Biodegradable wafers releasing Temozolomide and Carmustine for the treatment of brain cancer

Shapira-Furman, Tovi; Serra, Riccardo; Gorelick, Noah; Doglioli, Marisol; Tagliaferri, Valeria; Cecia, Arba; Peters, Michael; Kumar, Awanish; Rottenberg, Yakir; Langer, Robert; Brem, Henry; Tyler, Betty; Domb, Abraham J.

doi:10.1016/j.jconrel.2018.12.048

Cited by 70 publications

(43 citation statements)

References 40 publications

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“…Our data reveal a significant overall survival benefit in surgery/PLGA/PEG/ temozolomide/etoposide-treated 9L orthotopic gliosarcomas, with adjuvant radiotherapy conferring long-term survivorship to more than half of the animals and histology confirming that LTS are disease-free. Our LTS is comparable with that of BCNU/carmustine previously reported as preclinical support for the clinical translation of Gliadel and also comparable with LTS of BCNU/temozolomide treatment arms reported recently, with both these studies utilizing the 9L orthotopic test bed (47,48). Indeed, survival in the 9L preclinical model with BCNU/ carmustine was highly predictive of efficacy in a clinical trial with Gliadel, validating this model as clinically relevant for neurosurgically applied drug delivery (49,50), with recent meta-analyses conducted on the safety and significant clinical efficacy (albeit modest), of Gliadel (51, 52).…”

Section: Discussionsupporting

confidence: 90%

Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste

Smith

Tyler

Gould

et al. 2019

Clinical Cancer Research

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Purpose: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood-brain barrier. We evaluate the unique intracavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid; PLGA) and poly(ethylene glycol; PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. Experimental Design: To prolong stability of temozolomide prodrug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytic methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized preclinically to develop Gliadel. Results: Combined etoposide and temozolomide in vitro release (22 and 7 days, respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG-invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/ PEG. In vivo studies revealed a significant overall survival benefit in postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain. Conclusions: The significant survival benefit of intracavity chemotherapy demonstrates clinical applicability of PLGA/ PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds.

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Section: Discussionsupporting

confidence: 90%

Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste

Smith

Tyler

Gould

et al. 2019

Clinical Cancer Research

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“…Physical disruption of the BBB will also allow drugs to enter the brain; this can be accomplished with radiation, electroporation, low intensity ultrasound, among others [47][48][49][50]. A Phase I/IIa clinical trial was recently completed in which low-intensity pulsed ultrasound (LIPU) was used to disrupt the BBB and allow entry of a drug into the brain.…”

Section: Bypassing the Bbbmentioning

confidence: 99%

“…The first is the use of Gliadel ® wafers to deliver BCNU directly onto GBM tumors. The Gliadel ® wafer is approved for the treatment of both primary and recurrent GBM and is usually implanted into the resection cavity at the time of surgery [47,50]. Currently, a new polymer wafer system is in development which combines BCNU with TMZ treatment in one wafer in order to deliver combinatorial therapy to GBM tumors [50].…”

Section: Bypassing the Bbbmentioning

confidence: 99%

Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma

Sanders

Debinski

2020

IJMS

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Glioblastoma (GBM) is the most common and aggressive malignant glioma, treatment of which has not improved significantly in many years. This is due to the unique challenges that GBM tumors present when designing and implementing therapies. Recently, immunotherapy in the form of immune checkpoint inhibition (ICI) has revolutionized the treatment of various malignancies. The application of immune checkpoint inhibition in GBM treatment has shown promising preclinical results. Unfortunately, this has met with little to no success in the clinic thus far. In this review, we will discuss the challenges presented by GBM tumors that likely limit the effect of ICI and discuss the approaches being tested to overcome these challenges.

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“…Therefore, new technology-based approaches are needed, such as microparticles, functionalised nanocarriers, liposomes and chimeric peptide technology. Currently, the only FDA-approved intracranial drug delivery system is biodegradable discs infused with carmustine (Gliadel), which are placed into the tumour-resection cavity [ 343 , 344 ]. A study by Spencer and Verma [ 337 ] targeted the receptors on the BBB by addition of the low-density lipoprotein receptor (LDLR)-binding domain of apolipoprotein B (ApoB) to enable protein delivery to the CNS [ 337 ].…”

Section: Polypeptide Deliverymentioning

confidence: 99%

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

et al. 2020

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Proteins and peptides have emerged in recent years to treat a wide range of multifaceted diseases such as cancer, diabetes and inflammation. The emergence of polypeptides has yielded advancements in the fields of biopharmaceutical production and formulation. Polypeptides often display poor pharmacokinetics, limited permeability across biological barriers, suboptimal biodistribution, and some proclivity for immunogenicity. Frequent administration of polypeptides is generally required to maintain adequate therapeutic levels, which can limit efficacy and compliance while increasing adverse reactions. Many strategies to increase the duration of action of therapeutic polypeptides have been described with many clinical products having been developed. This review describes approaches to optimise polypeptide delivery organised by the commonly used routes of administration. Future innovations in formulation may hold the key to the continued successful development of proteins and peptides with optimal clinical properties.

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Biodegradable wafers releasing Temozolomide and Carmustine for the treatment of brain cancer

Cited by 70 publications

References 40 publications

Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste

Overall Survival in Malignant Glioma Is Significantly Prolonged by Neurosurgical Delivery of Etoposide and Temozolomide from a Thermo-Responsive Biodegradable Paste

Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

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