A hydrogel-based implant enables sustained-release delivery of valproic acid for improved treatment of intracranial glioblastoma.
Glioblastoma is the most common primary malignant brain tumor, accounting for 52 percent of all primary brain tumors, and is typically fatal within 15 months after diagnosis. Standard treatment involves tumor resection followed by radiation and chemotherapy. Gliadel, a polymeric chemotherapeutic wafer, is the only FDA-approved intracranial implant for the treatment of de novo glioblastoma. Despite initial promise, polymeric wafers are prone to microshearing of surrounding tissue as they migrate within the brain, and have resulted in malignant brain edema and non-healing wounds.
Clinicians and bioengineers at the University of Pennsylvania have developed a hydrogel-based implant capable of delivering sustained release of valproic acid (VPA), a histone deacetylase inhibitor, anti-oncogenic, and radiosensitizing agent, for placement into the resection cavity after surgery. The hydrogel is comprised of two polymers (cyclodextrin-modified branched polyethyleneimine (CD-PEI) and adamantane-modified 8-arm polyethylene glycol (Ad-PEG)) that self-assemble in solution and exhibit shear-thinning properties to ease delivery and minimize surrounding tissue damage once implanted.
Favorable electrostatic and hydrophobic interactions between VPA and the hydrogel enable sustained release of VPA, which is shown to reduce glioma cell viability in vitro. This hydrogel formulation may also serve as a scaffold for sustained delivery of other drugs, specifically those with significant negative charge.
- VPA already routinely used as an off-label anti-epileptic drug
- Reduced potential for mechanical damage
- Reduced toxicity of VPA by local administration
- Shear-thinning and self-assembling properties allow delivery by syringe
- Synergistic with radiation therapy
- Development of novel hydrogels that incorporate negatively charged compounds
- Treatment of cancer where histone deacetylase inhibitors are approved for use
- Treatment of intracranial glioblastoma or alternative intracranial brain cancers
Cyclodextrin-modified branched polyethyleneimine (CD-PEI) and adamantane-modified 8-arm polyethylene glycol (Ad-PEG) self-assemble into a hydrogel that exhibits shear-thinning properties.
Stage of Development:
- Optimized hydrogel formation (polymer ratio) and maximal loading with VPA
- In vitro demonstration of delayed release of VPA and effects on glioma cell viability