Advancements in nanoparticle-based treatment approaches for skin cancer therapy

Skin cancer, encompassing melanoma and non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma), poses a major global health challenge. The incidence is alarmingly high, exacerbated by factors like ultraviolet radiation exposure, chemical carcinogens, genetic predisposition, and immunosuppression. Existing treatment options, including surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapy, face considerable hurdles. Surgical approaches may leave scars and are not suitable for all stages or locations. Radiotherapy can be costly and may not always be effective. Chemotherapy, while more affordable, often suffers from poor efficacy and severe side effects due to issues like poor bioavailability, inadequate solubility and permeability, and chemoresistance. Immunotherapy and targeted therapy, while offering promising results, are often prohibitively expensive and associated with poor patient compliance. The five-year survival rate for advanced-stage melanoma remains unacceptably low. Therefore, the need for novel therapeutic strategies to overcome these limitations and improve patient outcomes is paramount. Nanotechnology, with its unique ability to manipulate materials at the nanoscale, offers a promising avenue for addressing these challenges. Nanoparticles (NPs), in particular, have emerged as versatile tools in cancer therapy, functioning as both therapeutic agents and drug carriers, thereby potentially offering a more effective and targeted treatment approach for skin cancer.

Several reviews have examined the application of nanotechnology in skin cancer treatment. However, this review distinguishes itself by providing a detailed classification of nanoparticles into inorganic, polymer, and lipid-based categories, offering a comprehensive and up-to-date overview of the field. Existing literature highlights the use of various nanomaterials such as nanofibers, nanosuspensions, nanoemulsions, and nanoclays. However, nanoparticles stand out due to their unique size-dependent physicochemical properties, enhancing drug delivery to tumor sites via the enhanced permeability and retention (EPR) effect, evading the reticuloendothelial system (RES), and improving skin permeability for topical delivery. The review further elaborates on FDA-and EMA-approved nanoparticles for other cancer types, highlighting the ongoing research and development efforts towards creating effective nanoparticle-based therapies specifically for skin cancer.

This review article meticulously analyzes existing research literature on nanoparticle-based approaches to skin cancer therapy. The authors systematically searched and reviewed relevant studies published in peer-reviewed journals, focusing on the classification, properties, and applications of various nanoparticles in treating different types of skin cancer. The literature search included publications focusing on the use of inorganic nanoparticles (e.g., mesoporous silica nanoparticles, gold nanoparticles, carbon nanotubes, zinc oxide nanoparticles, cerium oxide nanoparticles), polymer-based nanoparticles (e.g., polymeric micelles, dendrimers, polymeric nanoparticles), and lipid-based nanoparticles (e.g., solid lipid nanoparticles, nanostructured lipid carriers, liposomes, niosomes, transferosomes, ethosomes) in skin cancer therapy. In addition to the in-vitro and in-vivo studies, the authors reviewed the patents and clinical trials associated with these nanoparticle-based approaches. The review focuses on mechanisms of action, efficacy, toxicity profiles, and potential advantages and limitations of each nanoparticle type. The article presents a systematic overview of the existing knowledge, identifies research gaps, and offers insights into future research directions for the development of effective and safe nanoparticle-based therapies for skin cancer.

The review provides comprehensive information on the different types and pathology of skin cancer, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. It details current treatment strategies—excisional surgery, Mohs surgery, curettage and electrodesiccation, cryotherapy, radiotherapy, and photodynamic therapy—alongside their limitations. The core of the review focuses on the diverse applications of nanoparticles in skin cancer therapy. **Inorganic Nanoparticles:** * **Mesoporous silica nanoparticles (MSNs):** Show promise in delivering various chemotherapeutic agents (cisplatin, dacarbazine) and phytoconstituents (resveratrol) while reducing toxicity. Studies demonstrated enhanced drug loading, controlled release, improved skin permeability, and tumor targeting. The combination of MSNs with photothermal therapy (PTT) also showed enhanced efficacy. * **Carbon nanotubes (CNTs):** Exhibit intrinsic anticancer properties and can deliver chemotherapeutic agents (paclitaxel, curcumin) and immunotherapy agents. They can be used for photothermal therapy (PTT), showing potential for synergistic effects. * **Zinc oxide nanoparticles (ZnO NPs):** Possess inherent cytotoxicity due to ROS generation and can be used in PTT/PDT. Studies highlight their use in drug delivery and as inherent anticancer agents. * **Gold nanoparticles (AuNPs):** Are effective photothermal agents due to their surface plasmon resonance (SPR) effect. They can inhibit angiogenesis and are used in drug delivery. Studies show biocompatible AuNPs coated with gum arabic as effective agents against melanoma. Also, there is a unique bacteria-imitating nanosystem using AuNPs for enhanced PTT/ immunotherapy. * **Silver nanoparticles (AgNPs):** Induce oxidative stress and can be used in PTT. Studies indicate potential in combination therapy with chemotherapeutic agents and immunotherapy. * **Cerium oxide nanoparticles (CeO2 NPs):** Possess both redox regulation and enzyme-like activity, modulating ROS levels. Studies show promising results in reducing melanoma cell viability. * **Other inorganic NPs:** Bioactive glass NPs, terbium oxide NPs, and graphene oxide NPs show potential, but require further research in skin cancer therapy. Platinum NPs combined with DOX and Copper NPs derived from natural extracts show promising anti-melanoma activity. **Polymer-based Nanoparticles:** * **Polymeric micelles (PMs):** Efficiently deliver drugs topically, improving skin permeability and reducing toxicity. Studies showed enhanced delivery of paclitaxel and siRNA. Combining PMs with microneedles (MNs) for enhanced PTT is also promising. * **Dendrimers:** Can deliver drugs and target specific pathways, enhancing efficacy and reducing side effects. Studies demonstrated improved delivery of Vismodegib and doxorubicin, showing targeted and controlled delivery. * **Polymeric nanoparticles:** Are used for targeted drug delivery, enhancing cellular uptake and tumor-specific distribution. Studies show reduction-responsive cross-linked PLGA nanoparticles can deliver Doxorubicin effectively. **Lipid-based Nanoparticles:** * **Solid lipid nanoparticles (SLNs):** Enhance drug bioavailability and reduce toxicity. Studies indicate increased efficacy of oral dacarbazine and paclitaxel. Topical delivery of Curcumin and Resveratrol-loaded SLNs showed promise. * **Nanostructured lipid carriers (NLCs):** Improve drug loading, stability, and controlled release. Studies showed enhanced efficacy of doxorubicin and lidocaine combinations for topical application. Delivery of Resveratrol and Quercetin via NLCs improved efficacy. * **Liposomes, niosomes, transferosomes, and ethosomes:** Liposomes efficiently encapsulate both hydrophobic and hydrophilic drugs, enhancing delivery of peptide vaccines and IDO inhibitors. Niosomes are potential carriers for siRNA, and transferosomes improve the skin permeability of photosensitizers like Rose Bengal. Ethosomes enhance transdermal drug delivery, improving the efficacy of Vismodegib.

The findings of this review demonstrate the significant potential of nanotechnology, specifically nanoparticle-based approaches, to improve skin cancer therapy. Nanoparticles' unique properties—such as enhanced tumor uptake, controlled drug release, reduced toxicity, and improved skin permeability—address many of the limitations associated with conventional treatments. The review highlights the efficacy of various nanoparticle types in delivering chemotherapeutic agents, immunotherapy agents, and phytoconstituents, often showing synergistic effects when combined with other treatment modalities like photothermal and photodynamic therapy. The detailed classification of nanoparticles and the inclusion of recent patents and clinical trials provide valuable insights into the current state of the field and highlight promising avenues for future research. The ability to achieve targeted delivery through various administration routes—intravenous, intratumoral, oral, and transdermal—demonstrates the versatility of these approaches and their potential to improve outcomes for patients with different types and stages of skin cancer.

Nanoparticle-based therapies hold immense promise for skin cancer treatment, offering improvements in efficacy, reducing toxicity, and potentially lowering costs. Further research is needed to optimize nanoparticle design, targeting strategies, and combination therapies to maximize their potential. Preclinical studies should focus on enhancing biocompatibility, biodegradability, and tumor-targeting capabilities. The translation of promising preclinical findings into robust clinical trials is crucial for developing safe and effective nanoparticle-based skin cancer therapies for widespread use.

This review is limited to the information available in the published literature. While the authors have made an effort to provide a comprehensive overview, certain aspects of nanoparticle-based skin cancer therapies may require further investigation. The lack of extensive clinical trial data for many nanoparticle formulations represents a limitation, hindering definitive conclusions regarding their long-term efficacy and safety profiles. The generalizability of preclinical findings to human populations also needs further confirmation through well-designed clinical studies. Future research should address these limitations to fully realize the potential of nanoparticle-based therapies in treating skin cancer.