RESUMO
Despite advances in breast cancer treatment, there remains a need for local management of noninvasive, low-grade ductal carcinoma in situ (DCIS). These focal lesions are well suited for local intraductal treatment. Intraductal administration supported target site drug retention, improved efficacy, and reduced systemic exposure. Here, we used a poly(N-isopropyl acrylamide, pNIPAM) nanoparticle delivery system loaded with cytotoxic piplartine and an MAPKAP Kinase 2 inhibitor (YARA) for this purpose. For tumor environment targeting, a collagen-binding peptide SILY (RRANAALKAGELYKSILYGSG-hydrazide) was attached to pNIPAM nanoparticles, and the nanoparticle diameter, zeta potential, drug loading, and release were assessed. The system was evaluated for cytotoxicity in a 2D cell culture and 3D spheroids. In vivo efficacy was evaluated using a chemical carcinogenesis model in female Sprague-Dawley rats. Nanoparticle delivery significantly reduced the IC50 of piplartine (4.9 times) compared to the drug in solution. The combination of piplartine and YARA in nanoparticles further reduced the piplartine IC50 (~15 times). Treatment with these nanoparticles decreased the in vivo tumor incidence (5.2 times). Notably, the concentration of piplartine in mammary glands treated with nanoparticles (35.3 ± 22.4 µg/mL) was substantially higher than in plasma (0.7 ± 0.05 µg/mL), demonstrating targeted drug retention. These results indicate that our nanocarrier system effectively reduced tumor development with low systemic exposure.
RESUMO
Considering the increased incidence of sporotrichosis and other fungal infections in rural and urban areas, and the limitations and adverse effects of oral itraconazole therapy, we studied nanostructured lipid carriers (NLC) as topical delivery systems to increase itraconazole localization in skin lesions and associate efficacy with reduced systemic exposure. Unloaded and itraconazole-loaded NLC showed nanometric size (~216-340 nm), negative zeta potential (~ -17 mV), and high entrapment efficiency (~97%). NLC treatment decreased transepidermal water loss, an index of cutaneous barrier function, in intact skin and in tissues damaged with a linear incision (to mimic lesions) by 23-36%, and reduced drug transdermal delivery by ~2-fold, demonstrating its ability to localize itraconazole within the skin. The unloaded and itraconazole-loaded NLC were considered safe, as indicated by scores of 0.5 and 0.6 in HET-CAM models, respectively, and lack of toxicity (measured by survival and health index) on the Galleria mellonella larvae. The values obtained for minimum inhibitory concentration and minimum fungicidal concentration on Sporothrix brasiliensis yeasts were 0.25 and 32 µg/mL, respectively. The drug in solution displayed similar values, indicating that encapsulation does not hinder itraconazole antifungal effect. NLC treatment improved the survival rate and health index of G. mellonella larvae infected with S. brasiliensis yeasts and C. albicans, demonstrating antifungal efficacy. Taken together, itraconazole encapsulation in NLC represents a viable strategy to optimize cutaneous localization without compromising its efficacy against fungal infections.