Self-assembling polypeptide-drug conjugates as innovative therapeutic candidates for glioblastoma treatment by enhancing intracranial residence time.

IF 4.1 Q1 CLINICAL NEUROLOGY

Neuro-oncology advances Pub Date : 2025-09-02 eCollection Date: 2025-01-01 DOI:10.1093/noajnl/vdaf187

Yunjeong Gwon, Jung Eun Kim, Wooram Jung, Soobin Kim, Kyuri Shin, Yejin Lee, Yoori Choi, Gi Jeong Cheon, Won Bae Jeon

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Abstract

Background: Glioblastoma (GBM) is the most lethal and incurable brain tumor, with limited treatment options. Systemic delivery of many promising drugs has proven inefficacious due to insufficient brain penetrance. Convection-enhanced delivery (CED) enables direct intracranial infusion of high drug concentrations. However, CED is impaired by rapid drug clearance from the brain, which diminishes its therapeutic benefits.

Methods: To develop CED-injectable therapeutics for GBM treatment, two polypeptides, XM147 and XM161, were engineered through tandem recombination of IL4Rα- or IL13Rα2-specific ligands with thermally responsive motifs. XM147-AZDye647 was created by labeling XM147 with the fluorescent dye AZDye647 to study clearance kinetics. Polypeptide-drug conjugates (PDCs), XM147-SN38 and XM161-SN38, were generated by conjugating these polypeptides with the topoisomerase I inhibitor SN38, which is potent but too toxic for use without a drug carrier. The antitumor efficacy of CED-infused XM147-SN38 and XM161-SN38 was evaluated in intracerebral GBM mouse models.

Results: XM147 and XM161 exhibited high selectivity and strong binding avidity for their respective receptors. Pharmacokinetic studies of XM147-AZDye647 in non-tumor-bearing mice demonstrated markedly prolonged brain retention following CED. In GBM xenografts, CED-administered XM147-SN38 and XM161-SN38 effectively suppressed tumor growth and significantly extended median survival.

Conclusion: These findings provide evidence supporting the use of CED-infused, long-acting PDCs a promising therapeutic strategy for GBM treatment.

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自组装多肽-药物偶联物通过增加颅内停留时间作为胶质母细胞瘤治疗的创新治疗候选物。

背景：胶质母细胞瘤（GBM）是最致命和最无法治愈的脑肿瘤，治疗方案有限。由于脑外显率不足，许多有希望的药物的全身递送已被证明无效。对流增强输注（CED）可以直接颅内输注高浓度药物。然而，药物从大脑中快速清除会损害CED，从而降低其治疗效果。方法：通过将IL4Rα-或il13r α2特异性配体与热响应基序串联重组，设计了两种多肽XM147和XM161，以开发用于GBM注射的ed治疗药物。用荧光染料AZDye647标记XM147制备了XM147-AZDye647，研究了清除动力学。多肽-药物偶联物（PDCs） XM147-SN38和XM161-SN38是由这些多肽与拓扑异构酶I抑制剂SN38偶联而产生的，SN38是有效的，但在没有药物载体的情况下毒性太大。在脑内GBM小鼠模型中，观察ced灌注的XM147-SN38和XM161-SN38的抗肿瘤作用。结果：XM147和XM161对各自的受体具有高选择性和强结合亲合力。在非荷瘤小鼠中的药代动力学研究表明，CED后，XM147-AZDye647的脑保留时间明显延长。在GBM异种移植物中，ced给药的XM147-SN38和XM161-SN38有效抑制肿瘤生长，显著延长中位生存期。结论：这些发现为使用注入ed的长效PDCs作为GBM治疗的有希望的治疗策略提供了证据。

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