| dc.description.abstract | Macrophages are the most abundant immune cell in most tumors and are drivers of the immunosuppressive tumor microenvironment. Macrophages exist across a range of phenotypes with the two extremes often termed “M1” for pro-inflammatory responses and “M2” for wound healing. Tumor-associated macrophages (TAMs) are mostly M2-like, which function to increase tumor progression, promote angiogenesis, and release immunosuppressive cytokines, thus lower the efficacy of other immunotherapies such as immune checkpoint blockades. However, because of the phenotypic plasticity associated with macrophages, TAMs provide an intriguing target for new immunotherapies designed to repolarize the M2-like TAMs into an M1, anti-tumor phenotype. We examined two separate mechanisms to repolarize TAMs: siRNA and pro-inflammatory cytokines. The chosen siRNA functions to knockdown expression of the inhibitor of Nuclear Factor-kappaB (NF-κB) alpha (IκBα), which activates the canonical NF-κB signaling pathway and drives a pro-inflammatory response in macrophages. Pro-inflammatory cytokines can promote M1 polarization similar to inflammatory responses that occur naturally in the body. However, for both of these therapies, delivery is crucial to their success. siRNAs are rapidly cleared by the body and cytokines can cause widespread toxicity when delivered freely. The overall goal of this work was to develop injectable biomaterial systems for delivering siRNA or inflammatory cytokines to TAMs to induce anti-tumor effects. This work developed a polymeric nanoparticle (NP) system designed to encapsulate oligonucleotides and induce endosomal escape upon cellular uptake with the addition of a targeting moiety for M2 macrophages: mannose. For cytokine delivery, we developed a macroporous, injectable cryogel designed to load biomolecules and allow for local injection of a TAM repolarization depot. The mannosylated NPs were used for intraperitoneal injections to treat ovarian cancer and demonstrated high affinity for TAMs in the tumor and ascites (a fluid build-up associated with ovarian cancer development) as well as significant suppression of tumor development. The injectable cryogels were used for peritumoral injections to treat breast cancer and also demonstrated local macrophage activation with significant suppression of tumor growth. Both of these systems represent the next steps in developing TAM-targeted cancer immunotherapies. This work is also the first characterization of injectable cryogels for locally repolarization TAMs. Both treatments provide support for future combination therapies to increase the low efficacy currently associated with treating solid tumors with immune checkpoint blockades. | |
