Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, São Paulo 05508-000, Brazil.
Departamento de Cirurgia, LIM26, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 455, São Paulo, São Paulo 01246903, Brazil.
Mol Pharm. 2021 Sep 6;18(9):3401-3417. doi: 10.1021/acs.molpharmaceut.1c00319. Epub 2021 Aug 17.
The need of pharmacological strategies to preclude breast cancer development motivated us to develop a non-aqueous microemulsion (ME) capable of forming a depot after administration in the mammary tissue and uptake of interstitial fluids for prolonged release of the retinoid fenretinide. The selected ME was composed of phosphatidylcholine/tricaprylin/propylene glycol (45:5:50, w/w/w) and presented a droplet diameter of 175.3 ± 8.9 nm. Upon water uptake, the ME transformed successively into a lamellar phase, gel, and a lamellar phase-containing emulsion as the water content increased and released 30% of fenretinide after 9 days. Consistent with the slow release, the ME formed a depot in cell cultures and increased fenretinide IC values by 68.3- and 13.2-fold in MCF-7 and T-47D cells compared to a solution, respectively. At non-cytotoxic concentrations, the ME reduced T-47D cell migration by 75.9% and spheroid growth, resulting in ∼30% smaller structures. The depot formed prolonged a fluorochrome release for 30 days without producing any sings of local irritation. In a preclinical model of chemically induced carcinogenesis, ME administration every 3 weeks for 3 months significantly reduced (4.7-fold) the incidence of breast tumors and increased type II collagen expression, which might contribute to limit spreading. These promising results support the potential ME applicability as a preventive therapy of breast cancer.
为了预防乳腺癌的发生，我们需要开发一种药理学策略，促使我们开发了一种非水微乳液（ME），该微乳液在乳腺组织中给药后能够形成一个储存库，并吸收间质液，从而实现视黄酸芬维 A 酯的长时间释放。所选的 ME 由磷脂酰胆碱/三辛酸甘油酯/丙二醇（45:5:50，w/w/w）组成，粒径为 175.3 ± 8.9nm。当吸收水分时，ME 依次转变为层状相、凝胶相和含有层状相的乳液，随着水分含量的增加，在 9 天后释放了 30%的芬维 A 酯。与缓慢释放一致，ME 在细胞培养中形成了一个储存库，与溶液相比，在 MCF-7 和 T-47D 细胞中分别使芬维 A 酯的 IC 值增加了 68.3-和 13.2 倍。在非细胞毒性浓度下，ME 使 T-47D 细胞迁移减少了 75.9%，球体生长减少了约 30%，导致结构更小。储存库的形成使荧光染料的释放延长了 30 天，且没有产生任何局部刺激的迹象。在化学诱导致癌的临床前模型中，每 3 周给药一次，共给药 3 个月，显著降低了乳腺癌的发生率（4.7 倍），并增加了 II 型胶原蛋白的表达，这可能有助于限制肿瘤的扩散。这些有前景的结果支持 ME 作为乳腺癌预防治疗的潜在适用性。
