PAMAM Dendrimers and Branched Polyethyleneglycol (Nanoparticles) Prodrugs of (-)-β-D-(2R, 4R)-dioxolane-thymine (DOT) and Their Anti-HIV Activity

Abstract

The synthesis, characterization, anti-HIV activity and cytotoxicity of dendrimers of (-)-β β-D-(2R,4R)-dioxolane-thymine (DOT) and polyethylene glycol (PEG)-DOT conjugates are described. Dendrimers in this study were polyamidoamine (PAMAM) generation 2.0, 3.0, 5.0 and 6.0, along with 8.0-branched PEG with a molecular weight of 40 kDa. DOT was attached to PAMAM dendrimers or branched PEG via ester or phosphate groups. Size exclusion chromatography was used to purify the dendrimers and PEG conjugates, which were characterized by NMR and MALDI-TOF mass spectrometry. The synthesized PAMAM dendrimers and PEG conjugates were evaluated for anti-HIV activity against HIV-1 LAI in primary human peripheral blood mononuclear cells (PBMCs) and cytotoxicity in PBMCs, CEM and Vero cells. PAMAM dendrimers of DOT with ester linkages and particularly phosphate linkers showed an increase in anti-HIV potency in comparison with DOT alone (140-and 56-fold, respectively). Unfortunately, the PAMAM dendrimers also exhibited increased cytotoxicity. Anti-HIV activity of PEG-DOT conjugates was found to be lower than that of DOT.

Hydrodynamic Solvation of Poly(amido amine) Dendrimer Monolayers on Silica

“…Dendrimers represent an important class of macroions. Due to their spherical shape, low dispersity, pH-dependent charge, flexibility in tuning their molecule structure and size during synthesis they are used in medicine, , electronics, catalysis, or light harvesting …”

“…Besides in basic research, PAMAM dendrimers have found application in the industry, e.g., as part of optical and electrochemical sensors, , in size exclusion chromatography, in medicine for pulmonary drug delivery, and in magnetic resonance imaging contrast agent delivery . They can also serve as a platform for adsorption of proteins and drugs …”

Dendrimer Prodrugs

“…Liang and coworkers [64] evaluated the anti-HIV activity of PAMAM derivatives (the authors designed the compounds using (−)-β- d -(2 R ,4 R )-dioxolane-thymine (a bioactive molecule, named as DOT), PAMAM generations 2.0, 3.0, 5.0 and 6.0, either with or without polyethylene glycol (PEG). The prodrugs were obtained by ester or phosphate linkages, purified by applying exclusion chromatography and characterized using NMR and MALDI-TOF mass spectrometry.…”