1. Supramolecular Hydrogel Based Post-Surgical Implant System for Hydrophobic Drug Delivery Against Glioma Recurrence
- Author
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Wanjale MV, Sunil Jaikumar V, Sivakumar KC, Ann Paul R, James J, and Kumar GSV
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glioma ,drug ,delivery ,brain ,tumor ,implant ,surgery ,hydrogel ,Medicine (General) ,R5-920 - Abstract
Mrunal Vitthal Wanjale,1,2 Vishnu Sunil Jaikumar,3 KC Sivakumar,4 Riya Ann Paul,2,5 Jackson James,5 GS Vinod Kumar1 1Nano Drug Delivery Systems (NDDS), Cancer Biology Division, Rajiv Gandhi Centre for Biotechnology, Thycaud P.O, Thiruvananthapuram, Kerala, 695014, India; 2Research Scholar, Department of Biotechnology, Faculty of Applied Sciences & Technology, University of Kerala, Thiruvananthapuram, Kerala, 695581, India; 3Animal Research Facility, Rajiv Gandhi Centre for Biotechnology, Thycaud P.O, Thiruvananthapuram, Kerala, 695014, India; 4Distributed Information Sub-Centre (Bioinformatics Centre), Bio-Innovation Center (BIC), Rajiv Gandhi Centre for Biotechnology, Poojappura, Thiruvananthapuram, Kerala, 695014, India; 5Neuro-Stem Cell Biology Lab, Rajiv Gandhi Centre for Biotechnology, Thycaud P.O, Thiruvananthapuram, Kerala, 695014, IndiaCorrespondence: GS Vinod Kumar, Tel +91 471 2781217, Fax +91 471 2348096, Email gsvinod@rgcb.res.inPurpose: 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.Graphical Abstract: Keywords: glioma, drug, delivery, brain, tumor, implant, surgery, hydrogel
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- 2022