(23a) Invited Talk: Macrophage-Targeted Drug Delivery for Systemic and Local Immune Modulation

Macrophages (MF) are mediators of the immune microenvironment that span diverse behaviors, ranging from prototypical inflammatory (M1-like) to pro-healing (M2-like) phenotypes. While small-molecule drugs are available to treat many diseases by modulating MF behavior, their efficacy remains limited by a poor understanding of which drugs can promote desirable MF cell-state transitions and inadequate drug pharmacokinetics (poor solubility, non-specific cell uptake, rapid blood clearance, and off-target effects). Biomaterial-based drug delivery systems enable cell- and tissue-targeting strategies to overcome these challenges. Furthermore, the recognition of drugs by macrocyclic hosts provides a readily adaptable method to encapsulate a variety of therapeutics for delivery, including within soluble nanoparticles (for systemic cell-targeted therapies) or injectable hydrogels (for local applications, such as focal tissue injury). This talk will discuss two applications of these systems, which include in the context of cancer immunotherapy and the prevention of post-ischemic heart failure.

Tumor-associated macrophages (TAMs) are abundant in solid cancers, assuming a pro-angiogenic and immunosuppressive M2-like phenotype that supports tumor growth and immune escape. Recent methods have focused on identifying therapeutic drugs that re-polarize TAMs to a tumor-destructive M1-like phenotype. Through high-content screening and qPCR analysis in primary murine and human cells, we identified a drug (R848) that potently induced a tumor-destructive state (IC50=7.2nM). Cyclodextrin nanoparticles (CDNPs) were prepared by crosslinking cyclodextrin with lysine. Drug-loaded CDNPs (CDNP-R848, >10%_w/w drug loading) accumulated in tumors by MF-specific update and eradicated tumors in multiple models (MC38, Gl261). Treatment synergized with frontline anti-PD1 checkpoint therapy.

In contrast, tissue injury such as myocardial infarction are characterized by exuberant local inflammation. We therefore developed hydrogels composed of CDNPs crosslinked by polymer-nanoparticle interactions. The hydrogels shear-thin for ease of injection and self-heal for local retention. Through cell-reporter assays, we identified celastrol’s ability to inhibit inflammatory MF signaling (IC50<100nM) and promote a pro-healing phenotype (qPCR, nanoString). Hydrogels released CDNP-celastrol for >14 days with >80% inhibition of inflammatory response. In a murine model of ischemia-reperfusion injury, targeted delivery of celastrol prevented left-ventricular remodeling and preserved heart function. In sum, small-molecules can potently modulate MF-state and their efficacy is improved through cell- and tissue-targeted delivery. These tools have widespread applications in the treatment of disease and tissue repair.