. in colon cancer patients vs. controls. Error bars denote Standard Deviation. p values for paired t-test * = < 0.05, *** = < 0.001. ns = not significant.

Figure 6

Signaling functions of cholesterol and cholesterol derivatives. Cholesterol and its derivatives interact with estrogen related receptors (ERRs), the estrogen receptor (ER), and G-protein coupled receptors (GPCRS) to induce more oncogenic signaling mediated by transcriptional activation of further downstream signaling.

Figure 7

AKT, Master Regulator of Cholesterol Accumulation. AKT plays a central role in receiving signals from various oncogenic drivers (Epidermal Growth Factor Receptor (EGFR), HER2, HER3, HER4, Insulin-like growth factor receptor (IGFR), and mTORC2) and then activating Molecular Target of Rapamycin Complex 1 (mTORC1) which then leads to activation of Sterol Regulatory Binding Protein (SREBPs) that then upregulate cholesterol synthesis and uptake.

Figure 8

Cholesterol Feedback Loop. AKT signaling drives increases in cholesterol biosynthesis and uptake mediated by mTORC1 and SREBPs which leads to increased levels of cholesterol that activates more oncogenic signaling leading to a more aggressive tumor.