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Polymer pro-drug nanoparticles for sustained release of cytotoxic drugs evaluated in patient-derived glioblastoma cell lines and in situ gelling formulations

Vasey, Catherine E.; Cavanagh, Robert J.; Taresco, Vincenzo; Moloney, Cara; Smith, Stuart; Rahman, Ruman; Alexander, Cameron

Polymer pro-drug nanoparticles for sustained release of cytotoxic drugs evaluated in patient-derived glioblastoma cell lines and in situ gelling formulations Thumbnail


Authors

Catherine E. Vasey

STUART SMITH stuart.smith@nottingham.ac.uk
Clinical Associate Professor



Abstract

Glioblastoma (GBM) is the most common, malignant and aggressive brain tumour in adults. Despite the use of multimodal treatments, involving surgery, followed by concomitant radiotherapy and chemotherapy, the median survival for patients remains less than 15 months from diagnosis. Low penetration of drugs across the blood-brain barrier (BBB) is a dose-limiting factor for systemic GBM therapies, and as a result, post-surgical intracranial drug delivery strategies are being developed to ensure local delivery of drugs within the brain. Here we describe the effects of PEGylated poly(lactide)-poly(carbonate)-doxorubicin (DOX) nanoparticles (NPs) on the metabolic activity of primary cancer cell lines derived from adult patients following neurosurgical resection, and the commercially available GBM cell line, U87. The results showed that non-drug-loaded NPs were well tolerated at concentrations of up to 100 µg/mL while tumour cell-killing effects were observed for the DOX-NPs at the same concentrations. Further experiments evaluated the release of DOX from polymer-DOX conjugate NPs when incorporated in a thermosensitive in situ gelling poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) matrix paste, in order to simulate the clinical setting of a locally injected formulation for GBM following surgical tumour resection. These assays demonstrated drug release from the polymer pro-drugs, when in PLGA/PEG matrices of two formulations, over clinically relevant time scales. These findings encourage future in vivo assessment of the potential capability of polymer–drug conjugate NPs to penetrate brain parenchyma efficaciously, when released from existing interstitial delivery systems.

Citation

Vasey, C. E., Cavanagh, R. J., Taresco, V., Moloney, C., Smith, S., Rahman, R., & Alexander, C. (2021). Polymer pro-drug nanoparticles for sustained release of cytotoxic drugs evaluated in patient-derived glioblastoma cell lines and in situ gelling formulations. Pharmaceutics, 13(2), https://doi.org/10.3390/pharmaceutics13020208

Journal Article Type Article
Acceptance Date Feb 1, 2021
Online Publication Date Feb 3, 2021
Publication Date Feb 1, 2021
Deposit Date Jun 23, 2021
Publicly Available Date Mar 29, 2024
Journal Pharmaceutics
Electronic ISSN 1999-4923
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 13
Issue 2
Article Number 208
DOI https://doi.org/10.3390/pharmaceutics13020208
Keywords Pharmaceutical Science
Public URL https://nottingham-repository.worktribe.com/output/5294102
Publisher URL https://www.mdpi.com/1999-4923/13/2/208

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