Curcumin combining temozolomide formed localized nanogel for inhibition of postsurgical chemoresistant glioblastoma
Abstract
Aim: To investigate the use of nanoparticle (NP)-encapsulated injectable thermosensitive hydrogel-formed nanogel for inhibition of postsurgical residual temozolomide (TMZ)-resistant glioblastoma (GBM) recurrence. Materials & methods: Curcumin (Cur) was coloaded with TMZ into PEG-PLGA NPs, then NPs were further encapsulated into a thermosensitive hydrogel to form a nanogel, which was injected into the resection cavity of the GBM postsurgery. Results: The prepared nanogel displayed excellent drug-loading capacity and long-term drug release. Estimated survival characteristics demonstrated that the nanogel could play a significant role in TMZ-resistant tumor inhibition with low drug-induced toxicity. The originally designed ratio of Cur/TMZ was sustained, making it an effective therapeutic outcome. Conclusion: Cur-combined TMZ-formed nanogels can be a promising candidate for the local inhibition of GBM recurrence.
Plain language summary
In this study, the animal model used was rats suffering residual brain tumor after resection. The selected drugs were temozolomide, a first-line chemotherapeutic drug for the clinical treatment of glioma, and curcumin, an extract from the ginger plant. With the use of temozolomide, brain glioma cells gradually develop resistance, resulting in poor efficacy of temozolomide. Therefore, the purpose of this study was to construct a drug-delivery system for temozolomide-resistant brain glioma residual tumor after surgery, namely, a temperature-sensitive gel containing drug-carrying nanopreparations – the so-called nanogels. This drug-delivery system can directly deliver drugs to residual tumor cells in situ after surgery. In situ drug-delivery systems can reduce the dose of drugs consumed and increase their potency compared to oral or intravenous administration.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Emerging therapies for glioblastoma: current state and future directions. J. Exp. Clin. Canc. Res. 41(1), 142–160 (2022).
- 2. Combinatorial effect of plk1 inhibition with temozolomide and radiation in glioblastoma. Cancers (Basel) 13(20), 5114–5132 (2021).
- 3. Evaluation of an assay for MGMT gene promoter methylation in glioblastoma samples. Anticancer Res. 40(11), 6229–6236 (2020).
- 4. Elucidating the mechanisms of temozolomide resistance in gliomas and the strategies to overcome the resistance. BBA Rev. Cancer 1876(2), 188616–188630 (2021). • Summarizes different strategies that intensify the temozolomide effect such as O6-methylguanine-DNA-methyltransferase inhibition, development of a novel imidazotetrazine analog and combination therapy to incorporate a successful treatment and increased overall survival.
- 5. . Temozolomide: mechanisms of action, repair and resistance. Curr. Mol. Pharmacol. 5, 102–114 (2012).
- 6. Progranulin promotes temozolomide resistance of glioblastoma by orchestrating DNA repair and tumor stemness. Oncogene 34(14), 1853–1864 (2015). •• Suggests that a new strategy combining current regimens with compounds targeting progranulin such as curcumin may significantly improve the therapeutic outcome of glioblastoma.
- 7. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021 (2004).
- 8. Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme. Ann. Oncol. 16(7), 1177–1184 (2005).
- 9. Curcumin based combination therapy for anti-breast cancer: from in vitro drug screening to in vivo efficacy evaluation. Front. Chem. Sci. Eng. 10(3), 383–388 (2016).
- 10. Curcumin/sunitinib co-loaded BSA-stabilized SPIOS for synergistic combination therapy for breast cancer. J. Mater. Chem. B. 5(22), 4060–4072 (2017). • Demonstrates that the optimal ratio of curcumin combination with drugs at the tumor target can yield the best synergistic effect and improve effective therapeutic outcomes.
- 11. . Technical aspects of preparing PEG-PLGA nanoparticles as carrier for chemotherapeutic agents by nanoprecipitation method. Int. J. Pharm. 533(1), 275–284 (2017).
- 12. Drug-loaded PEG-PLGA nanoparticles for cancer treatment. Front. Pharmacol. 13, 990505–990515 (2022).
- 13. Biodegradable wafers releasing temozolomide and carmustine for the treatment of brain cancer. J. Control. Rel. 295, 93–101 (2019).
- 14. . Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70(2), 440–446 (2010).
- 15. N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption. ACS Appl. Mater. Interfaces 7(28), 15430–15441 (2015).
- 16. Glycerophosphate-based chitosan thermosensitive hydrogels and their biomedical applications. Carbohydr. Polym. 117, 524–536 (2015).
- 17. Long acting carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor resection. Front. Chem. Sci. Eng. 16(4), 536–545 (2021). •• A dual-sensitive hydrogel drug-delivery system consisting of a thermo-sensitive hydrogel loading two free drugs and drug-encapsulated reactive oxygen species-sensitive poly(lactic-co-glycolic acid) nanoparticles, was prepared to inhibit the recurrence of residual glioblastoma after tumor resection.
- 18. . NF-κb and STAT3 signaling in glioma: targets for future therapies. Expert Rev. Neurother. 10, 575–586 (2010).
- 19. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003).
- 20. Dual-sensitive drug-loaded hydrogel system for local inhibition of post-surgical glioma recurrence. J. Control. Rel. 349, 565–579 (2022).
- 21. . Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70(2), 440–446 (2010).
- 22. IRGD-mediated core-shell nanoparticles loading carmustine and O(6)-benzylguanine for glioma therapy. J. Drug Targ. 25(3), 235–246 (2017).
- 23. . Temozolomide resistance in glioblastoma multiforme. Genes Dis. 3(3), 198–210 (2016).
- 24. MicroRNA-146a inhibits g protein-coupled receptor-mediated activation of NF-κb by targeting CARD10 and COPS8 in gastric cancer. Mol. Cancer 11, 71–84 (2012).
- 25. Induction of microRNA-146a is involved in curcumin-mediated enhancement of temozolomide cytotoxicity against human glioblastoma. Mol. Med. Rep. 12(4), 5461–5466 (2015).
- 26. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Eng. J. Med. 352(10), 987–996 (2005).
- 27. Identification of a human glioma-associated growth factor gene, granulin, using differential immuno-absorption. Cancer Res. 60(5), 1353–1360 (2000).
- 28. Ar ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-mediated redox homeostasis. Redox Biol. 30, 101413–101425 (2020).
- 29. . Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr. Cancer 62(7), 919–930 (2010). • Describes how curcumin acts as a chemosensitizer and radiosensitizer by sensitizing tumors to different chemotherapeutic agents.
- 30. . Safety and anti-inflammatory activity of curcumin: a component of tumeric (curcuma longa). J. Altern. Complem. Med. 9(1), 161–168 (2003).
- 31. Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol. Cancer Ther. 5(7), 1854–1863 (2006).
- 32. . Optimizing combination chemotherapy by controlling drug ratios. Mol. Interv. 7(4), 216–223 (2007).
- 33. Optimization of PLGA formulation containing protein or peptide-based antigen: recent advances. J. Biomed. Mater. Res. A 106(9), 2540–2551 (2018).
- 34. A review on injectable chitosan/beta glycerophosphate hydrogels for bone tissue regeneration. Int. J. Biol. Macromol. 121, 38–54 (2019).
