The goal of the proposed work is to develop a new strategy for targeting hepatocellular carcinoma (HCC) tumors with high specificity, as a means of simultaneously delivering immunotherapeutic cargo and reprogramming the tumor immune landscape.

Galectin-3 (Gal-3) is a carbohydrate-binding protein that is highly overexpressed by HCC tumors and is correlated with poor prognosis. Moreover, Gal-3 binds to the surface of T cells and suppresses their tumoricidal action in tumors, leading to tumor immune escape. Herein, carbohydrate-polymer conjugates (CPCs) that bind to Gal-3 with high affinity in the tumor microenvironment will be developed and synthesized to include immunotherapeutic moieties alo...

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The goal of the proposed work is to develop a new strategy for targeting hepatocellular carcinoma (HCC) tumors with high specificity, as a means of simultaneously delivering immunotherapeutic cargo and reprogramming the tumor immune landscape.

Galectin-3 (Gal-3) is a carbohydrate-binding protein that is highly overexpressed by HCC tumors and is correlated with poor prognosis. Moreover, Gal-3 binds to the surface of T cells and suppresses their tumoricidal action in tumors, leading to tumor immune escape. Herein, carbohydrate-polymer conjugates (CPCs) that bind to Gal-3 with high affinity in the tumor microenvironment will be developed and synthesized to include immunotherapeutic moieties along the polymer backbone. These materials will be designed such that when CPCs bind Gal-3 in the tumor site, hydrogels will form as a consequence of high-affinity, multivalent interactions between the polymer sidechains and the protein.

This will cause CPCs to accumulate within HCC tumors in a highly targeted manner and enable them to function as dual-action immunotherapeutics, in that:

1. CPCs will prevent the deleterious interactions that normally occur between Gal-3 and T cells by sequestering Gal-3 upon binding
2. Immunotherapeutics will be programmed to be released from the CPC scaffold following hydrogelation

To achieve this, CPCs bearing substrates for Gal-3 will be synthesized and systematically evaluated to identify materials that most efficiently bind the protein and induce hydrogel formation (Aim 1). With these materials in hand, their ability to bind Gal-3 in the TME in vivo and form hydrogels in situ will be maximized and used to visualize tumor boundaries through the incorporation of diagnostic moieties in the CPC (Aim 2). Finally, CPCs bearing immunotherapeutic molecules will be employed in in vivo HCC models as dual-action immunotherapeutics (Aim 3).

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