Cytokine-based immunotherapies have the potential to treat a wide range of diseases including cancer. Unfortunately, pro-inflammatory cytokines with potent antitumor activity are frequently toxic upon systemic exposure. The lack of effective local delivery strategies capable of controlling the distribution cytokines has prevented cytokine therapeutics from impacting cancer immunotherapy. This project proposes a novel delivery technology in which a potent recombinant cytokine, interleukin-12 (IL-12), is chemically-linked to a biodegradable polysaccharide called chitosan prior to intratumoral (i.t.) injection. This novel strategy is expected to provide sustained, high concentrations of IL-12 in the tumor microenvironment, while minimizing potentially harmful systemic dissemination. The proposed project is comprised of three aims focusing on the development and evaluation of IL-12-chitosan bioconjugates in preclinical tumor models. In the first aim, novel IL-12-chitosan bioconjugates will be synthesized and evaluated in vitro for bioactivity. The mutation of solvent accessible amino acids will allow for site-specific conjugation of IL-12 to chitosan.
Aim 2 will assess safety by documenting the spatiotemporal distribution of IL-12-chitosan bioconjugates and any potential toxicities associated with IL-12-chitosan administration.
Aim 3 will evaluate antitumor efficacy of IL-12-chitosan bioconjugates as well as the elaboration of tumor-specific immunity in relevant preclinical models. The overall goal of this project is to determine if conjugation to chitosan can maintain the potent antitumor activity of IL-12 while alleviating toxicity concerns. I the long-term, validation of this cytokine-chitosan delivery platform may pave the way for additional cytokine therapeutics in cancer immunotherapy.

Public Health Relevance

The administration of pro-inflammatory cytokines has demonstrated remarkable antitumor activity in numerous preclinical studies. Unfortunately, these cytokines have not been widely effective in humans due to the lack of effective delivery strategies which maximize appropriate cytokine levels in tumors while minimizing toxicities associated with their systemic spread. This project will overcome these limitations by developing and evaluating a novel delivery strategy, based on linking cytokines with the biodegradable polysaccharide chitosan for the local, sustained delivery of pro-inflammatory and T cell activating cytokines to the tumor microenvironment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
North Carolina State University Raleigh
Engineering (All Types)
Schools of Engineering
United States
Zip Code
Davis, Julie Eberle; Gundampati, Ravi Kumar; Jayanthi, Srinivas et al. (2018) Effect of extension of the heparin binding pocket on the structure, stability, and cell proliferation activity of the human acidic fibroblast growth factor. Biochem Biophys Rep 13:45-57
Ravindranathan, Sruthi; Nguyen, Khue G; Kurtz, Samantha L et al. (2018) Tumor-derived granulocyte colony-stimulating factor diminishes efficacy of breast tumor cell vaccines. Breast Cancer Res 20:126
Davis, Julie Eberle; Alghanmi, Arwa; Gundampati, Ravi Kumar et al. (2018) Probing the role of proline -135 on the structure, stability, and cell proliferation activity of human acidic fibroblast growth factor. Arch Biochem Biophys 654:115-125
Kang, Seong W; Jayanthi, Srinivas; Nagarajan, Gurueswar et al. (2018) Identification of avian vasotocin receptor subtype-specific antagonists involved in the stress response of the chicken, Gallus gallus. J Biomol Struct Dyn :1-15
Jayanthi, Srinivas; Koppolu, Bhanu Prasanth; Nguyen, Khue G et al. (2017) Modulation of Interleukin-12 activity in the presence of heparin. Sci Rep 7:5360
Smith, Sean G; Baltz, John L; Koppolu, Bhanu Prasanth et al. (2017) Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer. Oncoimmunology 6:e1259050
Prudovsky, Igor; Kacer, Doreen; Davis, Julie et al. (2016) Folding of Fibroblast Growth Factor 1 Is Critical for Its Nonclassical Release. Biochemistry 55:1159-67
Chintapalli, Sree V; Jayanthi, Srinivas; Mallipeddi, Prema L et al. (2016) Novel Molecular Interactions of Acylcarnitines and Fatty Acids with Myoglobin. J Biol Chem 291:25133-25143
Ravindranathan, Sruthi; Koppolu, Bhanu Prasanth; Smith, Sean G et al. (2016) Effect of Chitosan Properties on Immunoreactivity. Mar Drugs 14:
Henderson, Rory C; Gao, Feng; Jayanthi, Srinivas et al. (2016) Domain Organization in the 54-kDa Subunit of the Chloroplast Signal Recognition Particle. Biophys J 111:1151-1162

Showing the most recent 10 out of 16 publications