Liu Chengkuan, Zhong Yangui, Huang Haibo, Lan Siyuan, Li Jing, Huang Deqiu, Zhang Wen
Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China.
Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China.
Mater Today Bio. 2024 Nov 25;29:101362. doi: 10.1016/j.mtbio.2024.101362. eCollection 2024 Dec.
Bone metastasis is a fatal consequence of breast cancer that occurs when patients fail to respond to conventional therapies and mainly result from a vicious cycle involving dysregulated bone homeostasis and uncontrolled tumor growth. Recent research has underscored the significance of Siglec-15, a membrane protein implicated in immunosuppression and osteoclast generation. Targeting Siglec-15 may disrupt the "vicious cycle" that causes bone metastases in patients with breast cancer. Herein, we explored the efficacy of targeting Siglec-15 in conjunction with photothermal chemotherapy to impede the progression of bone metastatic during breast cancer and repair tumor-induced osteolysis. First, we formulated an injectable photothermal bioactive glass (BG)-based hydrogel for the local delivery of Siglec-15 shRNA and doxorubicin. The results demonstrated that the hydrogel could kill tumor cells directly through photothermal chemotherapy, provoke intense immune responses and improve the local immunosuppressive microenvironment, which could effectively prevent tumor metastasis and recurrence in a murine model. The combined effect of BGs and Siglec15 shRNA can normalize dysregulated bone homeostasis at the bone metastasis site and significantly reduced bone destruction. Overall, the use of Siglec-15-targeting integrated BG hydrogels may provide a promising therapeutic strategy for treating bone metastasis caused by breast cancer.
骨转移是乳腺癌的致命后果，发生在患者对传统疗法无反应时，主要源于涉及骨稳态失调和肿瘤生长失控的恶性循环。最近的研究强调了Siglec-15的重要性，Siglec-15是一种与免疫抑制和破骨细胞生成有关的膜蛋白。靶向Siglec-15可能会破坏导致乳腺癌患者发生骨转移的“恶性循环”。在此，我们探讨了靶向Siglec-15联合光热化疗在抑制乳腺癌骨转移进展和修复肿瘤诱导的骨溶解方面的疗效。首先，我们制备了一种基于可注射光热生物活性玻璃（BG）的水凝胶，用于局部递送Siglec-15短发夹RNA（shRNA）和阿霉素。结果表明，该水凝胶可通过光热化疗直接杀死肿瘤细胞，引发强烈的免疫反应并改善局部免疫抑制微环境，从而在小鼠模型中有效预防肿瘤转移和复发。BG与Siglec-15 shRNA的联合作用可使骨转移部位失调的骨稳态正常化，并显著减少骨质破坏。总体而言，使用靶向Siglec-15的复合BG水凝胶可能为治疗乳腺癌引起的骨转移提供一种有前景的治疗策略。
