The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel “Y”-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery.

中文翻译：

---

一种用于神经胶质瘤靶向药物递送的新型肽-药物缀合物

血脑屏障（BBB）和血脑肿瘤屏障（BBTB）的存在极大地限制了化疗在胶质瘤中的应用。为了应对这一挑战，最佳的药物输送系统必须有效地穿过 BBB/BBTB 并特异性地将治疗药物输送到神经胶质瘤细胞中，同时最大限度地减少全身毒性。在这里，我们证明了葡萄糖调节蛋白78（GRP78）和多巴胺受体D2在患者来源的胶质瘤组织中高表达，并且多巴胺受体在BBB上高表达。随后，我们合成了一种新型的“Y”型肽，并比较了不同连接体对该肽的受体亲和力和靶向能力的影响。衍生出一种对神经胶质瘤细胞具有更好亲和力和更高溶解度的肽-药物缀合物（pHA-AOHX-VAP-阿霉素缀合物，pHA-AOHX-VAP-DOX）用于神经胶质瘤治疗。 pHA-AOHX-VAP-DOX可以同时穿过BBB和BBTB多巴胺受体以及GRP78受体，最终靶向胶质瘤细胞，显着延长颅内胶质瘤裸鼠的生存时间。此外，pHA-AOHX-VAP-DOX显着降低了DOX的毒性并增加了最大耐受剂量（MTD）。总的来说，这项工作为克服多重障碍并有效地将化疗药物递送至神经胶质瘤细胞铺平了一条新途径，同时为识别神经胶质瘤靶向药物递送的潜在受体提供了关键证据。