Synthetic high-density lipoprotein nanoparticles: Good things in small packages

Abstract

Medicine has been a great beneficiary of the nanotechnology revolution. Nanotechnology involves the synthesis of functional materials with at least one size dimension between 1 and 100 nm. Advances in the field have enabled the synthesis of bio-nanoparticles that can interface with physiological systems to modulate fundamental cellular processes. One example of a diverse acting nanoparticle-based therapeutic is synthetic high-density lipoprotein (HDL) nanoparticles (NP), which have great potential for treating diseases of the ocular surface. Our group has developed a spherical HDL NP using a gold nanoparticle core. HDL NPs: (i) closely mimic the physical and chemical features of natural HDLs; (ii) contain apoA-I; (iii) bind with high-affinity to SR-B1, which is the major receptor through which HDL modulates cell cholesterol metabolism and controls the selective uptake of HDL cargo into cells; (iv) are non-toxic to cells and tissues; and (v) can be chemically engineered to display nearly any surface or core composition desired. With respect to the ocular surface, topical application of HDL NPs accelerates re-epithelization of the cornea following wounding, attenuates inflammation resulting from chemical burns and/or other stresses, and effectively delivers microRNAs with biological activity to corneal cells and tissues. HDL NPs will be the foundation of a new class of topical eye drops with great translational potential and exemplify the impact that nanoparticles can have in medicine.

Keywords: Chemical burn; Cholesterol; Cornea; Eye drop; Inflammation; Lipoprotein; Nanotechnology; Wound healing; microRNA.

Figure 1:. Bioengineered synthetic HDL NPs using inorganic (gold) core scaffold.

Synthesis scheme for HDL NPs made using a 5 nm diameter citrate stabilized gold nanoparticle scaffold (red) surface-functionalized with apoA-I (blue) and a phospholipid layer (tan).

Figure 2:. Therapeutic effect of HDL NPs on wound healing of mouse corneal epithelium.

Corneal images (a) and epithelial corneal wound closure percentage (b) in DIO mouse corneas treated with HDL NPs or control. Green fluorescence represents corneal wound. N=8. *p<0.05. The figure is taken from Junyi Wang et al. with permission [23].

Figure 3:. HDL NP treatment reduces inflammation after alkali burn.

Mice were treated with HDL NPs, control NPs, or PBS (topically) following 30s alkali burns. (a) Representative images. (b). Degree of haze. (c-d). H&E 7 days post burn. N=8. The figure is taken from Junyi Wang et al. with permission [23].

Figure 4:. HDL NP has anti-inflammation activity.

Filter paper (1 mm) soaked in NaOH (1 m) was placed on the corneal surface of 6 week old WT mice for 30 s and then washed extensively with PBS. Corneas were topically treated with HDL NPs, control NPs (inert AuNP core, passivated with polyethyleneglycol (PEG)), or PBS daily for 7 d. Whole corneal tissues were dissected and total RNAs were isolated for RT-qPCR for inflammation-related genes at post injury day 1, 3, and 7 (N = 8). *p < 0.05. Unpaired t-tests were conducted. The figure is taken from Junyi Wang etal. with permission [23].

Figure 5:. Bioengineered synthetic HDL NPs using organic (PL4 and DNA-PL4) core scaffold.

Organic tetrahedral phospholipid (PL4) or PL4 with bioprogrammable DNA “arms” (DNA-PL4) are used as scaffolds for ocHDL NPs. Synthesis of ocHDL NPs made using organic scaffolds proceeds similar to the ones made using AuNPs.

Figure 6:. High-Density Lipoprotein Nanoparticle Eye Drop