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.

Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates

“…Lipoproteins are particularly advantageous for some liver delivery applications due to their high delivery efficiency and specificity (16,17). Recent reports have demonstrated delivery of cholesterol-modified siRNA via lipoprotein-based materials (15,18). Amino acids and peptides are natural building blocks of apolipoproteins, and previous studies have examined the potential of amino acid derivatives for gene delivery or siRNA delivery (19)(20)(21)(22)(23)(24).…”

Synthetic Lipid Nanoparticles Targeting Steroid Organs

“…Accumulation in steroidogenic organs could be accounted for by both the nanometer size and the lipid nature of lipidots, turning them into "chylomicron/VLDL-like" particles after interaction with blood components. Indeed, lipoprotein receptors are overexpressed in adrenals and in the liver (29) and there are structural similarities between lipidots and natural chylomicrons or VLDL, including roughly similar sizes (75-1,200, 30-80, and 55 nm for chylomicrons, VLDL, and lipidots, respectively) and a high shell content in phospholipids (30,31). The surface of natural chylomicrons and VLDL is stabilized by amphophilic apolipoproteins, mainly apolipoprotein B-48 for chylomicrons and apolipoproteins B-100 and E for VLDL, and apolipoproteins are the main plasma proteins that interact with PEGylated solid lipid nanoparticles (32,33).…”

“…Overexpression of lipoprotein receptors by breast, ovarian, and prostate tumors (39) has been used for lipoprotein delivery of drugs and contrast agents for imaging and therapeutic purposes (29,30). Two of the most frequent human carcinomas (breast and prostate) often express high levels of sex steroid receptors, and their proliferative capacity depends on sex steroid hormones (39,40).…”

Lipoprotein Structure and Dynamics: Low Density Lipoprotein Viewed as a Highly Dynamic and Flexible Nanoparticle

“…tumor or atherosclerotic plaque. Once recognized by the receptor, the functionalized LDL particles become internalized, accumulate in the tissue and exert an enhanced effect (reviewed by [65]). The intrinsic targeting properties of LDL to atherosclerotic plaques are already utilized for early diagnosis and detection of atherosclerotic lesions by different imaging modalities (for reviews see refs.…”

“…This is done by covalent attachment of substances to the lysine and cysteine amino acid residues of apo-B100. Such substances include fluorophores, radionuclides or metal ions for molecular imaging [65]. Alternatively, targeting sequences (e.g.…”