Supramolecular Hydrogel Based Post-Surgical Implant System for Hydrophobic Drug Delivery Against Glioma Recurrence.

Purpose: The brain, protected by the cranium externally and the blood-brain barrier (BBB) internally, poses challenges in chemotherapy of aggressive brain tumors. Maximal tumor resection followed by radiation and chemotherapy is the standard treatment protocol; however, a substantial number of patients suffer from recurrence. Systemic circulation of drugs causes myelodysplasia and other side effects. To address these caveats, we report facile synthesis of a polyester-based supramolecular hydrogel as a brain biocompatible implant for in situ delivery of hydrophobic drugs. Methods: Polycaprolactone-diol (PCL) was linked to polyethyleneglycol-diacid (PEG) via an ester bond. In silico modeling indicated micelle-based aggregation of PCL-PEG co-polymer to form a supramolecular hydrogel. Brain biocompatibility was checked in Sprague Dawley rat brain cortex with MRI, motor function test, and histology. Model hydrophobic drugs carmustine and curcumin entrapment propelled glioma cells into apoptosis-based death evaluated by in vitro cytotoxicity assays and Western blot. In vivo post-surgical xenograft glioma model was developed in NOD-SCID mice and evaluated for efficacy to restrict aggressive regrowth of tumors. Results: 20% (w/v) PCL-PEG forms a soft hydrogel that can cover the uneven and large surface area of a tumor resection cavity and maintain brain density. The PCL-PEG hydrogel was biocompatible, and well-tolerated upon implantation in rat brain cortex, for a study period of 12 weeks. We report for the first time the combination of carmustine and curcumin entrapped as model hydrophobic drugs, increasing their bioavailability and yielding synergistic apoptotic effect on glioma cells. Further in vivo study indicated PCL-PEG hydrogel with a dual cargo of carmustine and curcumin restricted aggressive regrowth post-resection significantly compared with control and animals with intravenous drug treatment. Conclusion: PCL-PEG soft gel-based implant is malleable compared with rigid wafers used as implants, thus providing larger surface area contact. This stable, biocompatible, supramolecular gel without external crosslinking can find wide applications by interchanging formulation of various hydrophobic drugs to ensure and increase site-specific delivery, avoiding systemic circulation.

Peptides as a therapeutic avenue for nanocarrier-aided targeting of glioma.

INTRODUCTION: Very few successful interventions have been possible in glioma therapy owing to its aggressive nature as well as its hindrance of targeted therapy together with the limited access afforded by the blood-brain barrier (BBB). With the advent of nanotechnology based delivery vehicles such as micelles, dendrimers, polymer-based nanoparticles and nanogels, the breach of the BBB has been facilitated. However, there remains the issue of targeted therapy for glioma cells. Peptide-mediated surface modification of nanocarriers serves this purpose, extending the ability to target glioma further than the enhanced permeability and retention effect. Areas covered: Here we have tried to re-establish the significance of peptides that could be used in various ways for treating glioma. Peptide-embellished nanocarriers used to deliver anticancer drugs; nucleic acids (siRNA, miRNA); micelles or dendrimers grafted with immunogenic glioma-derived peptides used for stimulating active immunity in vaccine therapy, glioma targets for cell penetrating peptides and homing to specific receptors are reviewed. Expert opinion: Peptides have multifunctional potential in targeting, BBB and cell penetration, and can serve as antagonists of various ligands and agonists of particular over-expressed receptors as discussed in this review. Using peptides in targeted personalized therapy would be one step forward and may offer new avenues for glioma therapeutics.