ArticleNeuro-oncology advances
Self-assembling polypeptide-drug conjugates as innovative therapeutic candidates for glioblastoma treatment by enhancing intracranial residence time.
Article in Neuro-oncology advances. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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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