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

Abstract

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.

Multi-Layered PLGA-PEI Nanoparticles Functionalized with TKD Peptide for Targeted Delivery of Pep5 to Breast Tumor Cells and Spheroids

“…The degree of Caspase-3 cleavage after Pep5-NPS treatment is depicted as the apoptotic index ( Figure 9C ). 48 Pep5-TPPN treated cells showed a higher apoptotic index than Pep5 alone and Pep5-PPN treated cells. These observations suggest that Pep5 induced cell death by apoptosis is stimulated when Pep5 is entrapped in PPNs, which is further potentiated when Pep5-PPN is conjugated to TKD.…”

“…Cells that received no treatment were served as control. At predetermined time points (24,48, and 72 hr) of treatment, MTT reagent solution (100 µL of 5 mg/mL MTT in DMEM) was added to the cells and incubated for 2hrs at 37°C. Absorbance reading was recorded at 570 nm using a Microplate Reader (iMark™ Biorad) after dissolving the developed purple formazan crystals with isopropanol.…”

Hydrogel on a Smart Nanomaterial Interface to Carry Therapeutics for Digitalized Glioma Treatment

“…There are many types of hydrogel, such as poly(ɛ-caprolactone)-poly(ethylene glycol) (PCL-PEG), hyaluronic acid, poly(ɛ-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ɛ-caprolactone-co-lactide) (PCLA-PEG-PCLA), and poly(vinyl alcohol) (PVA) [ 15 , 16 , 17 , 18 , 19 , 20 , 24 , 32 , 33 ]. Natural products such as gelatin, triglycerol monostearate, pig diesel, and collagen have been employed as hydrogel scaffolds [ 25 , 27 , 29 , 31 ].…”

Polymeric Gel Systems Cytotoxicity and Drug Release as Key Features for their Effective Application in Various Fields of Addressed Pharmaceuticals Delivery

“…Hydrogels 20–30 nm in size (“nanogels”) are capable of incorporating hydrophobic drugs into the core and delivering them to their destination, providing their prolonged release. In particular, hydrogel delivery systems for enzymes [ 6 ], proteins [ 7 ], antibiotics [ 8 , 9 , 10 , 11 ], adenoviruses [ 12 ], anticancer drugs, for example, doxorubicin [ 13 , 14 , 15 ], paclitaxel [ 16 ], 5-fluorouracil [ 17 , 18 , 19 ], kaempferol [ 20 ], vincristine [ 21 ], oxaliplatin [ 22 ], cyclophosphamide [ 23 ], carmustine and curcumin [ 24 ], drugs for the treatment of skin diseases [ 25 , 26 , 27 ], anesthetics for the treatment of acute postoperative pain [ 28 ], antimicrobial silver nanoparticles and quantum dots for wound healing [ 29 , 30 ] are known and studied currently. The rate of release of these mentioned drugs from hydrogels is affected by the degree of cross-linking and the degree of swelling of the hydrogels.…”