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Evaluation of the efficiency of modified PAMAM dendrimer with low molecular weight protamine peptide to deliver IL‐12 plasmid into stem cells as cancer therapy vehicles

Interleukin 12 (IL‐12) is considered as an important molecule for cancer immunotherapy with significant roles in hindering tumor activity, mostly mediated by tumor‐associated macrophages and anti‐angiogenic factors. Mesenchymal stem cells (MSCs) have been come out as promising carriers to increase the accumulation of drug/gene in tumor sites. As a vehicle, MSCs have various advantages, including tumor‐specific propensity and migratory ability; however, they have limited transfection efficiency, compared to other cells. In this study, we introduced a novel delivery system based on poly‐(amidoamine) (PAMAM) (G5) to deliver a plasmid encoding IL‐12 to MSCs. Initially, 30% of the amine surface of PAMAM was substituted by 10‐bromodecanoic acid. Then, the low molecular weight of protamine peptide was conjugated to PAMAM and PAMAM‐alkyl with N‐succinimidyl 3‐(2‐pyridyldithio) propionate as a linker. Physicochemical properties of this modified PAMAM were evaluated, including size and surface charge, toxicity, transfection efficiency to deliver reporter and IL‐12 genes into MSCs and finally the migration potential of the engineered stem cells into cancer and normal cell lines (HepG2 and NIH/3 T3). The results showed that alkyl‐peptide modified PAMAM with low toxicity had a higher potential to deliver green fluorescent protein and IL‐12 genes to stem cells, than PMAMAM, PAMAM‐alkyl and PAMAM‐peptide. These engineered stem cells had a greater ability to migrate to cancer cells than normal cells. It can be concluded that engineered stem cells containing the IL‐12 gene can be considered as an efficient cell carrier for cancer immunotherapy. Further clinical studies are needed to confirm these results.