From Structure to Function: The Promise of PAMAM Dendrimers in Biomedical Applications

Abstract

PAMAM dendrimers are distinguished by their capacity for functionalization, which enhances the properties of the compounds they transport, rendering them highly versatile nanoparticles with extensive applications in the biomedical domain, including drug, vaccine, and gene delivery. These dendrimers can be internalized into cells through various endocytic mechanisms, such as passive diffusion, clathrin-mediated endocytosis, and caveolae-mediated endocytosis, allowing them to traverse the cytoplasm and reach intracellular targets, such as the mitochondria or nucleus. Despite the significant challenge posed by the cytotoxicity of these nanoparticles, which is contingent upon the dendrimer size, surface charge, and generation, numerous strategies have been documented to modify the dendrimer surface using polyethylene glycol and other chemical groups to temporarily mitigate their cytotoxic effects. The potential of PAMAM dendrimers in cancer therapy and other biomedical applications is substantial, owing to their ability to enhance bioavailability, pharmacokinetics, and pharmacodynamics of active ingredients within the body. This underscores the necessity for further investigation into the optimization of internalization pathways and cytotoxicity of these nanoparticles. This review offers a comprehensive synthesis of the current literature on the diverse cellular internalization pathways of PAMAM dendrimers and their cargo molecules, emphasizing the mechanisms of entry, intracellular trafficking, and factors influencing these processes.

Keywords: PAMAM; cytotoxicity; dendrimers; endocytosis.

Figure 1

Schematic representation of the hierarchical and branched architecture of a dendrimer molecule, illustrating its core, repetitive branching units, and terminal functional groups.

Figure 2

Illustration of different mechanisms of endocytosis of PAMAM-associated nanoparticles. (A) Clathrin-mediated endocytosis, showing the assembly of clathrin to the plasma membrane and the formation of the clathrin-coated vesicle with the dendrimer inside, followed by the late endosome, which then fuses with the lysosome for degradation. (B) Caveolae-mediated endocytosis, showing the formation of a caveolar vesicle with the dendrimer inside, showing the ability of this pathway to bypass the lysosomes by not heading towards the route leading to the late endosome and instead heading towards the endoplasmic reticulum by fusing with the organelle called the caveosome. (C) Macropinocytosis: We observed the formation of membrane ruffles that engulfed the dendrimer, forming an intracellular vacuole called a macropinosome, which then fused with lysosomes for degradation. (D) Passive diffusion: We observed the passive diffusion of PAMAM using a membrane permeation enhancer, causing nanopores that allow its diffusion through the membrane.

Figure 3

Illustration of the toxic effects and innate biological actions of PAMAM dendrimers. Toxic effects of PAMAM dendrimers include cell death and hemolysis. Innate biological actions are also observed, for example, acting as an antimicrobial, modulator of the inflammatory response, interfering in signal transduction pathways, among others [15].