Introduction: Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. Despite surgery and chemo/radiation, recurrence is common. The efficacy of chemotherapy in GBM patients is limited due to the blood brain barrier (BBB). We have developed a self-assembling proprietary camptothecin (SAC) nanofiber hydrogel system for local therapy, with controlled drug release over an extended period of time and high penetration into the brain tissue, with cytotoxic efficacy in vitro. We evaluated Cy5 labeled SAC in a newly developed animal resection model that replicates the clinical conditions of GBM patients.

Methods: 20 immunosuppressed mice were injected into the cortex with luciferase-positive primary-cultured human GBM cells from our patients. Tumor growth was assessed using bioluminescence (BLI), and tumor resection was performed to recapitulate the human treatment. Mice were randomized into 2 groups (n=10): 1) Resection 2) Resection+SAC. SAC (5µl) was placed in the cavity. Mice were followed. Brains were processed. Tumor area, drug penetration and survival were determined.

Results: Our tumor resection model allowed us to evaluate a new local therapy in a clinically relevant setting. SAC hydrogel remained in the resection cavity, The SAC released from the hydrogel diffused into the brain parenchyma and decreased tumor growth resulting in prolonged survival. SAC treatment animals showed a three-fold decrement in BLI intensity versus non-treated group (p=0.0076). A significantly increased in survival in SAC vs resection only was found (41d vs 35d respectively, p=0.01). Histology revealed a remarkable decreased in tumor growth in the SAC group (p=0.0370, mean=10.47mm2,SEM=1.013mm2).Deep drug brain parenchyma penetration with a mean of 0.7312±0.088 mm2 was found in SAC group.

Conclusions: We present an in vivo orthotopic brain tumor resection and recurrence model using human GBM cells. The SAC hydrogel system is an innovative treatment for local cancer therapy that exhibits high penetration and survival benefit. SAC hydrogel is an excellent vehicle for drug delivery in brain cancer, allowing the surgeons have an effect on treatment in the infiltrating part of the tumor, essential for cancer recurrence, disability and death; avoiding potential adverse effects of systemic drug administration.

Patient Care: This new strategy for local drug delivery in glioma is meant to target tumor cells remaining post-resection which lead to recurrence and fatal outcomes in patients. This technique represents an innovative and translational strategy because of its intraoperative nature.

Learning Objectives: 1. Learn about tumor resection models in rodents that resemble GBM treatment in the clinic 2.Discover new local therapies for GBM developed using cutting edge nanotechnology 3. Evaluate the efficacy of GBM local treatments.

References: 1. Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P.Genetic pathways to glioblastoma: A population-based study. Cancer Research. 2004;64(19):6892-9. doi: Doi 10.1158/0008-5472.Can-04-1337. PubMed PMID: WOS:000224292400011. 2. Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nature Reviews Cancer. 2006;6(6):425-36. doi: Doi 10.1038/Nrc1889. PubMed PMID: WOS:000237806700010. 3. Siegel R, Ma JM, Zou ZH, Jemal A. Cancer Statistics, 2014. Ca-a Cancer Journal for Clinicians. 2014;64(1):9-29. doi: Doi 10.3322/Caac.21208. PubMed PMID: WOS:000329734100004. 4. Chaichana KL, Jusue-Torres I, Navarro-Ramirez R, Raza SM, Pascual-Gallego M, Ibrahim A, Hernandez-Hermann M, Gomez L, Ye X, Weingart JD, Olivi A, Blakeley J, Gallia GL, Lim M, Brem H, Quinones-Hinojosa A. Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma. Neuro Oncol. 2014;16(1):113-22. doi: 10.1093/neuonc/not137. PubMed PMID: 24285550; PubMed Central PMCID: PMC3870832. 5. Schinkel AH, Wagenaar E, Mol CAAM, vanDeemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. Journal of Clinical Investigation. 1996;97(11):2517-24. doi: Doi 10.1172/Jci118699. PubMed PMID: WOS:A1996UQ23800016. 6. Cheetham AG, Zhang PC, Lin YA, Lock LL, Cui HG. Supramolecular Nanostructures Formed by Anticancer Drug Assembly. Journal of the American Chemical Society. 2013;135(8):2907-10. doi: Doi 10.1021/Ja3115983. PubMed PMID: WOS:000315618900011. 7. Cheetham AG, Ou YC, Zhang PC, Cui HG. Linker-determined drug release mechanism of free camptothecin from self-assembling drug amphiphiles. Chemical Communications. 2014;50(45):6039-42. doi: Doi 10.1039/C3cc49453e. PubMed PMID: WOS:000335984700025. 8. Lin YA, Cheetham AG, Zhang P, Ou YC, Li Y, Liu G, Hermida-Merino D, Hamley IW, Cui H. Multiwalled nanotubes formed by catanionic mixtures of drug amphiphiles. ACS Nano. 2014;8(12):12690-700. doi: 10.1021/nn505688b. PubMed PMID: 25415538. 9. Cheetham AG, Zhang P, Lin YA, Lin R, Cui H. Synthesis and self-assembly of a mikto-arm star dual drug amphiphile containing both paclitaxel and camptothecin. Journal of Materials Chemistry B. 2014;2(42):7316-26. doi: Doi 10.1039/C4tb01084a. PubMed PMID: WOS:000343038600003. 10. Zhang PC, Cheetham AG, Lock LL, Cui HG. Cellular Uptake and Cytotoxicity of Drug-Peptide Conjugates Regulated by Conjugation Site. Bioconjugate Chemistry. 2013;24(4):604-13. doi: 10.1021/bc300585h. PubMed PMID: WOS:000317872900011.