Biofunctional Materials for the Modulation of Macrophage Phenotype and Polarization

Abstract

Macrophages have been proposed as a potential therapeutic target because of their central role in the progression of a number of debilitating diseases, such as cancer and cardiovascular diseases. However, macrophages are resident in almost all healthy tissues. Therefore, immunotherapies targeted to macrophages in pathologic tissues require the development of site-specific techniques to target these pathologic macrophages while leaving healthy ones unaffected.

In this work, I pursued the design and validation of macrophage-targeted biomaterials, including the following steps: (1) Optimization of nanoparticle characteristics that would reduce non-specific recognition of the particles by macrophages that may exist outside of the desired site of intervention, (2) Optimization of nanoparticle characteristics that would increase site-specific recognition of pathologic macrophages, (3) Design of a localized delivery platform that may serve as an implantable patch for delivery of nanoparticles to a site of pathologic inflammation, and (4) Identification of potential molecular and gene pathway targets for biomaterials-mediated, therapeutic intervention in vivo. Finally, I also demonstrate some work in the development of assays to quantify T-cell-mediated immune responses in human patients following immunotherapy. This is important because most immunotherapies are designed with the ultimate goal of effecting T-cell responses, whether by generating T-cells reactive against the pathologic site (in the context of cancer), or generating regulatory T-cells and other immunosuppressive T-cells (in the context of autoimmune diseases).

Looking forward, significant challenges exist for future work by my successors and other future lab members, including (1) the identification of immunotherapeutic agents—small molecules or peptides or nucleic acids, that can reprogram tumor-associated macrophages into anti-tumor ‘drug depots’, (2) optimization of nanoparticle properties for efficient in vivo targeting of TAMs within primary and metastatic tumor sites, (3) the creation of new in vitro assays to evaluate and characterize the serum stability of nanoparticles and their interactions with blood cells in circulation, and (4) the optimization of cell-based assays to facilitate their adoption into other immunotherapeutic clinical trials and studies.