BME PhD Defense: Carolina Villarreal: "Localized Delivery of Immunotherapy Using Gellan Gum-based Hydrogels for Colorectal Cancer Treatment"

PhD Dissertation Defense 

Localized Delivery of Immunotherapy Using Gellan Gum-based Hydrogels for Colorectal Cancer Treatment 

Carolina Villarreal 

Thursday, March 27, 2025 

Gateway Park, Room GP 1002 

9:00am-10:00 am 

Abstract: Colorectal cancer (CRC) is the second most common cause of cancer deaths in the United States with an estimated rate of almost 53,000 deaths in 2025. CRC is one of the most widespread and fatal cancers globally. The survival rate is 70 – 90% when is localized but drops significantly to 13 – 17 % once metastasized. Treatment approaches can be local, such as surgery, ablation, embolization, or radiation therapy; or systemic where therapy is provided directly into the blood stream, such as chemotherapy, targeted therapeutic drugs, or immunotherapy. Although the use of immunotherapy is growing for the clinical treatment of cancer, patients suffer from autoimmune reactions, and exploration of alternative delivery pathways of treatment options are under evaluation. Currently, the immunotherapy anti-programmed cell death protein-1 (aPD-1) has proven early success in treating metastatic CRC patients with mismatch repair deficiency. However, systemic side effects present a challenge to the patient’s quality of life. To improve upon this, biomaterial-based approaches are under investigation for the local delivery of immunotherapy.  

Over the past decade, gellan gum (GG) has emerged as a promising material for drug delivery and tissue engineering applications. GG, a linear, anionic exopolysaccharide produced by Sphingomonas elodea, is FDA approved for use in both pharmaceutical and food industries. It has mucoadhesive properties, and its mechanical characteristics can be fine-tuned by adjusting the pH of the media, crosslinkers, processing time, and temperature to meet specific needs. Its low cost, high production rates, established manufacturing process, and broad availability, makes it a viable candidate for large-scale production and translational research. However, high temperature crosslinking is often required, representing a limiting factor for the incorporation of thermosensitive therapeutic agents such aPD-1 for drug delivery applications.  

This research focused on developing and characterizing a GG-based hydrogel for intratumoral delivery of aPD-1 for CRC treatment. We successfully demonstrated that GG can be crosslinked at a low temperature (38 °C) using a simple fabrication process that utilizes a peptide-based molecule, trilysine (TLA), as an alternative to traditional mono- or divalent ion crosslinkers. The drug release potential was demonstrated using immunoglobulin G (IgG), that showed a burst release in the first 24 h followed by a gradual release for up to 5 days. A comparable release profile was confirmed with the therapeutic agent, aPD-1. In vivo evaluations with a CRC murine model showed that intratumoral delivery of aPD-1 using the GG-based hydrogel resulted in 1.5-fold and 3-fold increases in plasma and tumor concentrations, respectively as compared to control groups.  These findings suggests that this approach is both comparable and safe relative to drug-free intratumoral or intraperitoneal injections. 

The main scientific contribution of this work lies in the development of a non-cytotoxic and biocompatible hydrogel, featuring a simple manufacturing process. This hydrogel demonstrated effectiveness in releasing, delivering, and retaining, thermosensitive macromolecules. Furthermore, it presents with an opportunity to serve as a platform technology applicable to a range of immunotherapy drugs and cancer types.  

For a zoom link, please email kharrison@wpi.edu