Supervised by: Yuhui Zhou, BA (Hons). Yuhui is a 5th year medical student at the University of Cambridge. She gained a First class degree in her intercalated year studying Pathology. She has an interest in Cancer & Immunology and has been awarded a Wellcome Trust Biomedical Vacation Scholarship to study host responses to infection.
Lung cancer is one of the deadliest forms of cancer worldwide, but what makes this disease so fatal? Research suggests that lung cancer makes up around 25% of cancer deaths, making the disease the leading cause of cancer-related deaths (15).
A lung cancer diagnosis is no simple task as signs and symptoms are minimal, particularly during the first stages. Lung cancer is diagnosed when abnormal cells which multiply at alarming rates are discovered in the patient’s lungs. These cells often begin invading tissues nearby, causing tumor growth and restricting an individual’s ability to breathe. Doctors divide lung cancer into two major types based on the appearance of cancerous cells under a microscope: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is most common in heavy smokers and spreads rapidly while NSCLC grows at a slower rate than SCLC and is more common. In 2016, the potential survival rate in all stages of non-small cell lung cancer patients remained below 20%, whereas in small cell cancer, the percentage was relatively higher (1). Comparatively, in 2021, the 5-year survival rate for all people with all types of lung cancer was determined to be 21%, with the rate for NSCLC being 25% and 7% for small cell lung cancer (15).
Both divisions of lung cancer can have detrimental symptoms, side effects, and long-term results during progression including coughing up blood, shortness of breath, chest pain, bone pain and headaches. If it is not treated as soon as possible, both can further lead to the development of Malignant Pleural Mesothelioma (MPM), which decreases the survival rate further to 10% (1). Developments in treatment options have led to more personalized care. Specifically, the ability to transition from traditional techniques such as radiotherapy to modern technology such as nanotherapy. While it is clear that technological advances have been developing over time, it is still obscure which technology, if any, has greater efficacy long term. This has raised a question: how does the efficacy of traditional radiotherapy and modern nanotherapy applications compare in the treatment of NSCLC and SCLC? A compare and contrast approach to answering this question will enable an analysis of the applications of the two treatments. Additionally, a new perspective might be introduced that will lead to a definitive conclusion on how modern technologies compare to traditional techniques in terms of efficacy.
This study is essential to the future development of technology by adding to the ongoing conversation about how technologies can continue to be improved. For the purposes of this paper, treatment of NSCLC and SCLC are reviewed separately due to the tremendous differences between the two. In this study, the pros and cons, drug delivery, and genetic applications of radiotherapy and nanotherapy will be compared against one another to cross-analyze the differences and similarities as well as the efficacy.
For the purposes of this paper, systematic searches utilizing well-known sources such as PubMed were conducted to find research literature using a well-framed review question. The data was recorded and is presented in the tabular review matrix located below for readers’ convenience.
The first documented case of cancer was recorded in Egypt around 3000 BC when surgical resections had been the primary treatment. Emile Grubbe began using X-rays to treat recurrent breast carcinoma in 1896, and surgical procedure and radiotherapy continued to be the primary remedies. Over time, scientists have made several advances in understanding the biology and chemotherapy of most cancers. A major significant reduction in cancer mortality happened during the 1990s and spurred the development of discoveries in cancer signaling pathways involved in tumor development, proliferation, and metastasis (16).
During three years of the 1990s developments, radiation therapy was utilized for cancer treatment. At the beginning of the 20th century, shortly after the implementation of radiation therapy, it was discovered that radiation could cause cancer as well as cure it. The methods and the equipment that deliver radiation therapy have steadily improved since then. For example, conformal radiation therapy (CRT) , which uses CT images and special computers to precisely map the location of cancer in three dimensions, gives more control in reducing the amount of radiation that reaches normal tissue while delivering a high dose to cancer. A related technique, conformal proton beam radiation therapy, uses a similar approach to focus radiation on cancer. However, instead of using x-rays, this technique uses proton beams, enabling proton beam radiation to deliver more radiation to cancer while possibly reducing damage to nearby normal tissues. The goal of research into these various types of radiation therapy is to develop agents that will make the tumor more sensitive without affecting normal tissues (17).
Despite radiotherapy having an abundance of history that led to its creation, nanotherapy, being a relatively new treatment, does not have the same history background. Radiotherapy research, and that of other cancer treatments, has nonetheless led to both developments in radiation therapy, and in the relatively new nanotherapy for cancer treatment.
Advantages and drawbacks
Radiation therapy is one of the most popular cancer treatments because it has an abundance of benefits including the ability to control or stop tumor growth, work alone or in combination with other treatments such as surgery, and not requiring hospitalization, instead being delivered as an outpatient treatment, with short session times of less than 30 minutes. However, the therapy itself is not perfect. Radiation therapy has side effects that vary from person to person depending on the site of the therapy including hair loss, skin irritation, dry mouth, nausea, bladder infection, and stomach problems. Additionally, not many people can commit to a 7-week course of daily radiation therapy, making the treatment unfeasible for some (17, 18, 20).
Nanotechnology is one of the most exciting innovations today with the treatment possibly being a cure for serious and hereditary illnesses. Like other new technologies, the potential benefits of nanotechnology are extremely promising. Nanotechnology produces changes at the cellular level; has the potential to reconstruct objects at the cellular level; has the ability to extend the human lifespan by changing cells at the nuclear level; can spawn self-healing techniques; and can be used to virtually repair anything. Beyond the medical, it also has the economic potential to create a high volume of highly-skilled jobs. However, nanotechnology is largely human-dependent, leaving room for a wide variety of disadvantages. One of the primary disadvantages is that nanotechnology is only as good as the programmer behind it. The technology is able to duplicate itself and can be difficult to beat without countermeasures. There is no guarantee that nanotechnology won’t be counterproductive and create new problems that there are currently no solutions for. Nanotechnology has the potential to create a new system of class identities, where the socio-economic class owns technology for its own benefit and has the ability to weaponize it. The strengths and weaknesses of nanotechnology show many exciting possibilities. Nevertheless, the possibility is still risky to an extent. These strengths and weaknesses need to be carefully weighed to determine the next step in this exciting STEM field (19).
Drug Delivery Applications
Radiotherapy in NSCLC
Systemic therapy is a type of treatment that targets the entire body rather than aiming at one area. Systemic radiation therapy is a type of radiation therapy that utilizes radioactive drugs, otherwise known as radiopharmaceuticals or radionuclides, to treat certain types of cancer including NSCLC and SCLC. These drugs are radioactive substances that are administered orally or through veins to travel throughout the body (11).
Recent studies have been conducted to evaluate the therapeutic efficacy of various radiopharmaceuticals in treating NSCLC. In a particular study conducted in October 2020, researchers used xenografted models of NSCLC containing characteristics of human primary tumors to conduct experiments in order to determine the therapeutic efficacy of Lu-EB-RGD, a peptide-based radiopharmaceutical (RGD) with improved pharmacokinetics (abilities to move drugs throughout the body). This radiopharmaceutical targeted the integrin αvβ3—a mechanical protein that is a receptor for vitronectin which is linked to cell adhesion and expression. Abnormal expression of v3 is linked to the development and progression of various diseases, including cancer, by supplying blood for irregular growth. A single dose of Lu-EB-RGD was found to be enough to completely eradicate the tumors or cause significant delays in tumor growth, with no sign of tumor recurrence during the observation period. The preclinical data from the use of this model suggested that Lu-EB-RGD may be an effective treatment option for NSCLC and should be further evaluated in human trials. The study summarized that utilizing RGD peptides may be an effective treatment option for NSCLC by spurring improved pharmacokinetics, which propose that human trials should be conducted (29, 30, 31, 32).
Comparatively, radio technology does not have an abundance of research or clinical trials in treating SCLC. This represents a limitation in radio technological research: since NSCLC is a form of lung cancer that is more deeply researched than SCLC, radio technologies’ efficacy against SCLC cannot be compared to that of nanotechnology.
Nanotechnology in Drug Delivery
Nanotechnology is a targeted therapy technology that is designed to manipulate individual atoms and molecules for medical purposes, particularly drug delivery. By altering nanoparticles (NPs) in the pharmaceutical market, medical professionals have conducted clinical trials where this technology is utilized as drug carriers or nanocarriers. The technology has been successful in the administration of nanomedicine agents, cancer identification and biomedical imaging (5). Nanocarriers act as drug delivery systems (DDS) that change the physicochemical properties of nanoscale materials such as morphology and intracellular uptake to determine how drugs move throughout the body (6). Utilizing various nanomaterials in the construction of DDS ensures that these properties can be altered to allow nanotechnology to be used in a variety of ways in respiratory oncology. The altering capabilities of the technology stimulate the efficacy and decreased side effects of traditional drugs that operate at higher doses and greater toxicity (5).
In the case of NSCLC treatment, recent studies have proven that nanocarriers can provide effective treatments in reducing cancer cell growth. In a 2020 study conducted by Pharm Res, NPs were altered to carry the FDA-approved antiretroviral drug, Nelfinavir (NFV) as the drug exhibited cancer cell growth inhibition and increased apoptosis (7). As mentioned in the study, NFV has the potential to target cancerous cell and tissue growth like tumors. However, the drug is most effective at a higher dosage, thereby increasing toxicity and limiting clinical potential. By altering the material of NPs to include biodegradable poly lactic-co-glycolic acid (PLGA) NPs of NFV, and characterizing NPs for morphology and intracellular uptake, scientists were able to conduct experiments to determine their efficacy in treating NSCLC. In-vitro assays were conducted including cytotoxicity, cellular migration, colony formation, and 3D spheroid culture designed to mimic the in-vivo tumor microenvironment. Effects on molecular pathways including apoptosis and endoplasmic stress were also studied to achieve accurate results on the efficacy of NP alteration in the case of NFV. Researchers concluded that nanotechnology is capable of repurposing drugs for therapeutic drug delivery for NSCLC. NFV when loaded into NP DDS was able to provide promising NSCLC treatment to induce apoptosis and efficient tumor penetration (7). The limitations of the paper, however, are that since nanotechnology remains a relatively new treatment and there are many materials that NPs can be conceived from, many clinical trials have not yet been conducted to determine the effects each material has on efficacy and reducing side effects. There is a huge amount of research that needs to be done in clinical trials to determine the full scope of nanotechnology’s capabilities. Even so, other studies that also focus on the effects of NPs in enhancing the anticancer properties of various drugs, provide supporting evidence that nanotechnology may help to reinforce drug solubility and drug efficacy in NSCLC treatment (9).
Similar to radiotherapy, nanotechnology does not have an abundance of research or clinical trials in treating SCLC. This, again illustrates the limitation in nanotechnology research as since NSCLC is a form of lung cancer that is more researched than SCLC, nanotechnology’s efficacy against SCLC cannot be compared to that of radiotechnology.
The implementation of the relatively new nanotechnology through drug delivery allows personalized cancer therapy treatments by enabling advanced targeting strategies and multifunctionality. While nanotechnology has proven to be effective in drug delivery treatment of NSCLC, radiotherapy and the use of radiopharmaceuticals have also been proven to do the same. Alternatively, both technologies can be used in unison to provide better treatment options for patients. For example, a study conducted in 2008 hypothesized that gold, being an excellent absorber of X-rays, could load higher drug doses to cancerous tissues compared to normal tissues during radiotherapy treatment with the enhancement possibly being as high as 200% or greater (34). The paper concluded that radiotherapy dose enhancement with gold NPs is a promising approach for improved cancer treatment by providing a flexible chemical platform (34). Such studies provide evidence that the use of metallic NPs offers possibilities in radiotherapy dose enhancement (33). When combined, the traditional treatment of radiotherapy and modern nanotherapy methods can significantly improve drug delivery and treatment outcomes for patients diagnosed with NSCLC.
Radiation in Genetics
A study to test if ionizing radiation will lead to the improvements of adenoviral targeting and transgene expressions concluded that radiation could increase the rate of gene transfer and significantly improve adenovirus-mediated transgene expression in tumors. The study found that this method can act as a potential strategy for gene therapy through the use of an adenoviral vector containing a CMV promoter-driven green fluorescent protein marker gene (CMV–GFP) to infect various types of cells. In a cell culture system, γ-radiation directly induced viral uptake by cells, leading to significantly improved gene transfer efficiency (35).
Gene Therapy on Lung Cancer: Why Use Nanotechnology?
Despite the groundbreaking discoveries of lung cancer growth and cutting-edge therapeutic techniques, lung cancer patients’ survival rates still remain low. To this extent, targeted gene therapy with nanoparticles has become one of the most quickly expanding and broad fields of lung cancer research in recent years, particularly with non-small cell lung cancer (NSCLC).
Non-small cell lung cancer occurs by mutation, a random change in the base sequence of the EGFR and KRAS gene, leading to the production of a protein that is constitutively activated. As a result, cells are constantly signaled to proliferate, resulting in tumor growth (1). A study of the mutation in the EGFR and KRAS gene in Chinese patients concluded that the EGFR gene mutation rate is related to gender which occurs more often in females, patients with smoking history and pathological types in NSCLC, and differentiation in adenocarcinoma patients with smoking history (21). However, a limitation of this study is that it focuses solely on Chinese patients, so the results may not be representative to people in other countries and cannot be generalized to the entire population. Studies in other countries may provide different findings.
Types of Nanoparticles
The three main types of nanoparticles used in gene delivery consist of inorganic, organic and biological NPs (23). For the purposes of this paper, a focus will be placed on inorganic and organic NPs as the extant literature shows that these are the most effective for genetic therapy of NSCLC. Due to their unique physical/chemical properties and excellent biocompatibility, inorganic NPs such as metallic-based nanoparticles have been actively researched as therapeutic agents in biomedical sectors, especially for cancer treatments. A study on the use of engineering through Ligand Design concluded that the use of inorganic NPs offers the potential to surpass obstacles and enhance efficiency in nanomedicine. These NPs utilize their surface functionalization to control nano-bio interactions, from modulation of enzymatic activity to selective localization in specific cell types (24). However, some drawbacks exist, as it remains difficult to construct these nanosystems on a large scale while maintaining reproducibility and homogeneity, especially for some complicated nanosystems (25). However, the implementation of new developments in gene therapy treatments for NSCLC can combat these previously prominent setbacks. For example, the use of oligonucleotides which are short, single strands of synthetic deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), can allow for more personalized treatments by targeting and regulating abnormal genetic expressions related to cancer development (1). These strands allow treatment that regular DNA and RNA biopolymers cannot provide since they lack the ability to permeate the cell membrane and effectively enter the nucleus to regulate abnormalities (1).
Organic NPs such as liposomes are also useful in gene delivery, providing mechanical stability and an easy means of protecting siRNA segments in oligonucleotides (26). Yet, systemic barriers and low toxicity are important constraints to developing safe liposomal human gene therapy (27). Additionally, safety standards in the study of nanoparticles and the evaluation of therapeutic efficacy should be made clear to guide the direction of research in gene therapy, in order to further extend the use of nanoparticle systems in clinical trials. Modern nanotechnology treatments such as these cater to NSCLC adaptability. This cancer requires in-vivo gene delivery or delivery through living organisms that nanotech provides while protecting encapsulated nucleotides and boosting uptake by target cells (1). Thus, nanoparticle-based targeted gene delivery could be used more broadly in lung cancer treatments in the future (1).
A variety of conventional lung cancer treatment options exist, including radiotherapy; however, there is some resistance encountered in clinical practice leading to the recurrence of the disease (22). This sparks the need to develop a novel state-of-the-art approach to lung cancer, which further inspires the development of nanotechnology to increase the survival rate of NSCLC patients.
Combination Therapy: Use of Nanotechnology on Radiation
Recently, nanotechnology developments have supplied new hope for next-generation cancer treatment. The combination of radiation therapy with nanotechnology provides a promising strategy to modify the radiation response and overcome the radioresistance of tumor cells. Traditional cancer treatments including radiotherapy require delivering high-intensity ionizing radiation to tumor tissue, resulting in the death of tumor cells. This includes drawbacks, such as the risk of harm to normal tissues in the surrounding area. Furthermore, abnormal cells might develop resistance to radiation, necessitating higher dosages, which eventually leads to the loss of healthy tissue (28).
This leads to the development of Nanomaterial Radiosensitizers, a process that selectively kills abnormal cells from irradiation in tumors while exhibiting no damage to normal tissues. This form of combination therapy works by using metal (mainly gold) nanoparticles. The densely packed metal particles can selectively scatter and absorb the high gamma and X-ray radiations. This allows for better targeting of cellular components within the tumor tissues, leading to more localized damage to abnormal cells (28).
Alongside this, the use of drug treatment also provides rapid and sensitive detection of cancer-related molecules, enabling scientists to detect molecular changes even when they occur only in a small percentage of cells. This leads to early detections, which can increase survival rates in cancer patients.
Radiotherapy and nanotherapy are two lung cancer therapies that have both benefits and challenges in drug delivery and genetics. Radiotherapy, being a traditional method, offers less personalized treatment since it can damage both cancer and healthy cell tissues. Nanotherapy is a modern treatment that allows for more personalized therapy by enabling more specific, targeted therapy in specific areas. Nanotherapy however is a treatment method that has improved efficacy and safety, and serves to reduce the toxicity of radiotherapy when used in combination.
In terms of drug delivery, both radiotherapy and nanotherapy provide effective and improved drug delivery treatment to allow dose enhancement. When combined, the traditional treatment of radiotherapy and modern nanotherapy methods can significantly improve drug delivery and treatment outcomes for patients diagnosed with NSCLC. In terms of genetics, nanotechnology developments have provided promising strategies to modify the radiation response and overcome the radioresistance of tumor cells in radiotherapy treatments. Traditional cancer treatments including radiotherapy require delivering high-intensity ionizing radiation to tumor tissue, resulting in the death of tumor cells. However, the incorporation of nanotechnology in radiotherapy could spur the development of various new technological forms such as nanomaterial Radiosensitizers to selectively kills abnormal cells, while exhibiting no damage to normal tissues.
If appropriate clinical trials are conducted to determine the full scope of nanotherapy treatment, as well as determine the effect of utilizing various nanomaterials in the construction of nanoparticles, nanotherapy is an effective modern treatment method that could replace traditional radiotherapy. However, alternatively, nanotherapy and radiotherapy could be used together to create combination therapy treatments that contribute greatly to cancer research and therapy. While modern treatment methods such as nanotherapy may provide great relief for drawbacks, traditional methods such as radiotherapy can still be incorporated into the new era of cancer treatment to improve survival rates and allow for personalized and targeted treatments.
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