# Navigating the Challenges of Metallopharmaceutical Agents: Strategies and Predictive Modeling for Skin Cancer Therapy

## TL;DR

This review explores innovative strategies and modeling techniques to improve metal-based drugs for skin cancer treatment, addressing challenges like poor solubility and skin permeability.

## Contribution

The paper provides a comprehensive overview of recent advances in metallopharmaceuticals and delivery systems for skin cancer, emphasizing predictive modeling and novel formulations.

## Key findings

- Metallopharmaceuticals show promise in inducing oxidative stress and modulating cancer pathways.
- Drug delivery systems like nanoparticles and microneedles enhance skin permeation and stability of metal complexes.
- Computational modeling supports the design of effective nanocarriers for targeted skin cancer therapy.

## Abstract

Skin cancer (SC) is the most prevalent malignancy worldwide, with subtypes varying in aggressiveness: basal cell carcinoma tends to be locally invasive, squamous cell carcinoma has a higher metastatic risk, and melanoma remains the deadliest form. Current treatments such as surgery, radiotherapy, and systemic chemotherapy are associated with aesthetic and functional morbidity, recurrence, and/or systemic toxicity. Although targeted therapies and immunotherapies offer clinical benefits, their high cost and limited accessibility underscore the need for innovative, affordable alternatives. Metal-based compounds (metallopharmaceuticals) are promising anticancer agents due to their ability to induce oxidative stress, modulate redox pathways, and interact with DNA. However, clinical translation has been limited by poor aqueous solubility, rapid degradation, and low skin permeability. This review discusses the most recent preclinical findings on gold, silver, platinum, palladium, ruthenium, vanadium, and copper complexes, mainly in topical and systemic treatments of SC. Advances in chemical and physical enhancers, such as hydrogels and microneedles, and in drug delivery systems, including bacterial nanocellulose membranes and nanoparticles, as well as liposomes and micelles, for enhancing skin permeation and protecting the integrity of metal complexes are also discussed. Additionally, we examine the contribution of photodynamic therapy to SC treatment and the use of mathematical and computational modeling to simulate skin drug transport, predict biodistribution, and support rational nanocarrier design. Altogether, these strategies aim to bridge the gap between physicochemical innovation and clinical applicability, paving the way for more selective, stable, and cost-effective SC treatments.