Rational design of poly-L-glutamic acid-palbociclib conjugates for pediatric glioma treatment.
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
- Tipo:
- Article
- Páginas:
- 385-394
- PubMed:
- 36746338
JOURNAL OF CONTROLLED RELEASE ELSEVIER SCIENCE BV
Citas Recibidas en Web of Science: 8
Documentos
- No hay documentos
Filiaciones
Keywords
- Diffuse intrinsic pontine glioma, Glioblastoma, Palbociclib, Pediatric gliomas, Poly-L-glutamic acid, Polypeptide-drug conjugates, Solution conformation
Proyectos asociados
SENSITIZING PANCREATIC CANCER TO IMMUNOTHERAPY WITH MULTIMODAL PRECISION NANOMEDICINES
Investigador Principal: MARIA JESUS VICENT DOCON
FUNDACIÓN LA CAIXA . 2019
Molecular Machines Functioning in Cells
Investigador Principal: MARIA JESUS VICENT DOCON
COMMISSION OF EUROPEAN COMMUNITIES . 2020
Aproximación sinérgica al desarrollo de terapias para tumores metastásicos y desórdenes neurodegenarativos utilizando conjugados polipetídicos versátiles
Investigador Principal: MARIA JESUS VICENT DOCON
MINISTERIO DE CIENCIA, INNOVACION Y UNIVERSIDADES . 2020
Novel therapeutic approaches in achondroplasia - TV3 Fundació La Marató. Proyecto de la Dra. Mª Ángela Nieto en el que colabora Mª Jesus Vicent y otros IPs del CIPF
FUNDACION LA MARATO DE TV3 . 2020
Versatile Polypeptide-based Intranasal Drug Delivery Platform(s) to Tackle CNS Disorders. ERC. POLYBRAINT
Investigador Principal: MARIA JESUS VICENT DOCON
COMMISSION OF EUROPEAN COMMUNITIES . 2022
Incorporacion nuevos grupos al CIBER CIBERONC. Punto 3.2 Immunoterapia para tumores sólidos. NOTA: el presupuesto concedido es para le CIBER no para el CIPF
Investigador Principal: MARIA JESUS VICENT DOCON
2022
Nanoplataforma Polipeptídica Multimodal de Precisión para el Tratamiento y Monitorización de Tumores Metastásicos. Colab I-36, I-12, I-63, servicio citómica, uji y gva (Esther Roselló)
Investigador Principal: MARIA JESUS VICENT DOCON
CONSELLERIA DE EDUCACION . 2022
New nanotechnological therapy for Parkinson´s disease: nose to brain delivery of GBA-polymer nanoconjugates
Investigador Principal: MARIA JESUS VICENT DOCON
FUNDACIÓN LA CAIXA . 2022
VI RSEQ Chemical Biology Group Meeting- ChemBioVI
Investigador Principal: MARIA JESUS VICENT DOCON
2023
MULTISMART, Multi-component Soft Materials Advanced Research Training Network
Investigador Principal: MARIA JESUS VICENT DOCON
COMMISSION OF EUROPEAN COMMUNITIES . 2023
Providing cutting edge cancer research services across Europe (CanSERV)
Investigador Principal: MARIA JESUS VICENT DOCON
COMMISSION OF EUROPEAN COMMUNITIES . 2022
Sinergias en descubrimiento de fármacos en España. ES-OPENSCREEN_2
Investigador Principal: MARIA JESUS VICENT DOCON
MINISTERIO DE CIENCIA, INNOVACION Y UNIVERSIDADES . 2023