The Importance of Biotinylation for the Suitability of Cationic and Neutral Fourth-Generation Polyamidoamine Dendrimers as Targeted Drug Carriers in the Therapy of Glioma and Liver Cancer

Abstract

In this study, we hypothesized that biotinylated and/or glycidol-flanked fourth-generation polyamidoamine (PAMAM G4) dendrimers could be a tool for efficient drug transport into glioma and liver cancer cells. For this purpose, native PAMAM (G4) dendrimers, biotinylated (G4B), glycidylated (G4gl), and biotinylated and glycidylated (G4Bgl), were synthesized, and their cytotoxicity, uptake, and accumulation in vitro and in vivo were studied in relation to the transport mediated by the sodium-dependent multivitamin transporter (SMVT). The studies showed that the human temozolomide-resistant glioma cell line (U-118 MG) and hepatocellular carcinoma cell line (HepG2) indicated a higher amount of SMVT than human HaCaT keratinocytes (HaCaTs) used as a model of normal cells. The G4gl and G4Bgl dendrimers were highly biocompatible in vitro (they did not affect proliferation and mitochondrial activity) against HaCaT and U-118 MG glioma cells and in vivo (against Caenorhabditis elegans and Wistar rats). The studied compounds penetrated efficiently into all studied cell lines, but inconsistently with the uptake pattern observed for biotin and disproportionately for the level of SMVT. G4Bgl was taken up and accumulated after 48 h to the highest degree in glioma U-118 MG cells, where it was distributed in the whole cell area, including the nuclei. It did not induce resistance symptoms in glioma cells, unlike HepG2 cells. Based on studies on Wistar rats, there are indications that it can also penetrate the blood–brain barrier and act in the central nervous system area. Therefore, it might be a promising candidate for a carrier of therapeutic agents in glioma therapy. In turn, visualization with a confocal microscope showed that biotinylated G4B penetrated efficiently into the body of C. elegans, and it may be a useful vehicle for drugs used in anthelmintic therapy.