Department of Oils, Lipid, Science & Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Ghaziabad 201002, India.
Mol Pharm. 2024 Oct 7;21(10):5053-5070. doi: 10.1021/acs.molpharmaceut.4c00468. Epub 2024 Sep 20.
Aggressive glioma exhibits a poor survival rate. Increased tumor aggression is linked to both tumor cells and tumor-associated macrophages (TAMs), which induce pro-aggression, invasion, and metastasis. Imperatively, for effective treatment, it is important to target both glioma cells and TAMs. Haloperidol, a neuropsychotic drug, avidly targets the sigma receptor (SR), which is expressed in higher levels in both the cell types. Herein, we present the development of a novel cationic lipid-conjugated reduced haloperidol (±RHPC8), which aims to mediate the SR-targeted antiglioma effect. Hypothetically, ±RHPC8 would act simultaneously as an SR-targeting ligand and anticancer agent. As the blood-brain barrier (BBB) obstructs direct targeting of in situ glioma, we used BBB-crossing glucose-based carbon nanospheres (CSPs) to deliver ±RHPC8 within the glioma tumor-bearing mouse brain. The resultant ±RHPC8-CSP nanoconjugate targeted SR-expressing glioma cells. In both orthotopic and subcutaneous mouse tumor models, ±RHPC8-CSP prolonged survival and regressed tumors compared to other treated groups. Notably, ±RHPC8-CSP was significantly taken up by SR-expressing TAMs thus resulting in macrophage polarization from M2 to M1, as exhibited by markedly reduced expression of immunosuppressive cytokines released by TAMs, including TGF-β, IL-10, and VEGF. In conclusion, the designed ±RHPC8-CSP nanoconjugate presented an effective nanodrug delivery system for brain cancer treatment.
侵袭性神经胶质瘤的存活率较低。肿瘤侵袭性的增加与肿瘤细胞和肿瘤相关巨噬细胞（TAMs）有关，它们会诱导促侵袭、转移和转移。至关重要的是，为了进行有效的治疗，靶向神经胶质瘤细胞和 TAMs 都很重要。氟哌啶醇是一种神经精神药物，它强烈靶向 sigma 受体（SR），而这种受体在这两种细胞类型中的表达水平都较高。本文介绍了一种新型阳离子脂质偶联还原氟哌啶醇（±RHPC8）的开发，旨在介导靶向神经胶质瘤的作用。理论上，±RHPC8 将同时作为靶向 SR 的配体和抗癌剂发挥作用。由于血脑屏障（BBB）阻止了原位神经胶质瘤的直接靶向，我们使用了能够穿过 BBB 的葡萄糖基碳纳米球（CSPs）将±RHPC8 递送至荷神经胶质瘤小鼠的脑内。所得的±RHPC8-CSP 纳米缀合物靶向表达 SR 的神经胶质瘤细胞。在原位和皮下小鼠肿瘤模型中，与其他治疗组相比，±RHPC8-CSP 延长了生存期并使肿瘤消退。值得注意的是，±RHPC8-CSP 被表达 SR 的 TAMs 大量摄取，从而导致巨噬细胞从 M2 向 M1 极化，这表现为 TAMs 释放的免疫抑制细胞因子（包括 TGF-β、IL-10 和 VEGF）的表达明显减少。总之，设计的±RHPC8-CSP 纳米缀合物为脑癌治疗提供了一种有效的纳米药物递送系统。
