Valle Ana Beatriz Caribé Dos Santos, da Silva Fábio Fernando Alves, Carneiro Maria Ângela Pepe, Espuche Bruno, Tavares Guilherme Diniz, Bernardes Emerson Soares, Moya Sergio Enrique, Pittella Frederico
Laboratório de Desenvolvimento de Sistemas Nanoestruturados, Faculdade de Farmácia, Universidade Federal de Juiz de Fora, Rua José Lourenço Kelmer, Juiz de Fora 36036-900, Brazil.
Instituto de Pesquisas Energéticas e Nucleares, Centro de Radiofarmácia (IPEN/CECRF), Comissão Nacional de Energia Nuclear, São Paulo 05508-000, Brazil.
Pharmaceuticals (Basel). 2024 Oct 4;17(10):1325. doi: 10.3390/ph17101325.
Acquired resistance and adverse effects are some of the challenges faced by thousands of Luminal A breast cancer patients under tamoxifen (TMX) treatment. Some authors associate the overexpression of HOXB7 with TMX resistance in this molecular subtype, and the knockdown of this gene could be an effective strategy to regain TMX sensitivity. Therefore, we used calcium phosphate hybrid nanoparticles (HNP) for the delivery of short interfering RNA molecule (siRNA) complementary to the HOXB7 gene and evaluated the RNA interference (RNAi) effects associated with TMX treatment in breast cancer in vivo.
HNP were prepared by the self-assembly of a methoxy-poly (ethylene glycol)-block-poly (L-glutamic acid) copolymer (PEG-pGlu) and the coprecipitation of CaPO to incorporate siRNA. The in vitro cell viability and migration were evaluated prior to in vivo experiments. Further, animals bearing early-stage and advanced Luminal A breast cancer were treated with HNP-siHOXB7, HNP-siHOXB7 + TMX, and TMX. Antitumoral activity and gene expression were evaluated following histopathological, hematological, and biochemical analysis.
The HNP were efficient in delivering the siRNA in vitro and in vivo, whilst HOXB7 silencing associated with TMX administration promoted controlled tumor growth, as well as a higher survival rate and reduction in immuno- and hepatotoxicity.
Therefore, our findings suggest that HOXB7 can be an interesting molecular target for Luminal A breast cancer, especially associated with hormone therapy, aiming for adverse effect mitigation and higher therapeutic efficacy.
获得性耐药和不良反应是数千名接受他莫昔芬（TMX）治疗的腔面A型乳腺癌患者面临的一些挑战。一些作者将HOXB7的过表达与这种分子亚型的TMX耐药性联系起来，而敲低该基因可能是恢复TMX敏感性的有效策略。因此，我们使用磷酸钙杂化纳米颗粒（HNP）来递送与HOXB7基因互补的小干扰RNA分子（siRNA），并在体内评估了与TMX治疗相关的RNA干扰（RNAi）效应。
通过甲氧基聚（乙二醇）-嵌段-聚（L-谷氨酸）共聚物（PEG-pGlu）的自组装和CaPO的共沉淀来制备HNP以掺入siRNA。在体内实验之前评估体外细胞活力和迁移。此外，对患有早期和晚期腔面A型乳腺癌的动物用HNP-siHOXB7、HNP-siHOXB7 + TMX和TMX进行治疗。在组织病理学、血液学和生化分析后评估抗肿瘤活性和基因表达。
HNP在体外和体内递送siRNA方面均有效，而与TMX给药相关的HOXB7沉默促进了肿瘤的可控生长，以及更高的存活率和免疫毒性及肝毒性的降低。
因此，我们的研究结果表明，HOXB7可能是腔面A型乳腺癌一个有趣的分子靶点，特别是与激素治疗相关，旨在减轻不良反应并提高治疗效果。
