State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
J Control Release. 2024 Nov;375:643-653. doi: 10.1016/j.jconrel.2024.09.034. Epub 2024 Sep 23.
BRAF-mutant colorectal cancer (CRC) is resistant to most first-line therapeutics, including the BRAF inhibitor dabrafenib and epidermal growth factor receptor (EGFR) inhibitor cetuximab. Although copper depletion shows promise in reversing dabrafenib/cetuximab resistance in BRAF-mutant CRC, its application is limited by the potential for excessive copper depletion in non-tumor objects. In this study, we have developed a hydrogel platform for confined copper depletion in BRAF-mutant CRC cells, which effectively reverses dabrafenib/cetuximab resistance and enhancing therapeutic efficiency. The hydrogel platform enables precise intracellular copper depletion through localized administration, acidity-triggered drug release, and oxidized activation of a copper prochelator. The dosage of this prochelator is 37.5 μg/kg in mouse models, which is significantly lower than the commonly used tetrathiomolybdate. Furthermore, both dabrafenib and the prochelator are preloaded into acid-responsive nanoparticles before being embedded in the hydrogel matrix to facilitate efficient endocytosis and acid-activatable drug release. Confined copper depletion inhibits MEK1 signaling and suppresses the MAPK signaling pathway when combined with BRAF and EGFR inhibitors. Moreover, the hydrogel platform inhibits tumor growth and prolongs survival in subcutaneous and postsurgical models of BRAF-mutant CRC. This study provides an innovative strategy for overcoming dabrafenib/cetuximab resistance in BRAF-mutant CRC through precise intracellular copper depletion.
BRAF 突变型结直肠癌（CRC）对大多数一线治疗药物具有耐药性，包括 BRAF 抑制剂达拉非尼和表皮生长因子受体（EGFR）抑制剂西妥昔单抗。尽管铜耗竭在逆转 BRAF 突变型 CRC 中的达拉非尼/西妥昔单抗耐药方面显示出一定的前景，但由于其在非肿瘤靶标中可能会发生过度铜耗竭，其应用受到限制。在这项研究中，我们开发了一种用于 BRAF 突变型 CRC 细胞中受限铜耗竭的水凝胶平台，该平台可有效逆转达拉非尼/西妥昔单抗耐药并增强治疗效果。水凝胶平台通过局部给药、酸度触发药物释放以及氧化激活铜配合物来实现精确的细胞内铜耗竭。该配合物在小鼠模型中的剂量为 37.5μg/kg，明显低于常用的四硫钼酸盐。此外，达拉非尼和配合物均在嵌入水凝胶基质之前被预载入到酸响应性纳米颗粒中，以促进有效的内吞作用和酸激活药物释放。受限的铜耗竭与 BRAF 和 EGFR 抑制剂联合使用时会抑制 MEK1 信号传导并抑制 MAPK 信号通路。此外，水凝胶平台在 BRAF 突变型 CRC 的皮下和手术后模型中抑制肿瘤生长并延长生存期。这项研究为通过精确的细胞内铜耗竭来克服 BRAF 突变型 CRC 中的达拉非尼/西妥昔单抗耐药提供了一种创新策略。
