Michelle Barreto Requena

Background/Objectives: Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) and its derivatives is an established non-surgical approach for non-melanoma skin cancer (NMSC), particularly basal cell carcinoma (BCC), squamous cell carcinoma (SCC) in situ, and premalignant lesions such as actinic keratosis. Despite favorable cosmetic outcomes and its ability to treat field cancerization, conventional topical ALA-PDT is better suited to superficial lesions because of limited precursor penetration, heterogeneous protoporphyrin IX (PpIX) accumulation, and insufficient light delivery to deeper tissue layers. This review critically examines the biological and physical barriers that limit ALA-based PDT efficacy in NMSC and discusses emerging multimodal strategies to address these challenges. Methods: This review examines the biological and physical factors that limit topical ALA-based PDT, drawing on current knowledge of heme biosynthesis, mitochondrial regulation of PpIX accumulation, skin optical properties, and oxygen dependence. It also highlights near-infrared photobiomodulation (PBM) and microneedle-assisted ALA delivery as complementary strategies that may help overcome these barriers. Results: Near-infrared PBM is a promising adjunct: in cell culture and exploratory human skin studies, it modulates endogenous PpIX production. Whether this translates into greater photosensitizer availability at depth, shorter incubation, or reduced treatment-related pain in NMSC remains hypothetical and untested clinically. Concurrently, dissolving microneedle arrays (MAs) have shown enhanced intradermal ALA delivery and increased PpIX accumulation and distribution in preclinical studies. These are independent strategies that address distinct barriers within the PDT pathway and may be combined to maximize therapeutic response. Conclusions: Overcoming the depth and delivery limitations of conventional ALA-PDT may be approached by improving precursor delivery, photosensitizer generation, and efficient irradiation. Near-infrared PBM and microneedle-assisted drug delivery are separate, mechanistically grounded strategies that could extend PDT efficacy to thicker, more challenging NMSC lesions; whether they also improve patient tolerability remains to be established. Future translational and clinical studies should prioritize optimizing these protocols and validating their impact on long-term PDT response, recurrence rates, and patient-reported outcomes.

Photodynamic therapy (PDT) is a promising minimally invasive treatment for non-melanoma skin cancer (NMSC). Still, its clinical efficacy is limited by light attenuation and drug distribution within tumor tissue, which restricts photosensitizer activation in deeper tumor regions. PDT with 5-aminolevulinic acid (ALA) is widely used as a precursor to induce accumulation of protoporphyrin IX (PpIX), followed by red light irradiation; it is effective for superficial lesions but often fails to achieve complete tumor control in thicker tumors, contributing to long-term lesion recurrence. To address this limitation, we investigated a two-photosensitizer, two-wavelength-PDT approach that combines ALA with indocyanine green (ICG), a near-infrared (NIR)-responsive photosensitizer that can be activated at greater tissue depths. This also promotes different cellular death targets, since ALA-mediated PDT mainly induces direct tumor cell killing through apoptosis and necrosis, whereas ICG-mediated PDT may contribute to treatment effects through deeper tissue activation and vascular-associated mechanisms. In this study, a preclinical model of cutaneous squamous cell carcinoma (SCC) was used, with animals assigned to control, single-photosensitizer PDT (ALA, ICG), and combined photosensitizer PDT treatment groups. The effect of photosensitizer administration and light irradiation sequence on therapeutic efficacy was also investigated, and tumor progression and survival outcomes were monitored over time. The results indicated that the combined ALA+ICG-PDT approach produced the most sustained suppression of tumor growth and significantly prolonged animal survival compared with single-photosensitizer PDT. Importantly, these findings demonstrated a strong dependence on the sequence in which the photosensitizer and light are applied. These findings indicate that integrating photosensitizers activated at complementary wavelengths may improve treatment coverage across the tumor and partially overcome depth-related limitations associated with PDT, representing a promising strategy to enhance PDT efficacy for NMSC and other solid tumors.

SignificancePneumonia remains a global health challenge, exacerbated by antimicrobial resistance, which limits the effectiveness of conventional treatments. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising alternative for lower respiratory infections; however, its in vivo performance is hindered by lung surfactant, which traps photosensitizers and reduces their ability to reach bacterial targets.AimTo address this limitation, recent studies demonstrated that combining indocyanine green (ICG) with the polymer Gantrez AN-139 enhances photodynamic activity even in the presence of lung surfactants.ApproachWe assessed the therapeutic potential of this formulation in a murine pneumonia model using pulmonary delivery followed by 808 nm infrared irradiation.ResultsNebulization of 200 μM ICG with 4% Gantrez AN-139 and irradiation at 120 J/cm2 yielded the best results, reducing bacterial load by up to 3 log10 and improving survival to 80%, compared with 40% in controls.ConclusionThese findings validate the formulation and the procedure for further animal studies.

SignificanceDissolving microneedles (MN) have emerged as a promising platform for drug delivery, providing a minimally invasive approach to bypass the skin’s natural barriers and enhance molecular penetration and diffusion. Their biocompatibility, user-friendly application, and ability to deliver precise therapeutic dosing make them particularly suitable for dermatological use. In addition to pharmacological benefits, dissolving MN possesses a geometric structure that enables optical waveguiding, thereby improving light penetration and distribution.AimWe address a key limitation of photodynamic therapy (PDT): the limited penetration of light into biological tissues. PDT relies on activating photosensitizing agents with specific wavelengths of light to generate cytotoxic species, selectively targeting abnormal or diseased cells while minimizing effects on surrounding healthy tissue.ApproachPyramidal dissolving MN arrays were fabricated from a biocompatible polymer and systematically characterized. Their light distribution profile under laser illumination was evaluated using image analysis.ResultsQuantitative analysis of light distribution demonstrates that MN can simultaneously facilitate drug delivery and light distribution.ConclusionsThis multifunctionality provides a synergistic therapeutic advantage, as localized drug release is complemented by optimized light delivery, thereby enhancing treatment outcomes. The dual-function platform has significant implications for PDT, enabling the design of integrated therapeutic systems that combine chemical and photonic modalities within a single, biodegradable device. Such systems may be particularly advantageous in resource-limited settings or outpatient care, where ease of use and effectiveness are essential. This strategy offers an approach to overcoming the limitations of conventional light-based therapies, supporting the development of more effective and accessible treatments for skin cancer and other dermatological conditions.

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.

Pneumonia remains one of the leading global public health challenges, with rising antimicrobial resistance severely limiting the effectiveness of conventional therapies. Antimicrobial Photodynamic Therapy (aPDT) has emerged as a promising alternative to combat lower respiratory tract infections. Nonetheless, its in vivo efficacy has been hampered by lung surfactant (LS), which sequesters photosensitizers (PS) and prevents them from reaching bacterial targets, thereby reducing therapeutic outcomes. To address this barrier, recent studies have demonstrated that indocyanine green (ICG) complexed with the copolymer Gantrez AN-139 maintains activity against Streptococcus pneumoniae in vitro , even in the presence of LS. Building upon these findings, the present study evaluated the effectiveness of this formulation in a murine pneumonia model. Among the tested protocols, nebulization of 200 µM ICG with 4% (w/w) Gantrez AN-139 followed by external near-infrared illumination (808 nm, 120 J/cm²) achieved nearly 3 log₁₀ bacterial reduction and improved survival (80% at 21 days). These

Dissolving microneedles (DMNs) is a promising technology for transdermal and intradermal drug delivery. However, effective decontamination protocols are necessary to ensure safety and efficacy in clinical applications. The challenge is to use a technique that preserves mechanical properties, does not introduce chemicals, and can decontaminate DMNs without affecting the drug. With its potent antimicrobial properties and minimal residual effects, ozone presents a novel and safe method for decontaminating DMNs. Specifically, the present study assesses ozone's efficacy in decontaminating DMNs loaded with aminolevulic acid, intended for photodynamic therapy in skin cancer treatment. The results showed that it effectively decontaminates E. coli and S. aureus without compromising the polymer properties or promoting drug degradation. Overall, ozone represents an approach that can be adopted to decontaminate DMNs, offering a safer and effective strategy that enhances their potential to translate to clinical application.

Photodynamic therapy is a treatment modality that can be used to treat various types of lesions. To produce cell death, reaching a certain threshold dose of reactive oxygen species (ROS) is required. The estimation of ROS production is of paramount importance to predict the depth of necrosis and to ensure that the volume to be treated receives doses higher than the threshold. In this study, we compared a theoretical model for PDT based on Monte Carlo simulations of light irradiance and rate equations with a rat liver model. At the end of the simulation, necrosis depths and volumes were estimated, as well as the photosensitizer (PS), oxygen, and ROS concentrations at each position of the treated area. From the in vivo study, we obtained the ROS concentration threshold of about 1 mM for Photogem in rat liver. This proposed method can be used for any PS or tissue, including tissues with multiple layers. The proposed method can be used to estimate parameters for any PS or tissue, including layered tissues, as long as their parameters are known. In addition, other protocols can be tested, or compared with the standard ones, providing the bases for analyzing a diverse range of photodynamic treatment scenarios.