The Use of High-Density Lipoprotein Nanoparticles to treat Cancer and Heart Disease

Natural high-density lipoproteins (HDL) are proteins that interact with cell receptors, enzymes, and other proteins, and they vary from 7 to 13 nanometers in diameter. They are considered dynamic as they are continually remodeled in the bloodstream as they interact with the substances mentioned above. Scientists have been able to create synthetic HDL-like nanoparticles (HDL-NPs) that are customizable, allowing them to control aspects of the nanoparticle such as structure and composition, which gives these HDL-NPs their own special functions.

A natural high density lipoprotein

In cancer, lipoproteins deliver cholesterol to malignant cells. HDLs have anti-inflammatory, anti-oxidant, anti-microbial, and pro-immunity properties that are key to the survival of tumor cells. But by loading HDL-NPs with cancer drugs, researchers can target cancer cells by preferentially allowing the therapeutic to accumulate in the malignant tumor cells and avoiding non-specific accumulation in healthy cells. This improves the therapeutic index of the drug, or how safe it is, while reducing the side effects caused by undesired drug delivery to healthy cells.

Similar to what was discussed in class about nanoparticle targeting and cell penetration, HDL-NPs target cancers cells by passive and active targeting mechanisms. Passive targeting is achieved because tumor tissues have leaky vasculature and low lymphatic drainage, which leads to an interstitial pressure gradient between the tumor’s center and its surroundings. This allows preferential accumulation of particles between 10-100 nm in the tumor, an effect known as the enhance permeability and retention (EPR) effect, which we learned about in class.

Active targeting of HDL-NPs occurs as the nanoparticles interact with scavenger receptor type B-1 (SR-B1) which is known to be over-expressed in malignant tumor cells. SR-B1 interactions allow the uptake of anticancer drugs from loaded HDL-NPs to the cytosol via a non-endocytic pathway, which allows the NPs to escape lysosomal degradation, a key property of useful nanoparticles as we learned in class. If NPs are degraded before they can do what they are meant to do, they have little use of course. Specifically, HDL-NP interaction with SR-B1 causes the NP to dissociate while the hydrophobic drug is internalized by a lipid-raft similar to the caveolae-mediated endocytosis mechanism mentioned in class.

HDL-NPs also have great use in treating atherosclerosis, a lipid-driven inflammatory disease that is the cause for many cardiovascular problems. In vitro and in vivo studies have shown that HDLs reduce the expression of endothelial adhesion molecules and stop the recruitment of monocytes to artery walls. Additionally, 3-Hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, known as statins, block the mevalonate pathway which is responsible for the attachment of small guanosine triphosphatases and their role in stimulating cell proliferation. Researchers from the Mulder group tested using HDL-NPs loaded with the HMG-CoA reductase inhibitor simvastatin to block macrophages accumulation to prevent the inflammation that progresses atherosclerotic plaques.

The authors tested their simvastatin-loaded HDL-NPs (s-HDL-NPs) on five experimental mice groups. All the mice were given a high cholesterol diet which induced atherosclerosis. The control group (“Control”) received no treatment. The next group received 9 weeks of oral statin (“Oral Statin”) which mimics the current standard of care for atherosclerosis. The third group went on a two-step treatment regimen which received 1-week high-dose s-HDL-NPs followed by eight weeks of oral statin (“Hi + Oral”). The fourth group received only 1-week high-dose of s-HDL-NPs without any treatment afterwards for 8 weeks (“Hi + No”). The final group, the positive control, received one week of high-dose s-HDL-NPs, then eight weeks of low-dose s-HDL-NPs (“Positive”).

The authors then used anti-CD68 immunostaining to track macrophage levels over the 9 weeks of treatments. They found that the groups that received the initial 1-week of high-dose s-HDL-NPs had 65% fewer macrophages than the control group and 60% fewer than the oral statin group. The groups that received 8-weeks of oral statin treatment kept low macrophage levels and resulted in 33% lower macrophage levels than the control group.  The effects of only oral statin treatment, the control group, only showed up after 5 weeks. Finally, after 9 weeks, the macrophage levels of the control group matched the two-step regiment groups.

From figure 5 of the Mulder paper. 1 week of high dose s-HDL-NPs reduced macrophage levels quicker than oral statin treatment.

The results show that early treatment of high-dose s-HDL-NPs reduces proliferation of macrophages and the 8 weeks of oral statin maintains these low levels, without any signs of toxicity. The high dose treatment of nanoparticles acts quicker than oral statin because it both specifically targets atherosclerosis plaque macrophages and avoids early elimination. This shows the benefit of a nanoparticle-based drug delivery system in treating diseases such as atherosclerosis. In the future it would be fascinating to see clinical trials to see if targeting is just as effective and if there are any cytotoxic effects.

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418545/

Mulder paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539616/

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