Peripheral Functionalization of Dendrimers Regulates Internalization and Intracellular Trafficking in Living Cells

Abstract

GATG (gallic acid-triethylene glycol) dendrimers represent appealing nanostructures for biomedical applications. The incorporation of specific ligands and targeting and imaging agents on their surface has resulted in promising tools in diagnosis and drug delivery. With the aim to further explore the versatility of GATG dendrimers in the biomedical field, in this work we study the effect of peripheral substitution on their uptake and intracellular trafficking in living cells. To this end, peripheral groups with different physicochemical properties and biological relevance have been installed on the surface of GATG dendrimers, and their interactions, uptake efficacy, and specificity for certain cell populations studied by confocal microscopy. Finally, this information was used to design a pH-sensitive drug delivery system for the selective release of cargo molecules inside cells after lysosomal localization. These results along with the easy functionalization and modular architecture of GATG dendrimers reveal these systems as promising nanotools in biomedicine.

Viologen-phosphorus dendrimers exhibit minor toxicity against a murine neuroblastoma cell line

“…By contrast, dendrimers such as PAMAM and cationic phosphorus dendrimers carry a large number of positive charges at the surface of the dendritic structure, which can easily interact with plasma membranes [47,49]. Furthermore, according to a current theory, dendrimers can enter the cell via clathrin-dependent endocytosis and/or macropinocytosis [50][51][52][53] and the process of dendrimer uptake has been shown to reach completion within 4 h [52][53][54]. Therefore, it is possible that VPD are internalized into the cell within the first hours after treatment, causing minor, reversible changes in the cell membrane integrity, which are repaired during the next hours and undetectable at 24 h. Ciepluch et al [26] demonstrated that only VPD2 and VPD3 at the highest concentrations caused a small but statistically significant decrease in erythrocyte membrane fluidity, which implies that these VPD can interact with the polar headgroup region of the phospholipid bilayer.…”

Synthesis, Cellular Delivery and <em>In vivo</em> Application of Dendrimer-based pH Sensors

“…The same protocol can be applied with minimal modification to alternative amine-bearing dendrimers. 5,17,13,14 Commercially available dendrimers and dyes can be used without further purifications. …”

“…Interestingly this approach can easily be applied to a variety of dendritic or polymeric scaffolds. 13,14 To achieve ratiometric imaging dendrimers were double-labeled with two sets of dyes: i) a pH indicator (i.e. fluorescein) and ii) a pH-independent fluorescent moiety (i.e.…”

In situ nanofabrication of hybrid PEG-dendritic–inorganic nanoparticles and preliminary evaluation of their biocompatibility

“…GATG dendrimers have recently emerged as a modular and versatile platform in the biomedical field with applications [23][24][25] in drug and gene delivery, [26][27][28][29] diagnosis, 30 antiviral agents, 31 or in the treatment of neurodegenerative diseases. GATG dendrimers have recently emerged as a modular and versatile platform in the biomedical field with applications [23][24][25] in drug and gene delivery, [26][27][28][29] diagnosis, 30 antiviral agents, 31 or in the treatment of neurodegenerative diseases.…”