Institute of Biomedical Engineering and Technology, Academy for Engineering & Technology, Fudan University, Shanghai 200433, China.
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
ACS Appl Mater Interfaces. 2024 Aug 28;16(34):44518-44527. doi: 10.1021/acsami.4c09394. Epub 2024 Aug 15.
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard therapy includes maximal surgical resection, radiotherapy, and adjuvant temozolomide (TMZ) administration. However, the rapid development of TMZ resistance and the impermeability of the blood-brain barrier (BBB) significantly hinder the therapeutic efficacy. Herein, we developed spatiotemporally controlled microneedle patches (BMNs) loaded with TMZ and niclosamide (NIC) to overcome GBM resistance. We found that hyaluronic acid (HA) increased the viscosity of bovine serum albumin (BSA) and evidenced that concentrations of BSA/HA exert an impact degradation rates exposure to high-temperature treatment, showing that the higher BSA/HA concentrations result in slower drug release. To optimize drug release rates and ensure synergistic antitumor effects, a 15% BSA/HA solution constituting the bottoms of BMNs was chosen to load TMZ, showing sustained drug release for over 28 days, guaranteeing long-term DNA damage in TMZ-resistant cells (U251-TR). Needle tips made from 10% BSA/HA solution loaded with NIC released the drug within 14 days, enhancing TMZ's efficacy by inhibiting the activity of O6-methylguanine-DNA methyltransferase (MGMT). BMNs exhibit superior mechanical properties, bypass the BBB, and gradually release the drug into the tumor periphery, thus significantly inhibiting tumor proliferation and expanding median survival in mice. The on-demand delivery of BMNs patches shows a strong translational potential for clinical applications, particularly in synergistic GBM treatment.
胶质母细胞瘤（GBM）是最常见和侵袭性最强的恶性脑肿瘤。标准治疗包括最大限度的手术切除、放疗和辅助替莫唑胺（TMZ）给药。然而，TMZ 耐药性的快速发展和血脑屏障（BBB）的通透性显著阻碍了治疗效果。在此，我们开发了载有 TMZ 和尼氯硝唑（NIC）的时空可控微针贴片（BMNs）来克服 GBM 耐药性。我们发现透明质酸（HA）增加了牛血清白蛋白（BSA）的粘度，并证明 BSA/HA 的浓度对高温处理的降解速率有影响，表明较高的 BSA/HA 浓度导致药物释放更慢。为了优化药物释放率并确保协同抗肿瘤作用，选择由 15%BSA/HA 溶液构成的 BMNs 底部来负载 TMZ，显示出超过 28 天的持续药物释放，确保 TMZ 耐药细胞（U251-TR）中的 DNA 持续损伤。由 10%BSA/HA 溶液制成的针尖负载 NIC 在 14 天内释放药物，通过抑制 O6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）的活性增强 TMZ 的疗效。BMNs 表现出优异的机械性能，绕过 BBB，并将药物逐渐释放到肿瘤周围，从而显著抑制肿瘤增殖并延长小鼠的中位生存时间。按需递送 BMNs 贴片具有很强的转化应用潜力，特别是在协同 GBM 治疗中。
