Injectable, Tough Alginate Cryogels as Cancer Vaccines
Ting-Yu Shih1,2, Serena Blacklow1, Weiwei Aileen Li1,2, Sidi Bencherif1,2, Sandeep Koshy1,2,3, David J Mooney1,2*
1School of Engineering and Applied Sciences, Harvard University; 2Wyss Institute for Biologically Inspired Engineering at Harvard University; 3Harvard-MIT Division of Health Sciences and Technology
Cancer vaccines have the potential to eliminate tumors and prevent recurrence. Recently, a covalently crosslinked methacrylated (MA)-alginate cryogel-based vaccine has been shown to successfully modulate host immune cells in situ and generate potent antitumor responses using irradiated autologous tumor cells as antigen. The cryogel allows minimally invasive delivery but is not mechanically robust and requires a large 16G needle for delivery. We hypothesized that combining covalent and ionic crosslinking would result in a tough MA-alginate cryogel with improved injectability. MA-alginate cryogels were first fabricated by free radical polymerization at -20°C overnight, and were then soaked in a calcium chloride solution to introduce ionic crosslinking. The cryogels were injected through a 16G and 18G needle and inspected for damage. Increasing the calcium concentration in the cryogel up to 37 mM led to enhanced toughness and all gels were intact after injection. A significant proportion of the gels sustained damage after injection at higher calcium concentrations. GM-CSF-releasing tough cryogels recruited 5 times more dendritic cells than blank gels by Day 7 in vivo. The tough cryogel vaccine induced a strong antigen-specific CD8 T cell response against a model antigen ovalbumin. A vaccine delivering irradiated HER2+ breast cancer cells as antigen generated significantly higher anti-HER2 antibody titers than blank gels, and prevented tumor formation in 80% of the mice for more than 4 months in a prophylactic vaccination study. The MA-alginate tough cryogels provide a promising minimally invasive delivery platform for cancer vaccinations.