Rational design of poly-L-glutamic acid-palbociclib conjugates for pediatric glioma treatment.

Fecha de publicación: Fecha Ahead of Print:

Autores de CIPF

Participantes ajenos a CIPF

  • Melnyk T

Grupos de Investigación

Abstract

Brain tumors represent the second most common cause of pediatric cancer death, with malignant gliomas accounting for ~75% of pediatric deaths. Palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has shown promise in phase I clinical trials of pediatric patients with progressive/refractory brain tumors using the oral administration route; however, pharmacokinetic limitations and toxicity issues remain. We synthesized a family of well-defined linear and star-shaped polyglutamate (PGA)-palbociclib conjugates using redox-sensitive self-immolative linkers to overcome limitations associated with free palbociclib. Exhaustive characterization of this conjugate family provided evidence for a transition towards the formation of more organized conformational structures upon increased drug loading. We evaluated the activity of conjugates in patient-derived glioblastoma and diffuse intrinsic pontine glioma cells, which display differing reducing environments due to differential glutathione expression levels. We discovered that microenvironmental parameters and the identified conformational changes determined palbociclib release kinetics and therapeutic output; furthermore, we identified a star-shaped PGA-palbociclib conjugate with low drug loading as an optimal therapeutic approach in diffuse intrinsic pontine glioma cells.

Datos de la publicación

ISSN/ISSNe:
0168-3659, 1873-4995

JOURNAL OF CONTROLLED RELEASE  ELSEVIER SCIENCE BV

Tipo:
Article
Páginas:
385-394
PubMed:
36746338

Citas Recibidas en Web of Science: 8

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Keywords

  • Diffuse intrinsic pontine glioma, Glioblastoma, Palbociclib, Pediatric gliomas, Poly-L-glutamic acid, Polypeptide-drug conjugates, Solution conformation

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