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.
Highlights
Glioblastoma (GBM) is the most common, malignant and aggressive brain tumour in adults, mainly due to its rapid proliferation and ability to penetrate and diffusely infiltrate healthy brain parenchyma [1]
Intracranial drug delivery has been developed over the last two decades in order to exploit the low transport of drugs across the blood-brain barrier (BBB), and ensure that locally delivered drugs remain in the brain [3]
We have recently reported polymer pro-drugs based on a PEGylated poly(lactide)poly(carbonate) copolymer [16,17], which is based on well-established chemistries and components already in clinical use
Summary
Glioblastoma (GBM) is the most common, malignant and aggressive brain tumour in adults, mainly due to its rapid proliferation and ability to penetrate and diffusely infiltrate healthy brain parenchyma [1]. Standard of care treatment currently involves a combination of surgery, radiotherapy and chemotherapy. Despite this multimodal treatment method, the median survival remains less than 15 months from diagnosis [2]. As surgery is the usual first step in the treatment of GBM, the rationale for intracranial drug delivery is based upon a unique treatment window immediately adjuvant to neurosurgery, in this case by delivering drugs directly to the site of minimal. Pharmaceutics 2021, 13, 208 volume residual tumour following surgery. More efficacious treatment methods are still necessary to eradicate residual tumour cells which remain beyond the resection cavity lining after surgery, as GBM recurrence is almost certain unless these cells are eradicated [4]
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