Effect of Size, Surface Charge, and Hydrophobicity of Poly(amidoamine) Dendrimers on Their Skin Penetration

Abstract

The barrier functions of the stratum corneum (SC) and the epidermal layers present a tremendous challenge in achieving effective transdermal delivery of drug molecules. Although a few reports have shown that poly(amidoamine) (PAMAM) dendrimers are effective skin penetration enhancers, little is known regarding the fundamental mechanisms behind the dendrimer-skin interactions. In this paper, we have performed a systematic study to better elucidate how dendrimers interact with skin layers depending on their size and surface groups. Franz diffusion cells and confocal microscopy were employed to observe dendrimer interactions with full-thickness porcine skin samples. We have found that smaller PAMAM dendrimers (generation 2 (G2)) penetrate the skin layers more efficiently than the larger ones (G4). We have also found that G2 PAMAM dendrimers that are surface modified by either acetylation or carboxylation exhibit increased skin permeation and likely diffuse through an extracellular pathway. In contrast, amine-terminated dendrimers show enhanced cell internalization and skin retention but reduced skin permeation. In addition, conjugation of oleic acid (OA) to G2 dendrimers increases their 1-octanol/PBS partition coefficient, resulting in increased skin absorption and retention. Here we report that size, surface charge, and hydrophobicity directly dictate the permeation route and efficiency of dendrimer translocation across the skin layers, providing a design guideline for engineering PAMAM dendrimers as a potential transdermal delivery vector.

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems

“…Confocal images showed that G2-NH2 could be internalized into the individual cell in both epidermal and dermal layers, while neither acetyl nor carboxyl modified PAMAM interacted with the cell. The study also found that conjugation of oleic acid to G2-NH2 could further increase the drug absorption and retention in the skin (Yang et al, 2012).…”

PAMAM dendrimers affect the in vitro release of clotrimazole from hydrogels irrespective of its molecular state

“…Since properties of dendrimers depend on their size and surface charge (Malik et al 2000), lower generation of PAMAM are more preferred for examination in dermal formulations, because of their stronger ability to enhance the permeation and lower toxicity (Heiden et al, 2007;Winnicka et al, 2009). PAMAM-NH 2 in contrast to neutral and anionic dendrimers can be accumulated in the skin upper layers (Yang et al, 2012), which makes them proper carriers for topical drug delivery. The effect of PAMAM dendrimers G2 and G3 with various surface groups on the release of CLO from hydrogels with CLO in two different molecular states and from water suspensions was studied, because the size and surface charge of dendrimers can influence the permeation of the drug.…”

Use of confocal microscopy for nanoparticle drug delivery through skin

“…15 A recent study with poly (amidoamine) (PAMAM) dendrimers conjugated with rhodamine B isothiocyanate reported penetration in porcine skin. 21 The authors used a Zeiss LSM 510 Meta confocal laser scanning microscope with a 1 mW helium-neon laser at 543 nm to image the localization of PAMAM in the skin. They hypothesized that these dendrimers at smaller sizes can penetrate the skin layers more efficiently than the larger dendrimers.…”