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<p>Intraoperatively applied local drug delivery systems (LDDS) offer a means of overcoming blood–brain barrier (BBB) impermeability. However, there is a paucity of LDDS development for paediatric tumours arising in the posterior fossa. Here we demonstrate applicability of an LDDS against medulloblastoma group 3 (G3 MB) and atypical teratoid/rhabdoid tumours (AT/RT), neoplasms associated with poor prognoses. A poly(ethyleneglycol)-poly(caprolactone)-poly(ethyleneglycol) (PECE) hydrogel loaded with chemotherapeutics identified as effective against primary G3 MB and AT/RT&#xa0;in vitro, was prepared as an injectable, biodegradable formulation. CHIR99021 (glycogen synthase kinase-3 inhibitor), ribavirin (guanosine analogue) and PG545 (heparanase inhibitor) were chosen based upon an inability to traverse the BBB. The hydrogel alone was well-tolerated, and drug-loaded hydrogel achieved &gt; 1-month therapeutic release.&#xa0;Orthotopic xenograft studies against G3 MB and AT/RT indicated good tolerability to combined CHIR99021 and PG545 or combined CHIR99021 and ribavirin loaded loaded LDDS respectively. Median survival of AT/RT arms receiving XRT alone was comparable to CHIR99021- and ribavirin-loaded LDDS, with long-term survivors observed only in the latter arm, demonstrating a significant survival benefit. LDDS against cerebellar tumours using PECE offers a promising therapeutic alternative and the possibility of circumventing radiation-induced adverse effects for children impacted by these diseases.</p> Graphical Abstract <p></p>

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Intraoperative drug delivery to hindbrain tumours via an injectable hydrogel is well tolerated and confers survival benefit against atypical teratoid/rhabdoid xenografts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月4日

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  • Cara Moloney,
  • Phoebe McCrorie,
  • Amr ElSherbeny,
  • Harry Porter,
  • Chiara Bastiancich,
  • Hasan Slika,
  • Aanya Shahani,
  • Emre Derin,
  • Esteban Velarde,
  • Jackson Miller,
  • John Theodore,
  • Khushi Varshney,
  • F. N. U. Ruchika,
  • Hulya Bayraktutan,
  • Umut Can Oz,
  • Pam Collier,
  • Simon M. L. Paine,
  • Paul Handley,
  • Keith Dredge,
  • Grzegorz Wicher,
  • Richard G. Grundy,
  • Henry Brem,
  • Karin Forsberg-Nilsson,
  • Stuart J. Smith,
  • Betty Tyler,
  • Cameron Alexander,
  • Ruman Rahman

摘要

Intraoperatively applied local drug delivery systems (LDDS) offer a means of overcoming blood–brain barrier (BBB) impermeability. However, there is a paucity of LDDS development for paediatric tumours arising in the posterior fossa. Here we demonstrate applicability of an LDDS against medulloblastoma group 3 (G3 MB) and atypical teratoid/rhabdoid tumours (AT/RT), neoplasms associated with poor prognoses. A poly(ethyleneglycol)-poly(caprolactone)-poly(ethyleneglycol) (PECE) hydrogel loaded with chemotherapeutics identified as effective against primary G3 MB and AT/RT in vitro, was prepared as an injectable, biodegradable formulation. CHIR99021 (glycogen synthase kinase-3 inhibitor), ribavirin (guanosine analogue) and PG545 (heparanase inhibitor) were chosen based upon an inability to traverse the BBB. The hydrogel alone was well-tolerated, and drug-loaded hydrogel achieved > 1-month therapeutic release. Orthotopic xenograft studies against G3 MB and AT/RT indicated good tolerability to combined CHIR99021 and PG545 or combined CHIR99021 and ribavirin loaded loaded LDDS respectively. Median survival of AT/RT arms receiving XRT alone was comparable to CHIR99021- and ribavirin-loaded LDDS, with long-term survivors observed only in the latter arm, demonstrating a significant survival benefit. LDDS against cerebellar tumours using PECE offers a promising therapeutic alternative and the possibility of circumventing radiation-induced adverse effects for children impacted by these diseases.

Graphical Abstract