|Institution:||University of Illinois – Chicago|
|Keywords:||PAMAM dendrimer; topical delivery; surface modification; endoxifen; breast cancer; dendron micelles; human skin; hairless mice.|
|Full text PDF:||http://hdl.handle.net/10027/11207|
The barrier functions of the stratum corneum and the epidermal layers present a tremendous challenge in achieving effective transdermal delivery of drug molecules. Among many nanocarriers that have been tested to improve topical drug delivery, poly(amidoamine) (PAMAM) dendrimers have shown to be a promising skin-penetration enhancer, and yet little is known regarding the fundamental mechanisms behind the dendrimer-skin interactions. In this dissertation research, we have performed a systematic study to better elucidate how dendrimers interact with skin layers using Franz diffusion cells and confocal microscopy. Results indicated that the 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 dendritic nanomaterials as potential transdermal drug delivery vectors. On the knowledge base obtained from using dendrimers, the study was expanded to a dendron micelle (DM) system as a novel topical nanocarrier in order to exploit the advantageous dendritic structure and versatility in drug choice. This study has revealed surface modifications of the DMs affect loading and release profile, without sacrificing efficacy of endoxifen (EDX), a chemo-preventive medicine that is skin impermeable. The DMs, especially those with carboxyl termini (-COOH), induced substantially enhanced permeation of EDX through both full-thickness mouse (up to 20-fold) and split-thickness human (up to 4-fold) skin samples compared to a traditional chemical penetration enhancer (ethanol). These results demonstrate the potential of dendrimers and DMs as topical drug delivery platforms and provide fundamental understanding on their skin interactions, which will potentially benefit for future development of nanoscale penetration enhancers based on dendritic polymers and other types of materials.