Re‐polarization of tumor‐associated macrophages via reconstituted high‐density lipoprotein nanoparticles

Abstract

Phenotypic plasticity of macrophages allows them to assume different functional profiles as they are called upon to respond to biological events. For example, the M1 phenotype of macrophage potentiates pro‐inflammatory and anti‐tumoral properties whereas the M2 phenotype is associated with immuno‐regulatory, tissue repair and pro‐tumoral properties. Tumor‐associated macrophages (TAMs) initially present anti‐tumoral behaviors via their “M1” phenotype. Under the stimulation of factors secreted by the malignant tumor, TAMs progressively take on a pro‐tumoral role via polarization to an “M2” phenotype. The M2 phenotype which supports immune‐dampening activities helps sustain tumor proliferation, immune system evasion, angiogenesis, tissue invasion and metastasis. TAMs, thus, make attractive targets for an anti‐cancer immunotherapy strategy. Considering the whole‐body distribution of macrophages, and their critical role in immune response, we propose to pursue the repolarization of M2‐type macrophages in the tumor microenvironment toward an M1 phenotype, utilizing a targeted drug delivery carrier.Lipoproteins are natural transporters of hydrophobic substances in the blood, including lipids, hormones and drugs. Our lab developed a biocompatible reconstituted high‐density lipoprotein (rHDL) nanoparticle with properties highly similar to the native HDL. Dynamic light scattering analysis and transmission electron micrographs have confirmed a sub‐50 nm size for our particles and a spherical shape. In addition to siRNA molecules, hydrophobic drugs such as paclitaxel and valrubicin were successfully encapsulated by the rHDL nanoparticle. Photophysical studies showed that as a carrier, the rHDL holds its cargo at its core. Receptor blocking studies showed that scavenger receptor, class B type 1 (SR‐B1) expressed on the surface of the target cell mediate the intracellular delivery of the nanoparticle's payload by interacting with ApoA1, a major protein component of the nanoparticle. Also, protein expression analysis showed that M2‐type macrophages exhibit higher levels of SR‐B1 compared to M1‐type macrophages. The rHDL nanoparticles can transport hydrophobic small molecule inhibitors or non‐coding RNAs often used in subtype reversal/re‐polarization (M2 to M1) strategies. Most importantly, the SR‐B1 expression profile of M2‐type macrophage indicates that the rHDL is particularly suited for selective targeted delivery of these agents to TAMs.Support or Funding InformationCerenis TherapeuticsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.