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

Abstract

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 µM. 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.

A Review on Increasing the Targeting of PAMAM as Carriers in Glioma Therapy

“…This finding correlated with a study by Liu et al [ 24 ], who used U251 human glioma cells. Biotin (i.e., vitamin B7) is another vitamin that has been used to modify PAMAM to target glioma [ 64 , 65 ]. Biotin can promote the growth of cells and rapidly proliferate tumor cells, requiring additional biotin.…”

Enhancing Skin Cancer Immunotheranostics and Precision Medicine through Functionalized Nanomodulators and Nanosensors: Recent Development and Prospects

“…This favors anti-tumor response by switching M2 macrophage phenotype to M1, thereby facilitating an anticancer response [ 120 ]. PAMAM G3 dendrimers substituted with R-glycidol and celecoxib/simvastatin demonstrate an efficient, targeted drug delivery potential and can be tested for immunotherapeutics [ 121 ].…”

Selective Cytotoxicity Effects of R-Glycidol and S-Glycidol on Vero and HCT 116 Cells in Evaluating the Incidence of Glycidyl Esters in Edible Oils and Fats

“…The use of dendrimers as carriers of bioactive compounds can solve many problems in biomedical approaches and have an advantage in improving their usage for clinical applications (Aurelia et al, 2020). The utilisation of drug combinations based on their targeted administration or drug delivery materials has become a new trend to optimise the therapeutic effects of the drugs with a reduction in adverse effects and potentially becomes a new strategy in the search for successful cancer therapy (Wróbel et al, 2022). In addition, according to a study by Wróbel et al (2022), 2-and 3-poly(amidoamine) (PAMAM G2 and G3) dendrimers covered with R-glycidol could penetrate cells faster and exhibited higher toxicity for cancerous cells than for normal cells compared to S-glycidol covered analogues.…”