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

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.