A Multi-Component, Dual-Release Topical Platform for Skin Cancer

Abstract

The central focus of this research was the design, development, and evaluation of a novel synergistic therapeutic approach for the treatment of skin cancer. Both non-melanoma skin cancer (NMSC) and malignant melanoma (MM) are highly prevalent, with MM causing significant mortality due to its metastatic nature and aggressive progression. NMSC is, however, more frequently diagnosed globally, accounting for a substantial portion of skin cancer cases, especially among Caucasians, with incidence rates steadily increasing over the last decade. Current treatments, although effective in early-stage skin cancers, are limited by numerous drawbacks, including drug resistance, off-target toxicity, high treatment costs, and undesirable side effects, especially in advanced cases. This thesis addresses these limitations by exploring a hydrogel-based nanotechnology-driven drug delivery system that combines chemotherapeutic and immunotherapeutic agents for enhanced efficacy, specificity, and patient compliance. Initially, this work reviews the current therapeutic options for skin cancers, from simple surgical excision in early cases to complex combination treatments like chemotherapy, radiotherapy, immunotherapy, and phototherapy in more advanced stages. These treatments, while achieving significant improvements in patient outcomes, often lead to multiple adverse effects and complications. For instance, chemotherapy can result in systemic toxicity, while immunotherapy, using agents such as interferon-alpha (IFNα), requires high doses that lead to side effects like myalgia and leukopenia. By examining these issues, this thesis underscores the need for a more targeted, controlled drug delivery approach that can minimize side effects, prevent relapses, and improve patient quality of life. To address these gaps, this research has investigated the potential of a non-surgical synergistic intervention combining iron oxide nanoparticles (FeONPs) functionalized with curcumin (Cur), a natural polyphenol with established anticancer properties, with IFNα, an immunotherapeutic agent for skin cancer, encapsulated within poly(lactic-co-glycolic acid) nanoparticles (IFNα-PLGANPs). Cur has shown the ability to disrupt cancer cell proliferation and invasion by affecting multiple signaling pathways, making it a promising candidate for melanoma treatment. It is, however, limited by a low bioavailability despite its known therapeutic potential. The FeONPs synthesized in this study therefore act as a carrier, enhancing curcumin’s bioavailability, allowing for bioaccumulation at the skin cancer site after topical administration. This functionalization was achieved using a one-step coprecipitation technique, producing nanoparticles (NPs) with an average size of 95.37 nm, vii preferred for effective topical drug delivery. The synthesis and characterization of the curcumin-functionalized (Cur-FeONPs) further demonstrated a stable structure, high biocompatibility, and enhanced therapeutic efficacy. Morphological analysis additionally confirmed a NP size below 100 nm, suitable for cellular uptake and improved bioavailability, with in vitro studies revealing selective cytotoxicity toward melanoma (A375) cells, with limited impact on NIH-3T3 fibroblast cells. A dual-release nanosystem was thereafter designed by combining the Cur-FeONPs with statistically optimized IFNα-PLGANPs (average size = 90.73 nm) developed for the controlled release of IFNα (≈88% after 5 days). This controlled release mechanism achieved multiple goals including protecting the drug from degradation, lowering the dose required at administration, therefore potentially decreasing treatment costs, but also for the separation of IFNα from Cur, which by its broad mechanisms of action has the potential to decrease treatment efficacy when combined with other anticancer interventions. The final therapeutic drug delivery platform developed in this research is a multi-component, dual-release platform for skin cancer incorporating both the Cur-FeONPs and optimized IFNα-PLGANPs within a hydrogel matrix for topical administration. Hydrogels are advantageous for skin cancer treatment due to their flexibility, moisture retention, and ability to provide sustained drug release. Alginate (Alg)-based hydrogels, in particular are useful for topical applications, allowing for direct and localized drug delivery to skin lesions, while minimizing systemic toxicity. In this work, Alg has been used to develop a hydrogel matrix that can support the co-delivery of the combinative agents, mimicking the tumor’s extracellular environment to improve cellular uptake and efficacy. Additionally, the inclusion of lecithin as a structural modifier enhances drug permeability, supporting optimal therapeutic agent release. Rheological studies on the combined NP-loaded platform revealed the hydrogel's temperature responsiveness, mechanical stability, and bioadhesion properties, making it suitable for sustained and localized drug delivery. The hydrogel platform also displayed dual-controlled permeation and release, ensuring prolonged therapeutic action in line with the aim of this study. In vitro antiproliferation and cytotoxicity studies further confirmed synergistic cytotoxic effects against melanoma cells while maintaining biocompatibility with fibroblast cells, highlighting their safety and efficacy. The research performed therefore validated the developed system's potential to achieve controlled drug delivery, minimize systemic toxicity, and enhance treatment outcomes using a synergistic nano-driven approach. Overall, this study advances the field of skin cancer treatment by demonstrating the potential of a hydrogel-based NP-loaded topical drug delivery system for the treatment of skin cancer. viii The combination of Cur-FeONPs and IFNα-PLGANPs researched presents a powerful therapeutic strategy, leveraging both non-surgical synergistic intervention effects to maximize efficacy, while minimizing adverse effects. The findings from this research underscore the promise of this multi-faceted approach in enhancing treatment outcomes, with the developed hydrogel delivery system potentially a valuable tool for developing more effective, patient-specific treatment strategies, opening new avenues for future research in the field of skin cancer therapeutics. Ultimately, this thesis contributes to a growing body of knowledge on the use of nanotechnology and synergistic treatments in oncology, presenting a pathway towards more personalized, efficient, and patient-friendly cancer treatments.