When you think of cancer, your mind may automatically jump to the terrifying realities of this disease: hair loss, pale skin, constant shivering, and nausea. All of these hallmarks of a cancer patient result from a current popular treatment regimen: chemotherapy. While these medications are effective for many cancer patients, they can be devastatingly hard to endure and are not always an option for every patient. Past cancer history and certain genetic mutations in tumor cells can lead to drug resistance that takes chemotherapy off the table as a treatment option. In an attempt to provide cancer patients with new medication options outside of chemotherapeutics, researchers have turned to an unassuming molecule: micro-RNA.
Micro-RNAs (miRNAs) are short, non-coding sections of RNA that function in gene regulation cascades. Through binding to a certain region of DNA, these small biomolecules can suppress the translation of that gene into a protein. While this suppression process is a normal function of human gene regulation and protein production, dysregulation of miRNAs can lead to different levels of protein expression throughout a cell, disrupting regular maintenance processes. This dysregulation is often observed in cancer cells, as miRNAs can function as significant influencers of many hallmarks of cancer, such as cell proliferation and immortality (Ferdows, Bijan Emiliano, et al). This ability to influence cancer growth and metastasis makes miRNAs promising targets for treatments that slow the progression of tumors.
Due to the degradation of foreign RNAs in the human body, delivering miRNA treatments to target cells has proven difficult. In order to lessen this challenge, scientists have turned to nanotechnology to increase the efficacy of miRNA-targeted treatments. Nanotechnology encompasses many different organic and synthetic casings that prevent molecules from being degraded by the human body’s natural defense systems. Lipid-based nanoparticles often take the forefront of nanotechnology research. These particles are easily assimilated into the body because of their biological similarity to the lipid-based cell membrane. Cationic lipids are able to bind with the negatively charged phosphate groups in miRNA particles, creating a protective layer around these miRNA particles that can easily bind to target cells (Ferdows, Bijan Emiliano, et al). The biocompatibility found with lipid-based nanoparticles is expanded upon in extracellular vesicles, a type of molecule secreted by cells to facilitate intercellular communication. These lipid pockets are a promising target for miRNA delivery because they share many of the same biological and chemical qualities as their mother cell. Although organic nanoparticles are proving to be effective drug-delivery machines, researchers have also begun to examine the potential of using inorganic compounds to protect miRNAs from degradation. One such compound is gold-iron oxide nanoparticles (GIONS). In addition to the negatively charged GION surface that allows it to bind and transport miRNA, this nanoparticle class can also aid in the diagnosis of tumors. These particles appear on CT and MRI scans, and their appearance can help physicians determine where a tumor is located and how treatment should progress (Ferdows, Bijan Emiliano, et al).
While nanoparticle-based miRNA treatments have yet to hit mainstream cancer treatment plans, current research projects show that these medications have a promising future. In mice with transplanted lung tumors taken from human patients, cationic lipid particles have been used to deliver miRNA particles to study the effect of these treatments on patients with late-diagnosis lung cancer. Researchers used these lipid-based nanoparticles to deliver miRNA-660 to the MIR660, a gene responsible for enabling the activation of the crucial p53 tumor suppressor that results in the killing of cancer cells. In 8 weeks, the mice were shown to have 50% reduced tumor growth compared to controls, a promising result for applying this treatment in human lung cancer patients (Moro, Massimo, et al).
GION-coated tumor-derived extracellular vesicles (TEVs) have also shown promising results as nanoparticles used in miRNA-based treatments for cancers such as breast cancer. Researchers have bound these particles to a type of naturally occurring miRNAs called anti-miRNA-21. This molecule suppresses oncomiR-21, a type of miRNA associated with assisting cancer development and growth by inhibiting apoptosis, a type of self-programmed cell death that occurs when a cell is functioning abnormally. OncomiR-21 deactivation enables a variety of proteins to regain function, allowing the cellular pathway that signals cell death to resume. When anti-miRNA-21 bound GION-TEVs were administered to breast cancer cells along with low levels of the chemotherapeutic doxorubicin, researchers found that the cells were killed almost three times quicker as compared to cells treated with doxorubicin alone (Bose RJC et al). This experimental result shows significant promise that nanoparticle-based miRNA treatments could be used in combination with chemotherapy in the future to help strengthen tumor cell apoptosis and reduce drug resistance that results from high doses of the same chemotherapeutic (Bose RJC et al).
While these treatments show extremely significant promise, more research is needed to determine their efficacy in human patients. Specifically, inorganic nanoparticles such as GIONs require additional research to ensure their delivery is minimally toxic to human patients (Ferdows, Bijan Emiliano, et al). Fortunately, the results of current experiments demonstrate that nanoparticle-based miRNA cancer drugs could have a significant role in the future treatment of cancer patients. These treatments are minimally invasive and have the potential to allow physicians and researchers to target miRNAs to patient-specific genetic markers in tumor cells. This individualization could give patients with uniquely mutated tumors a chance for a longer lifespan or remission. In addition, the use of these treatments could reduce reliance on chemotherapy, thereby lessening drug resistance found in cancer patients with tumor recurrences (Ferdows, Bijan Emiliano, et al). Through further funding and research, nanoparticle-based miRNA cancer treatments could become the next big wave of cancer drugs to hit hospitals across the world, giving patients new hope for recovery and life after cancer.
References
Bose RJC, Uday Kumar S, Zeng Y, Afjei R, Robinson E, Lau K, Bermudez A, Habte F, Pitteri SJ, Sinclair R, Willmann JK, Massoud TF, Gambhir SS, Paulmurugan R. Tumor Cell-Derived Extracellular Vesicle-Coated Nanocarriers: An Efficient Theranostic Platform for the Cancer-Specific Delivery of Anti-miR-21 and Imaging Agents. ACS Nano. 2018 Nov 27;12(11):10817-10832. doi: 10.1021/acsnano.8b02587. Epub 2018 Oct 22. PMID: 30346694; PMCID: PMC6684278.
Ferdows, Bijan Emiliano, et al. “RNA Cancer Nanomedicine: Nanotechnology-Mediated RNA Therapy.” Nanoscale, vol. 14, no. 12, 2022, pp. 4448–55. DOI.org (Crossref), https://doi.org/10.1039/D1NR06991H.
Moro, Massimo, et al. “Coated Cationic Lipid-Nanoparticles Entrapping MiR-660 Inhibit Tumor Growth in Patient-Derived Xenografts Lung Cancer Models.” Journal of Controlled Release, vol. 308, Aug. 2019, pp. 44–56. DOI.org (Crossref), https://doi.org/10.1016/j.jconrel.2019.07.006.