Formulações farmacêuticas contendo nanocápsulas poliméricas de óleo de romã e 3,3’-diindolmetano com potencial aplicação na terapia do melanoma cutâneo

Abstract

Cutaneous melanoma is a skin cancer originated in the melanocytes and is considered the biggest cause of deaths considering all cutaneous neoplasms. Because of its aggressiveness, researching for new therapies applying bioactives is especially important. In this context, 3,3'-diindolmethane (DIM) is a phytochemical from cruciferous vegetables with already reported antitumor effects. However, DIM has some limitations that may compromise its therapeutic performance. Pomegranate oil has also been calling the attention due to its antioxidant, anti-inflammatory and antitumor therapeutic potentials. Considering these constituents’ benefits, as well as DIM limitations, the development of polymeric nanocapsules associating pomegranate oil and DIM may be an alternative for melanoma therapy, since polymeric nanocapsules are known to modulate the distribution profile of actives on the skin, enhancing therapeutic effects. In addition, nanocapsules can be incorporated in hydrogels or polymeric films, promoting an adequate permanence and performance on the skin. Considering this, this work aimed to develop suspensions of polymeric nanocapsules of pomegranate oil containing DIM and incorporate them in hydrogels and karaya gum polymeric films, aiming new therapeutic propositions for the cutaneous melanoma therapy. The nanocapsules presented nanometric size (<180 nm) and unimodal distribution (IPD < 0.2), positive or negative zeta potential, according to the polymeric material, slightly acidic pH, DIM content close to theoretical (1 mg/mL) and encapsulation efficiency above 97%. The developed nanocapsules were able to protect DIM from photodegradation, proving to be safe against vascular events (HET-CAM) and with reduced cytotoxic and genotoxic potential (Allium Cepa). Furthermore, pomegranate oil and DIM nanocapsules presented an enhanced in vitro antioxidant and antitumor potential. The developed hydrogels showed a nanometer-scale particle size, a DIM content close to the theoretical one (1 mg/g), adequate spreadability factor, pseudoplastic behavior and were classified as non-irritating (HET-CAM). The polymeric nanocapsules presence promoted greater bioadhesive potential on the skin. The in vitro release profile showed that the hydrogels containing nanoencapsulated DIM had a controlled release profile, corroborating with the cutaneous permeation profile obtained where a smaller amount of active reached different skin layers. The polymeric films were transparent, with uniform thickness, weight and DIM content (106 μg/cm2), being considered hydrophilic (θ > 90°) and bioadhesive. The nanoencapsulated DIM films were more resistant to rupture and more rigid (58.9 ± 2.66 mPa) and promoted a controlled in vitro release profile of the bioactive, keeping the cutaneous permeation levels in different skin layers. The films’ antioxidant activity indicated that they are able to maintain the bioactive antioxidant potential. Finally, the polymeric films proved to be non-hemolytic (hemolysis test) and non-irritating (HET-CAM). The results demonstrated the association benefits of pomegranate oil and DIM in polymeric nanocapsules, as well as the development of hydrogels or karaya gum polymeric films containing nanosystems. Both pharmaceutical formulations represent an interesting alternative treatment for the local cutaneous melanoma therapy.