Lipoprotein-inspired nanoparticles for cancer theranostics

Abstract

Over hundreds of millions of years, animals have evolved endogenous lipoprotein nanoparticles for shuttling hydrophobic molecules to different parts of the body. In the last 70 years, scientists have developed an understanding of lipoprotein function, often in relationship to lipid transport and heart disease. Such biocompatible, lipid-protein complexes are also ideal for loading and delivering cancer therapeutic and diagnostic agents, which means that lipoprotein and lipoprotein-inspired nanoparticles also offer opportunities for cancer theranostics. By mimicking the endogenous shape and structure of lipoproteins, the nanocarrier can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body's defenses. The small size (less than 30 nm) of the low-density (LDL) and high-density (HDL) classes of lipoproteins allows them to maneuver deeply into tumors. Furthermore, lipoproteins can be targeted to their endogenous receptors, when those are implicated in cancer, or to other cancer receptors. In this Account, we review the field of lipoprotein-inspired nanoparticles related to the delivery of cancer imaging and therapy agents. LDL has innate cancer targeting potential and has been used to incorporate diverse hydrophobic molecules and deliver them to tumors. Nature's method of rerouting LDL in atherosclerosis provides a strategy to extend the cancer targeting potential of lipoproteins beyond its narrow purview. Although LDL has shown promise as a drug nanocarrier for cancer imaging and therapy, increasing evidence indicates that HDL, the smallest lipoprotein, may also be of use for drug targeting and uptake into cancer cells. We also discuss how synthetic HDL-like nanoparticles, which do not include human or recombinant proteins, can deliver molecules directly to the cytoplasm of certain cancer cells, effectively bypassing the endosomal compartment. This strategy could allow HDL-like nanoparticles to be used to deliver drugs that have increased activity in the cytoplasm. Lipoprotein nanoparticles have evolved to be ideal delivery vehicles, and because of that specialized function, they have the potential to improve cancer theranostics.

Figure 1

Key discoveries and theranostic advances in lipoprotein cancer research.

Figure 2

Examples of drugs, imaging agents, and targeting ligands incorporated into different locations of lipoprotein-like nanoparticles.

Figure 3

(a) Gamma scintigraphy image of mouse bearing B-16 melanoma tumor upon uptake of ^99mTc-labeled LDL (ref (17)). (b) Magnetic resonance imaging of mouse xenograft (ref (20)). (c) Optical imaging of cancer tumor. (d) Demonstrated uptake of LDL loaded with CT contrast in HepG2 cancer cells (ref (25)). Panels a, b, and d are reproduced with permission from the corresponding references.

Figure 4

(a) Schematic diagram showing the process of rerouting lipoproteins to new cancer targets. (b) Whole body fluorescence image showing folate-modified LDL uptake in FR-positive and negative cell lines (ref (24)). (c) Rerouting of HDL nanoparticles from SR-BI to the FR (ref (35)). Panels b and c are reproduced with permission from their corresponding references.

Figure 5

(a) Optical imaging of a SR-BI expressing cancer tumor using HDL nanoparticles loaded with NIR fluorescent photosensitizer bacteriochlorin e₆ bisoleate (ref (40)). (b) Fluorophore-loaded HDL (red) showing distribution to GFP-expressing tumor (green) through the bloodstream (cyan). Figure 5A is reproduced with permission from the corresponding reference.

Figure 6

(a) Structural comparison between discoidal and spherical structure generated using ApoA-1 (first row) (ref (36)) or 4F phospholipid (second row) (ref (49)). (b) Schematic diagram illustrating transfer of HPPS core components to cells through a nonendocytic pathway (ref (49)). (c) Cytosolic delivery of HPPS (ref (50)). (d) Drug shielding and targeting of paclitaxel oleate-loaded HPPS. (e) Delivery of bcl-2 targeting siRNA to cancer cells imaged using confocal microscopy along with analysis of protein expression in treated versus untreated groups (ref (53)). Panels a, b, c and e are reproduced with permission from their corresponding references.