Skin cancer, with all its variations, is the most common type of cancer worldwide. Chemotherapy by topical application is an attractive strategy because of the ease of application and non-invasiveness. At the same time, the delivery of antineoplastic agents through the skin is difficult because of their challenging physicochemical properties (solubility, ionization, molecular weight, melting point) and the barrier function of the stratum corneum. Various approaches have been applied in order to improve drug penetration, retention, and efficacy. This systematic review aims at identifying the most commonly used techniques for topical drug delivery by means of gel-based topical formulations in skin cancer treatment. The excipients used, the preparation approaches, and the methods characterizing gels are discussed in brief. The safety aspects are also highlighted. The combinatorial formulation of nanocarrier-loaded gels is also reviewed from the perspective of improving drug delivery characteristics. Some limitations and drawbacks in the identified strategies are also outlined and considered within the future scope of topical chemotherapy.

Background/Objectives: Natural substances have been a widely studied source of both pharmaceutical excipients and drugs. Berberine (BRB) is a benzylisoquinoline alkaloid isolated from different plant sources. It possesses various pharmacological properties including antibacterial, antitumor, antidiabetic, neuroprotective, hepatoprotective, anti-inflammatory, antioxidant, etc. However, the limited aqueous solubility hinders its application. Nanosized drug delivery systems are an innovative approach for addressing various challenges regarding drug delivery via different routes of administration. Their utilization could improve the solubility of active constituents. Methods: A melt-emulsification and ultrasonication technique was applied for the preparation of nanostructured lipid carriers (NLCs). They were thoroughly physicochemically characterized by the means of Dynamic Light Scattering, TEM, FTIR, DSC, TGA, and In Vitro release. The In Vitro efficacy and safety were evaluated on cholangiocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, lymphoma, fibroblast, and cardioblast cells, as well as rat liver microsomes by means of cytotoxicity assays and the comet assay. Results: The obtained nanoparticles had a spherical shape and size around 158.2 ± 1.8 nm with negative zeta potential. They revealed successful drug loading and improved dissolution of berberine in physiological conditions. The In Vitro safety studies showed that loading BRB in NLCs resulted in improved or retained cytotoxicity to tumor cell lines and reduced cytotoxicity to normal cell lines and liver microsomes. The NLC itself increased microsomal malondialdehyde (MDA) and comet formation. Conclusions: A successful preparation of NLCs with berberine is presented. The nanocarriers show favorable physicochemical and biopharmaceutical properties. The cellular experiments show that the NLC loading of berberine could improve its anticancer efficacy and safety. These findings highlight the potential applicability of berberine in gastrointestinal neoplasms and build the foundation for future practical translation.

Mesoporous silica nanoparticles (MSNs) are inorganic nanocarriers presenting versatile properties and the possibility to deliver drug molecules via different routes of application. Their modification with lipids could diminish the burst release profile for water-soluble molecules. In the case of oleic acid (OA) as a lipid component, an improvement in skin penetration can be expected. Therefore, in the present study, aminopropyl-functionalized MSNs were modified with oleic acid through carbodiimide chemistry and were subsequently incorporated into a semisolid hydrogel for dermal delivery. Doxorubicin served as a model drug. The FT-IR and XRD analysis as well as the ninhydrin reaction showed the successful preparation of the proposed nanocarrier with a uniform particle size (352–449 nm) and negative zeta potential. Transmission electron microscopy was applied to evaluate any possible changes in morphology. High encapsulation efficiency (97.6 ± 1.8%) was achieved together with a sustained release profile over 48 h. The composite hydrogels containing the OA-modified nanoparticles were characterized by excellent physiochemical properties (pH of 6.9; occlusion factor of 53.9; spreadability of factor 2.87 and viscosity of 1486 Pa·s) for dermal application. The in vitro permeation study showed 2.35 fold improvement compared with the hydrogel containing free drug. In vitro cell studies showed that loading in OA-modified nanoparticles significantly improved doxorubicin’s cytotoxic effects toward epidermoid carcinoma cells (A431). All of the results suggest that the prepared composite hydrogel has potential for dermal delivery of doxorubicin in the treatment of skin cancer.

The topical administration of in situ hydrogels for ocular pathologies is a promising application strategy for providing high effectiveness and patient compliance. Curcumin, a natural polyphenol, possesses all the prerequisites for successful therapy of ophthalmic diseases, but unfortunately its physicochemical properties hurdle the practical use. Applying a composite in situ thermoresponsive hydrogel formulation embedded with polymer nanoparticles is a potent strategy to overcome all the identified drawbacks. In the present work we prepared uniform spherical nanoparticles (296.4 ± 3.1 nm) efficiently loaded with curcumin (EE% 82.5 ± 2.3%) based on the biocompatible and biodegradable poly-(lactic-co-glycolic acid). They were thoroughly physicochemically characterized in terms of FTIR, SEM, TGA, and DLS, in vitro release following Fickian diffusion (45.62 ± 2.37%), and stability over 6 months. Their lack of cytotoxicity was demonstrated in vitro on HaCaT cell lines, and the potential for antioxidant protection was also outlined, starting from concentrations as low as 0.1 µM and reaching 41% protection at 5 µM. An in situ thermoresponsive hydrogel (17% w/v poloxamer 407 and 0.1% Carbopol) with suitable properties for ophthalmic application was optimized with respect to gelation temperature (31.40 ± 0.36 °C), gelling time (8.99 ± 0.28 s) upon tears dilution, and gel erosion (90.75 ± 4.06%). Upon curcumin-loaded nanoparticle embedding, the in situ hydrogels demonstrated appropriate pseudoplastic behavior and viscosity at 35 °C (2129 ± 24 Pa∙s), 6-fold increase in the permeation, and prolonged release over 6 h.