Synthesis of Biotinylated PAMAM G3 Dendrimers Substituted with R-Glycidol and Celecoxib/Simvastatin as Repurposed Drugs and Evaluation of Their Increased Additive Cytotoxicity for Cancer Cell Lines

Simple Summary New anti-cancer drugs can be created through the combination of well-known substances acting on different molecular targets. Repurposed drugs selected in this way can then be attached to special carriers that have specific, high affinity for cancer cells. In this study, two anti-glioma drugs, celecoxib and simvastatin, were chosen and linked to the PAMAM G3 dendrimer targeted to cancer cells by attached biotin and R-glycidol. In vitro studies performed with human glioblastoma (U-118 MG) and squamous cell carcinoma (SCC-15) cells revealed that dendrimer conjugate containing both celecoxib and simvastatin was 20-50 times more potent than either drug administered alone or in combination. Thus, the obtained combined conjugate can be considered as a potential candidate for a new therapy of malignant glioblastoma. Recent achievement in anticancer therapy considers the application of repurposed drugs in optimal combinations with the use of specific carriers for their targeted delivery. As a result, new optimized medications with reduced side effects can be obtained. In this study, two known anticancer drugs, celecoxib and/or simvastatin, were conjugated covalently with PAMAM G3 dendrimer and tested in vitro against human squamous carcinoma (SCC-15-15) and glioblastoma (U-118 MG) cells, as well as normal human fibroblasts (BJ). The obtained conjugates were also substituted with biotin and R-glycidol to increase their affinity for cancer cells and were characterized with NMR spectroscopy and dynamic light scattering technique. Conjugates furnished with two celecoxib and four simvastatin residues revealed the very high effectiveness and dramatically decreased the SCC-15 and U-118 MG cell viability at very low concentrations with IC50 equal to about 3 mu M. Its action was 20-50-fold stronger than that of either drug alone or as a mixture. Combined conjugate revealed also additive action since it was 2-8-fold more effective than conjugates with either single drug. The combined conjugate revealed rather low specificity since it was also highly cytotoxic for BJ cells. Despite this, it may be concluded that biotinylated and R-glycidylated PAMAM G3 dendrimers substituted with both celecoxib and simvastatin can be considered as a new perspective anticancer agent, effective in therapy of malignant, incurable glioblastomas.