Nanomedicine Unleashed: Harnessing Metformin and Nanoparticles for Glioblastoma Therapy

Shikha Raghuram

Thomas Jefferson High School for Science and Technology

This article placed 3rd in the 2023 Teknos Summer Writing Contest.

Lipid-polymer hybrid nanoparticles (LPHNPs) are an emerging innovation capable of changing how we approach drug delivery. Current nanoparticle vectors, although widespread, have numerous issues that harm patients. Liposomes (lipid nanoparticles), while biocompatible, often have troubles with drug leakage and storage instability, leading to shorter shelf life. Polymeric nanoparticles are stable but often have issues with complex synthetic materials, resulting in the need for numerous biocompatibility tests before clinical testing. By combining the favorable aspects of polymeric nanoparticles and liposomes, LPHNPs combat the challenges associated with both separately. These nanoparticles contain three main components: a polymer core, a lipid shell, and Lipid-Polyethylene Glycol (PEG). The polymer core may be hydrophobic or hydrophilic; it contributes to efficient drug storage mechanisms and sustained drug release. The lipid shell offers higher biocompatibility while improving overall stability. Lastly, the PEG prevents the aggregation of the nanoparticles while also decreasing immune recognition to ensure optimal function. LPHNPs adopt a mechanism known as active targeting, which facilitates the uptake of the nanoparticles by the tumor cells themselves [2]. More specifically, these nanoparticles use receptor-mediated targeting as they are coated with targeting ligands to target overexpressed receptors in cancer cells. Subsequently, the nanoparticles are engulfed by the cell through receptor-mediated endocytosis. By delivering the drug directly to the affected area, LPHNPs eliminate the adverse effects caused by traditional cancer treatments by leaving the rest of the body unharmed. Combined with their small size and high surface-area-to-volume ratio, LPHNPs inherently maximize drug transportation efficiency while remaining safe for biological systems [6].

Metformin is a biguanide drug used as a first-line medication to treat type 2 diabetes. It works by suppressing glucose synthesis in the liver, sensitizing cells to insulin, increasing glucose uptake, and reducing glucose absorption in the gastrointestinal tract. Recently, its potential influence on tumor development has been observed, specifically its inhibition of the activity of protein complex mTOR. Mammalian target of rapamycin (mTOR) is a protein that receives information from various sources, including growth factors (such as IGF-1 and IGF-2) and amino acids, so it knows what actions to take. mTOR also senses cellular nutrients, oxygen, and energy levels [15] Under normal conditions, mTOR regulates cell growth and division. However, in tumor cells, mTOR is abnormally activated, causing it to release signals telling tumor cells to grow, spread, and invade healthy tissues. mTOR is typically inactivated when there are not enough nutrients to ensure that cell material and energy supply remain stable.

Since mTOR is a crucial player in regulating metabolism, abnormal activity of the mTOR pathway contributes significantly to the growth of brain tumors. Consequently, the use of Metformin, a safe inhibitor of this pathway, has been associated with better overall survival of patients with glioblastomas. The alternative use of Metformin as a cancer treatment is being assessed in multiple clinical trials for many cancer types, notably brain cancers. The drug will be incorporated into the LPHNPs using a one-step synthesis process to store Metformin for brain delivery. This procedure constitutes creating a polymeric solution containing Metformin and combining the mixture with an aqueous lipid solution to synthesize the nanoparticles [13].

To facilitate the direct delivery of LPHNPs to glioblastomas, epidermal growth factor receptors (EGFRs) may be targeted. EGFR is a tyrosine kinase protein receptor that plays a role in cell growth and differentiation. It is a promising, validated therapeutic target for anticancer therapy, especially for brain and breast cancer [11]. EGFR receptor-linked hybrid polymer lipid nanosystems are proven to boost receptor-mediated targeting. By attaching Epidermal growth factors (EGF) to the PEG to function as ligands, the nanoparticle unit enables endocytosis and subsequent LPHNP uptake following the binding of EGF to the EGFR on the surface of the glioblastoma [5].

Although LPHNPs are widely considered to be the most efficient nanoparticle treatment option, there are risks and limitations to using them. Biocompatibility and large-scale production procedures pose challenges, as scientists need to determine the ideal solvent used during synthesis [3]. This solvent affects LPHNP stability, and its inefficient removal could cause toxicity issues [12]. If LPHNPs prove ineffective in delivering Metformin to the brain for the treatment of glioblastomas, it may be necessary to consider alternative approaches. This includes other nanoparticle systems, such as gold nanoparticles or dendrimers, which have exhibited the capacity to cross the blood-brain barrier. Furthermore, it may be necessary to investigate alternative drug delivery methods, such as intrathecal injection or convection-enhanced delivery [9].

Additionally, one rare yet lethal side effect is lactic acidosis, wherein lactic acid builds up in the bloodstream due to excessive Metformin use [14]. Though not typically observed, this adverse effect may render Metformin ineffective in treating patients with glioblastomas. Alternative methods may include the use of KL-50, a novel drug in recent development possessing a molecular structure similar to temozolomide (TMZ), a DNA-damaging agent that frequently induces rapid resistance in brain tumors [7]. Notably, KL-50 exhibited improved efficacy in suppressing tumor growth with reduced toxicity compared to TMZ during experimental trials conducted in mice. Considering these findings, in conjunction with LPHNPs, KL-50 emerges as a promising alternative to Metformin in the treatment of glioblastomas, warranting further investigation.

References

[1] Aldape, K., Brindle, K.M., Chesler, L. et al. Challenges to curing primary brain tumours. Nat Rev Clin Oncol 16, 509–520 (2019). https://doi.org/10.1038/s41571-019-0177-5

[2] Bazak, Remon et al. “Cancer active targeting by nanoparticles: a comprehensive review of literature.” Journal of cancer research and clinical oncology vol. 141,5 (2015): 769-84. https://doi.org/10.1007/s00432-014-1767-3

[3] Gavas, S., Quazi, S., & Karpiński, T. M. (2021). Nanoparticles for Cancer Therapy: Current Progress and Challenges. Nanoscale Research Letters, 16(1). https://doi.org/10.1186/s11671-021-03628-6

[4] Hadinoto, K., Sundaresan, A., & Cheow, W. S. (2013). Lipid–polymer hybrid nanoparticles as a new generation therapeutic delivery platform: A review. European Journal of Pharmaceutics and Biopharmaceutics, 85(3), 427–443. https://doi.org/10.1016/j.ejpb.2013.07.002

[5] Kim, W., Na, KY., Lee, KH. et al. Selective uptake of epidermal growth factor-conjugated gold nanoparticle (EGF-GNP) facilitates non-thermal plasma (NTP)-mediated cell death. Sci Rep 7, 10971 (2017). https://doi.org/10.1038/s41598-017-11292-z

[6] Krishnamurthy, S., Vaiyapuri, R., Zhang, L., & Chan, J. M. (2015). Lipid-coated polymeric nanoparticles for cancer drug delivery. Biomaterials Science, 3(7), 923–936. https://doi.org/10.1039/c4bm00427b

[7] Lin, Kingson et al. “Mechanism-based design of agents that selectively target drug-resistant glioma.” Science (New York, N.Y.) vol. 377,6605 (2022): 502-511. https://doi.org/10.1126/science.abn7570

[8] Mazurek, Marek et al. “Metformin as Potential Therapy for High-Grade Glioma.” Cancers vol. 12,1 210. 15 Jan. 2020, https://doi.org/10.3390/cancers12010210

[9] Mehta, A M et al. “Convection-Enhanced Delivery.” Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics vol. 14,2 (2017): 358-371. https://doi.org/10.1007/s13311-017-0520-4

[10] Mohanty, A., Uthaman, S., & Park, I.-K. (2020). Utilization of Polymer-Lipid Hybrid Nanoparticles for Targeted Anti-Cancer Therapy. Molecules, 25(19), 4377. https://doi.org/10.3390/molecules25194377

[11] Murphrey, Morgan B., et al. “Biochemistry, Epidermal Growth Factor Receptor.” StatPearls, StatPearls Publishing, 12 September 2022. https://www.ncbi.nlm.nih.gov/books/NBK482459/

[12] Persano, F., Gigli, G., & Leporatti, S. (2021). Lipid-polymer hybrid nanoparticles in cancer therapy: current overview and future directions. Nano Express, 2(1), 012006. https://doi.org/10.1088/2632-959x/abeb4b

[13] Shah, Saurabh et al. “Lipid polymer hybrid nanocarriers: Insights into synthesis aspects, characterization, release mechanisms, surface functionalization and potential implications.” Colloid and Interface Science Communications (2022). https://doi.org/10.1016/j.colcom.2021.100570

[14] Yetman, Daniel. “Metformin Side Effects: Common and Severe.” Healthline, 17 Feb. 2023, https://tinyurl.com/55nts8tb

[15] Zou, Z., Tao, T., Li, H. et al. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci 10, 31 (2020). https://doi.org/10.1186/s13578-020-00396-1