Lipoproteins and lipoprotein mimetics for imaging and drug delivery

Abstract

Lipoproteins are a set of natural nanoparticles whose main role is the transport of fats within the body. While much work has been done to develop synthetic nanocarriers to deliver drugs or contrast media, natural nanoparticles such as lipoproteins represent appealing alternatives. Lipoproteins are biocompatible, biodegradable, non-immunogenic and are naturally targeted to some disease sites. Lipoproteins can be modified to act as contrast agents in many ways, such as by insertion of gold cores to provide contrast for computed tomography. They can be loaded with drugs, nucleic acids, photosensitizers or boron to act as therapeutics. Attachment of ligands can re-route lipoproteins to new targets. These attributes render lipoproteins attractive and versatile delivery vehicles. In this review we will provide background on lipoproteins, then survey their roles as contrast agents, in drug and nucleic acid delivery, as well as in photodynamic therapy and boron neutron capture therapy.

Keywords: Computed tomography; Drug delivery; Fluorescence imaging; High-density lipoprotein; Low-density lipoprotein; MRI; Photodynamic therapy; siRNA.

Figure 1

Schematic depiction of the different lipoproteins, indicating their different compositions (not to scale). Figure reproduced with permission from reference [50].

Figure 2

Illustration of the numerous ways in which lipoproteins can be modified to act as contrast agents, therapeutics, or both. Multiple of these modifications can be made on the same platform, e.g. inclusion of a targeting ligand and a fluorophore.[43]

Figure 3

HDL-based nanoparticle active for PET, NIRF and photodynamic therapy. A) Schematic depiction of the HDL-based nanoparticle. B) Negative stain TEM characterization of the nanoparticles (scale bars are 100 and 20 nm in the larger view and inset, respectively). C) Analysis of photodynamic therapy effects on glioma tumors (PLP is the term for the nanoparticle). D) PET imaging of prostate cancer. E) Fluorescence molecular tomography of prostate cancer. F) Interoperative imaging aiding prostate cancer resection i) before and ii) after resection. Figure reproduced with permission from reference [120].

Figure 4

Gold-core LDL (Au-LDL) as a contrast agent for computed tomography. A) Schematic depiction of Au-LDL. B–D) Negative stain TEM images of lipid-coated gold nanoparticles (Au-MHPC), LDL and Au-LDL. E–G) Fluorescence microscopy images of B16-F10 cells that have been incubated with various agents. H) Gold content of blood of wild type (WT) and LDL receptor knockout (LDLr KO) mice injected with Au-LDL. I, J) Spectral CT images of a mouse bearing a B16-F10 tumor. Bones are denoted in grayscale and gold is given a yellow color. This figure is reproduced with permission from reference [39].

Figure 5

Statin loaded HDL as a therapeutic in atherosclerosis. A) Schematic depictions of statin loaded HDL, as well as TEM characterization. B) MR imaging of the aorta of an atherosclerotic mouse pre- and 24 hours post-injection with [Gd-dye-S]-rHDL. C) Fluorescence imaging of the excised aortas of atherosclerotic mice that had been injected with either saline or [Gd-dye-S]-rHDL 24 hours previously. D) Histology of the aorta roots of atherosclerotic mice. E,F) Quantitative analysis of histology images. Figure reproduced with permission from reference [44].

Figure 6

Gold core HDL for DNA delivery. A) Schematic depiction of gold core HDL. B) Results from an LDH assay showing that the formulation is biocompatible. C) Suppression of miR-210 by DNA-HDL conjugates. D) Western blot of E2F3a (an miR-210 target) levels. Figure reproduced with permission from reference [92].