Development of Iontophoresis-Responsive Oleogels for Facile Delivery of Upconversion Nanoparticle and Drug across the Skin

Abstract

According to the World Health Organization, one out of every three cancers detected these days is skin cancer, which grows and spreads within epidermis and dermis. Photon induced therapy through the generation of reactive oxygen species (ROS); although shows a promising potential toward the treatment of skin cancers, the practical application of such therapeutic modality has been extremely limited due to the difficulty in localizing the photo-therapeutic agents to the inner skin structure via transdermal route. Near infra-red (NIR) activated upconversion nanoparticle (UCNP), in spite of exhibiting a well-established photo-theranostic effect against many different types of cancers in vivo; could not be explored in the therapeutic context of skin cancers. The major reason of this limitation lies in the fact that the stratum corneum (SC) layer of human skin is practically impermeable and it is a major challenge to deliver and localize any therapeutic nanoparticles including UCNP to the inner layers of the skin i.e. epidermis and dermis via transdermal route. The prime content of this Ph.D. thesis is thus focussed on developing a method to localize UCNP, capable of generating NIR-induced ROS to the inner skin structure; overcoming the SC barrier by non-invasive skin permeation. The context and the significance of this dissertation has been presented in the first chapter as Introduction.
There exist two major non-invasive pathways to overcome the SC barrier. One, is the use of skin permeation-enhancing agents and the other is the use of external electrical current-induced iontophoresis. Soybean oil-based oleogel was selected as the host matrix of delivering UCNP across the skin. The stearic acid present as the gelator in the soybean oil-based oleogels and other unsaturated fatty acids found in the soybean oil have been reported to act as skin permeation enhancer. It is hypothesized that incurring iontophoretic property within such oleogels would exert the dual effects of both type of skin permeation enhancement strategy and thus expected to the development of a facile transdermal delivery system (TDS) for UCNP. 2

The first aim is to develop an iontophoresis-responsive oleogel, which is capable of showing drug delivery triggered by incorporating alternating electric field-induced iontophoresis. For this purpose, magnetic nanoparticle (MNP) incorporated soybean oil-based oleogels were developed. The details are included in the second chapter of this thesis (Colloids Surf. B, 157 (2017) 118-129).
Next, in the third chapter, the skin permeation capability of UCNP incorporated oleogels was explored. This system was designed to deliver UCNP across the full thickness of an animal skin model by overcoming the impermeable barrier of stratum corneum based on the skin-permeation enhancing effect of the components of the oleogel (Chem Eng J., 379 (2020) 122272). In an attempt to develop a faster and controlled delivery of UCNP and drug, the iontophoretic property was introduced within UCNP containing oleogel, by incorporating MNP within the same to magnify the skin-permeation enhancement effect. The details have been presented in the fourth chapter (Nano Express, 1 (2020) 010012).
Further, an effort was made to demonstrate the transdermal delivery of photosensitizer-linked UCNP across the skin for the generation of singlet oxygen (1O2) based ROS upon activation by NIR radiation. The ability of localizing ROS generating UCNP to the inner skin tissue was expected to enable such TDS suitable for its potential application in skin cancer. This work has been presented as the fifth chapter (Colloids Surf. B, 190 (2020) 110945). Finally, by incorporating gold nanoparticles within UCNP-oleogel, an attempt was also made to design a superior iontophoresis-responsive, controlled drug and UCNP delivery system, which was able to deliver therapeutic UCNP across the skin in the fastest possible manner among all the TDS described in this thesis as described in the sixth chapter. These results are expected to pave the way for the potential anti-skin cancer application of UCNP in future.