Abstract
Cyclic GMP-AMP (cGAMP) has lately been extensively investigated in cancer immunotherapy due its activation of the innate immunity stimulation of interferon genes (STING) pathway within antigen presenting cells (APC) leading to an increase in tumor specific CD8+ T cells. As negatively charged dinucleotides are prone to enzymatic degradation before being taken up by APC, there is a need for an appropriate carrier. Therefore, polyethylenimine (PEI), a gold standard for oligonucleotide delivery, was selected. Molecular weight, type of PEI and N/P ratio between PEI/cGAMP were investigated in terms of toxicity, efficacy and physicochemical properties of the nanocomplexes (NCs) such as size, zeta potential and shape. Due to lack of nano-medicine regulations and the need for a case-by case assessment, here we examine these parameters by several orthogonal methods, such as dynamic light scattering (DLS), nanoparticle tracking analysis (NTA) and online asymmetric flow field flow fractionation (AF4) connected to DLS. N/P ratio of 2/1 ratio using linear PEI 25 kDa resulted in larger, positively charged particles of elongated shape, which were shown to have the best toxicity/efficacy ratio among different PEIs and ratios tested.
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