A multidomain peptide hydrogel-liposome composite for controlled release of a cyclic dinucleotide in oral cancer

While immunotherapy is a promising treatment strategy for cancer, the majority of head and neck squamous cell carcinoma (HNSCC) patients treated with single-agent immunotherapy do not respond. Therefore, researchers are investigating combination treatments with immunostimulatory molecules that can maximize anti-tumor responses. Cyclic dinucleotides (CDNs) are STING agonists that hold promise in combination approaches, but they require frequent intratumoral administration when used in both preclinical models of HNSCC and clinical trials. To reduce administration frequency, we have created a peptide hydrogel-liposome composite system, K₂-Lip(CDN), for local and prolonged availability of CDN. We investigated the loading limits of cationic liposomes in both anionic (E₂) and cationic (K₂) peptide hydrogels and found that E₂ caused aggregation to occur at the desired lipid:peptide molar ratio, which led to our use of K₂ in the composite system. At a molar ratio of 8:1 lipid:peptide, K₂-Lip(CDN) formed a self-healing composite hydrogel and resulted in prolonged release of CDN in vitro and indocyanine green (ICG) in vivo. This composite material resulted in cellular cytotoxicity in ROC1 oral cancer cells in vitro and extended survival in an aggressive ROC1 tumor-bearing murine model compared to a single CDN injection. The overall survival using only a single dose of K₂-Lip(CDN) was equivalent to that achieved with six repeated doses of CDN. The material properties and extended-release capabilities displayed by peptide hydrogel-liposome composite systems could translate to broad treatment applications that require the delayed release of localized therapeutics.