The future of cancer diagnosis and treatment through nanomedicine.
Is a personalised approach via nanoparticles achievable?
Cancer is one of the major factors contributing to global mortality rates, contributing to one out of six deaths world wide. Traditional methods for diagnosis and treatment are often not precise enough to accurately map out the tumour and destroy the cancerous cells without causing a series of side effects, which could lead to patient mortality. In order to improve cancer diagnostics and treatments, researchers have invested in incorporating nanotechnology into the medical field starting from the late 20th century. The use of nanoparticles allows delivery of drugs to a targeted site in the body, or can be used to outline the size and location of tumours down to the millimetre, which is more accurate than traditional methods.
Nanotechnology is a branch of science that works with particles of diameters ranging from 10 to 100 nm, where 1 nm equates to one billionth of a metre. Their size grants their biggest advantage: they can carry, detect, and manipulate cells on a molecular level. When applied clinically, nanoparticles (NPs) can aid doctors during the diagnosis and treatment processes of cancer. This can shorten the period of diagnosis from lasting weeks or months down to just hours. NPs can deliver drugs to a targeted area in the body without causing unwanted side effects.
Research has been conducted regarding the incorporation of NPs into medicine, but nanomedicine is still a developing field; there are different aspects of nanotechnology that require improvements. For instance, the uniqueness of each tumour can change the efficiency of drug delivery to the targeted cancer cells, and the rate of NP travel can fluctuate with a difference in blood flow.
Figure 1: NPs categorised according to their material, size, surface, and shape.
There is a variety of organically and inorganically synthesised NPs, each with their own unique properties. This essay will be focused on the inorganic gold nanoparticle (AuNP) and how they can be utilised in modern oncology (see Figure 1.)
2. Clinical Importance and Interest
As the third leading cause of death in the world, cancer is a global epidemic that requires immediate attention. An average of 1 in 3 people are diagnosed with cancer in their lifetime: sometimes this is a benign tumour that can be removed in a surgical procedure; in other cases it will be malignant cells that have infiltrated the patient’s whole body. Infrequent checkups, delayed diagnosis, and inaccurate imaging are often the main causes of cancer developing past the point beyond which it can be effectively eradicated.
Cancer diagnosis generally comes in two parts – the diagnosis itself, and determining the stage or the extent of the cancer. The first is achievable through a range of tests; this includes lab tests such as blood and urine examinations, biopsies, and imaging using X-ray, CT (Computed Tomography) scans, ultrasound, and MRI (Magnetic Resonance Imaging). Diagnostic imaging relies on the final image to determine whether or not there is a cancerous mass in the body, which is not always accurate. For this reason, biopsies often mark the final positive or negative diagnosis for cancer. The stage diagnosis can include imaging to see if the cancer has spread; the doctors then define the stage using roman numerals from I to IV with IV being the latest stage.
The main challenge faced by cancer diagnosis today is a lack of accurate detection tools. CT scans and X-rays allow doctors to direct patients to the stage of their cancer development, but will not be able to reflect the precise locations and depths of tumours or the exact mapping. With the aid of NPs, accurate diagnostic imaging will be provided for doctors as a tool to determine the progression of cancer spread and propose a suitable treatment method. An unambiguous diagnosis is essential to build a strong foundation for treatment.
2.1 Application in Drug Delivery
Proceeding from diagnosis is nano drug delivery. The aspect of nano drug delivery that makes it so unique, and potentially the most effective treatment for cancer, is its ability to deliver chemotherapy drugs to cancerous cells in a targeted manner. Without travelling to any normal tissues, chemotherapy drugs will be eliminating cancer with more precision than they’ve ever had. Traditional cancer treatments operate indiscriminately in the body, causing a whole host of side effects including pain, hair loss, kidney dysfunction, and the death of white blood cells. A decrease in white blood cells equates to a weaker immune system, making the patient much more vulnerable to other diseases. Nanotechnology-based treatments that work in a specialised and targeted manner can prevent these side effects.
NPs enter the tumour via the Enhanced Permeability Retention (EPR) effect, a mechanism similar to diffusion (see Figure 2) which can operate both passively and actively. The former takes place with NPs not conjugated with targeting molecules and the latter occurs when NPs are synthesised with targeting agents such as antibodies. This application is enabled by the characteristic leaky tumour vasculature and poor lymphatic drainage of the tumour. Tumour blood vessels are leaky due to gaps present in the endothelial walls, with sizes ranging from 100 nm to 2 µm. As normal blood vessels will not have abnormalities in their endothelial walls, accidental false drug delivery to normal tissue cells can be avoided. A rapid increase in cancer cell size and number generates local compressive pressure on the lymphatic vessels, leading to poor lymphatic drainage. When the drug is delivered, it is retained in the tumour for a period of time before excreting out of the body through the liver and kidneys. This allows more time for the drug to act.
Figure 2: The principal of the EPR effect through the movement of NPs in normal versus tumour vasculature. The top shows the lack of pores in normal endothelial cell linings within vasculatures, therefore the lack of penetration of NPs. The bottom shows the EPR effect in action: NPs move into tumour tissues via leaky vasculature. The NPs are retained in the tumour due to lack of lymphatic system.
2.2 Application in Diagnosis
Another major function of NPs in cancer is that of imaging. They can act as contrasting agents, and their targeted approach to cancer cells allows for a more exact image to be produced. For example, the introduction of NPs as contrasting agents with functionalized antibodies or proteins will make CT scans clearer than ever.
3. Overview of AuNPs
3.1 Charge, Size, and Shape
In active cancer nano-therapy, a complex is formed for chemotherapy drug delivery. Specific molecules, such as antibodies or proteins, can be attached to the surface of a plasmonic NP containing chemotherapy drugs; these NPs will then be interacting with the cancer cells via endocytosis in the blood vessels. Gold is one of the best NPs for drug delivery and diagnosis due to its unique surface electron movements and effectiveness of surface functionalization.
Figure 3: Examples of AuNPs used in oncology. A) Nanoshells with silica core with a diameter of about 100nms; hollow nanoshells can also be made. They have great plasmonic photothermal activities. B) Gold nanorods are solid and cylindrical shapes. C) Solid nanospheres.
The three most important factors in choosing a suitable NP are charge, size, and shape. The lack of a negative charge on an AuNP’s surface means that they can be modified easily, such as the addition of drugs or targeting agents. Derivatives of AuNPs have a unique ability to be moulded into different geometrical forms and sizes; this includes nanoshells (50-150nm across the diameter), nanorods (25-45nms long), and nanospheres (see Figure 3.) Gold nanospheres (AuNSs) are the most commonly used AuNPs for drug delivery and one of the most commonly synthesised. This is due to their monodispersity and uniform size.
3.2 Gold in Drug Delivery
As previously mentioned, AuNPs can enter tumour muscles owing to the passive EPR effect and active drug delivery through AuNPs with conjugated surfaces. However, when tested in vivo, the EPR effect was less effective than predicted. It is important for AuNPs to accumulate in a specific site for a relatively long period of time in order to sustain the high efficacy of drug delivery. This could be disturbed by the body’s reticuloendothelial system (RES), a part of the immune system, which uses the process of opsonisation via the protein opsonins, which are found in the bloodstream. This is a way for the body to raise a red flag about foreign invaders. Opsonins bind to the surface of a non-self invading species and alarm the RES. Then the RES’s leukocyte components, such as monocytes and macrophages, target the foreign body to remove them from the area through non-specific immune defences such as phagocytosis.
A solution to this is to synthesise AuNPs with coatings of polyethylene glycol, or PEG (see Figure 4.) PEG prevents opsonisation by reducing the contact between the NP and the opsonins, thus decreasing the immune system’s identification of AuNPs as non-self bodies. PEG is also hydrophilic, meaning that AuNPs with PEG coatings are less vulnerable to attack from the RES than plain hydrophobic AuNPs.
Fig 4: Transition from monomer ethylene glycol into polymer chain PEG.
As drug carriers, AuNPs can also assist in treating drug-resistant cancer cells. For example, a study regarding breast cancer has been carried out by attaching the cancer drug doxorubicin (DOX) to AuNPs through a pH-sensitive linker. As the DOX-AuNP conjugate enters the acidic cancer cell organelles, the pH environment lowers. Subsequently, the drugs are released. This enhanced intracellular release of drugs contributes to the enhanced toxicity against MCF-7/ADR breast cancer cells.
3.3 Gold in Diagnostics
The usage of AuNPs in diagnostics is exemplified in X-ray based CT scans. Current CT scanning, unlike MRI, does not visualise and measure molecular and cellular processes. No targeted molecular imaging molecules have been developed specifically for contrasting values in CT scans. CT scans detect the difference in the amount of X-ray signal that can penetrate through different tissues. This is due to the variation of atomic number between the tissues; there is a positive correlation between the two factors and X-ray attenuation. As atomic number increases, the X-ray attenuation increases, so the X-ray signal decreases.
Many current CT contrasting agents are iodine-based dyes, which are effective at absorbing X-rays, but lack longevity as they are discarded by the body’s kidneys and are unable to be functionalized i.e. non-targeted, thus less desirable. Gold’s higher atomic number and electron number makes it an even stronger absorber and AuNPs contain both of the properties that iodine-based molecules don’t have, making AuNPs a very attractive material for contrasting imaging. Apart from NP-specific properties, AuNRs also possess a unique characteristic: they are not limited by the depth of the cancer or its position within the body. No matter how deep or shallow the cancer cells are, the intensity of signals will remain the same. The only factor determining the clarity of the CT scans is the volume of AuNR used. This means even the smallest of tumours can be detected, so treatment can occur before it is able to grow and become more threatening.
An example of this is CT scanning for head and neck cancer. These cancer cell masses are usually composed of 90% squamous cell carcinoma (SCC), a form of skin cancer that can branch into the head and neck area. It is difficult to differentiate SCC from normal tissues with traditional physical examinations. Characterised by the over-expression of the A9 antigen, SCC can be target-imaged through the biomolecule UM-A9 antibody. The AuNR is complete as a contrasting agent after conjugation with the antibody. With the addition of AuNR and UM-A9 antibody, the cancer’s attenuation increased up to 200HU, creating a larger contrast in comparison to the normal body tissue’s 0-50HU (Hounsfield Units, used to measure X-ray attenuation), as seen in Figure 5. This allows the SCC to be imaged effectively where it would otherwise remain undetected.
Without accurate imaging, doctors cannot locate and treat smaller, secondary, and malignant cancer masses in other areas. These masses known as metastases are often the cause of cancer recurrence. Traditional CT scans are limited in the sense that they can only detect tumours when they are above the size of several millimetres, or approximately 10 million cells. Metastases with a size smaller than that cannot be detected, thus making the scans ineffective for future prognosis. Of course, this issue could be eliminated by incorporating NPs in CT, intensifying even the smallest signals.
Figure 5: This bar graph shows the CT attenuation of different types of tissues/cancers with or without AuNRs and bioconjugated with either correlating or non-correlating antibodies. As the graph shows, larynx and oral cancers with AuNRs functionalized with the correct UM-A9 antibodies have much stronger attenuations than those cancers that aren’t imaged with AuNRs.
The ability of AuNPs to be functionalized needs to be further developed in order to maximise the precision of NPs.Functionalization allows active, specific targeting and replacement of potentially cytotoxic chemicals used in the synthesis process. This can be achieved through two forms of connection: covalent bonding that involves chemical attachments, or non-covalent interactions that include intra and intermolecular forces (see Figure 6.)
Figure 6: Biofunctionalised NP using covalent and non-covalent forces. Dative bonding, amide, thiourea, and carbamate linkages are covalent interactions whereas electrostatic and hydrophobic entrapment are non-covalent Interactions.
3.4.1 Covalent Interactions
Covalent interactions, as the name suggests, are interactions that involve covalent bonds. Covalent interactions are preferred as they provide greater stability and reproduction of biofunctionalization.
Sometimes the structures of the added functional groups undergo unwanted changes due to direct interaction between them and the AuNP. For example, some proteins can experience changes that alter their biological activities. For drug delivery, this is disadvantageous and undesirable as an alteration in protein structure can possibly lead to inaccurate targeting, the polar opposite of their function. In these cases, linkages are used to connect the functional groups to the AuNPs. Some common linkers are amides (-NH₃⁺), carboxyl (-COO⁻), and isothiocyanate (-N=C=S); they are usually modified onto PEG polymers. The DOX-AuNP conjugate uses an example of a pH-sensitive linker, which dissociates after entering the acidic environment of a cancer cell. One can observe from Fig. 5 that the elements connecting to the addition – nitrogen, oxygen, nitrogen, and sulphur – are all basic. To put it in simpler terms, the mechanism works as the bonds become less stable in an acidic intracellular environment, therefore they break when they enter the cell.
3.4.2 Non-covalent Interactions
Specifically, non-covalent forces are electrostatic attractions, van der Waals forces (dipole-dipole forces), and hydrophobic entrapment. These interactions are generally used to attach biomolecules onto an oppositely charged AuNP surface. These include DNA, peptides, and antibodies that allow active targeting.
An example of non-covalent functionalization is connecting an anti-epidermal growth factor receptor antibody onto an AuNP or utilising the negatively charged phosphate backbone of DNA to form gold clusters.
3.4.3 Importance of Correct Functionalization Group
Having an antibody-specific functionalization group is essential to improving diagnostics. Figure 7 is a clear example of how a correct antibody can lead to a much more precise imaging. The two images on the left are those after AuNRs functionalized with non-A9 antigen-specific antibodies are introduced into the body whereas the right two are those after UM-A9 functionalised AuNRs are introduced. Apart from the obvious improvement in clarity, the small 20nm cells are detected and these metastases can be eliminated.
The targeted approach of NPs promises a bright future into personalised medicine, especially in the field of oncology. However, it is impossible to talk about nanomedicine without addressing its problems.
The specificity of tumours brings about a major challenge to drug distribution in the body by disrupting the administration of drugs through the EPR (Enhanced Permeability and Retention) effect. The complexity and heterogeneity of the vast numbers of tumours are difficult to target. Even minimal changes in these factors can influence the biological steps involved in drug distribution. Data from research undertaken between 2007 and 2017 concluded that only 0.7% of the NPs administered into the body will reach the targeted tumour.
In addition, most of the current understanding of pharmacokinetics is derived from data which originated from studies which used animals, not humans. Thus in clinical situations, it is difficult to map out how the factors correlate and how they will influence each other in different species. Specifically for nanomedicine, many experiments are conducted on mice, where the tumours are planted into their systems. NP destinations are highly dependent on blood circulation rates and NP-protein interactions, which can be different due to the size differences between mice and humans. It is false to say that research conducted on mice can be altogether ignored, but it is essential to conduct clinical trials in order to improve the reliability of the data.
4.2 Autoimmune Response
When a foreign body, which does not have any antibody or protein adaptations recognised by the body, enters the patient, it could result in an undesired response from the immune system. AuNPs can unexpectedly trigger a condition known as the CARPA-phenomenon (Complement Activation Related PseudoAllergy). This is caused by their relative sizes, which are similar to those of viruses that range from 20 to several hundred nanometers. The patient’s immune system senses an alarming non-self body, so it launches an attack on the NPs. The immune system’s response could lead to common allergy symptoms, such as cardiac distress, difficulty breathing, chest and back pain, or fainting, hence the name PseudoAllergy. The CARPA-phenomenon can affect up to 100 patients each day and occasionally, this pseudo reaction can lead to one death every ten days.
Both immunotherapy and AuNP drug delivery are promising treatments for cancer. This section will explore both methods, using a case of breast cancer involving HER2 genes. It will compare the effectiveness and safety of both immunotherapy and NP drug delivery.
Immunotherapy utilises the patient’s immune system to battle against cancer. An example of this incorporates the newly developed multivalent bi-specific nanobioconjugate engager (mBiNE). The particle, attached with antibodies that target HER2 genes present in 40% of breast cancers, will stimulate HER2-targeted phagocytosis. This has led to a 70-80% reduction in tumour size when mice are treated with this type of immunotherapy. Memory cells are then recreated to combat possible future recurrences of HER2 positive breast cancer. Studies have shown that although initially the immunotherapy was dependent on the presence of HER2 receptors, further during the trials mBiNE also showed positive effects without said receptors.
5.2 Which is More Effective?
A group of researchers tested the efficacy of a group of histidine-rich glycoprotein RNA-functionalized AuNPs on a group of 120 breast cancer patients for three different types of cancer genes status, including the gene HER2. The histidine-rich glycoprotein RNA-AuNP reported a 90% sensitivity and specificity.
Upon an attempt at comparing the specific examples of reducing cancer with HER2 genes, the AuNP drug delivery seems to be more effective, owing to its higher specificity. However, the fundamental idea of targeted treatment is to eradicate all cancer cells safely and efficiently. Neither studies show a near 100% success rate in treating cancer. As well as the lack of thorough elimination, the microenvironment of the cancer tissue is changing all the time. Therefore, questions can be raised about the longevity of the specificity in the patient trials and as to whether or not the high efficacy can be maintained.
A proposition for a more comparable study could be raised where both the immunotherapy and the AuNP drug delivery are conducted on two separate groups of patients with cancer expressing the same gene. These two groups would require controls such as the same number of patients involved and data collection for the same cause (such as specificity or concentration of cancer cells after each trial). Especially in NP cancer research, the dependability and accuracy of the research is dependent on the controls remaining the same at all times and only the desired variable to change.
6.1 Current Stages of NP Incorporation in the Clinic
The first NP approved by the FDA in 1995 was Doxil, PEG functionalized liposomal doxorubicin. From then on until January 2016, there have been 46 NPs under clinical trial and 26 NPs that are clinically approved by the FDA and EMA.
Going back to gold, there are currently still very few AuNPs in clinical trials owing to their high specificity (see Figure 8.) Any internal individual difference would lead to a change in the effectiveness of the AuNP.
6.2 Assessment of Future Progression
The annual mortality rate of cancer in 2018 was 9.56 million across the globe and the number of new cancer cases per year is expected to rise to 23.6 million in 2030. Current diagnosis, prognosis, and treatment methods are not accurate and effective enough to battle cancer. Whilst CT and X-ray scans provide a rough outline of the cancer location, no current imaging allows doctors to precisely diagnose a patient. Secondary metastases are often overlooked due to their minor sizes, as they are smaller than the resolution that can be imaged using traditional methods. They are often the cause for recurring cancer in patients: doctors cannot make a correct prognosis without having a look at the whole picture. Furthermore, chemotherapy and radiotherapy, whilst providing effective treatments, almost always also harm healthy body cells. The side effects these treatments bring about are sometimes even more destructive than the malignant cancer itself.
That being said, advanced cancer research will not occur without the foundations of current cancer diagnostics and treatments. More often than not, NPs are created to improve current methods, such as enhancing CT scans using AuNPs’ high X-ray attenuation or carrying chemotherapy drugs to specifically desired sites.
One could almost compare NPs to Ehrlich’s magic bullets. Similar to his “hitting the germs only and not other cells” ideology in treating syphilis, a targeted approach to diagnosing and treating cancer is the future of oncology. The main uncertainty holding scientists and doctors back from clinical trials are the constantly changing microenvironment of the body. Every single minimal difference can bring about unknown consequences in the efficacy of drug delivery, although this has less of an effect on diagnosis.
After evaluating the positives and negatives of nanomedicine, one can conclude that a personalised approach for cancer diagnosis and treatment is achievable. The growth for the inclusion of NPs in diagnosis will likely start sooner than for treatments. Studies have shown a clear inclination to incorporate NPs in diagnosis as they are mostly utilised upon the basis that they are there for improving current diagnosis and treatments. It is far less risky and preferable to amend fully developed techniques than to create new ones from scratch, rather like that of NP drug delivery. Regardless of the time frame or specific usage, demand for advancement in clinical nanomedicine research is rising and will continue to rise as patients seek for more effective diagnosis and treatment methods. The potential uses of NPs in cancer diagnosis and treatment are endless, with countless possibilities for future research. The development of these methods would allow cancer to be more accurately diagnosed and treated, allowing for a better quality of life for patients across the world.
NP(s) – Nanoparticle(s)
EPR – Enhanced Permeability Retention
NIR – Near Infrared Radiation
nm(s) – nanometres(s)
AuNC(s) – Gold Nanocage(s)
AuNP(s) – Gold Nanoparticle(s)
AuNR(s) – Gold Nanorods
AuNS(s) – Gold Nanosphere(s)
RES – Reticuloendothelial System
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Figure 1: Hendrik H., Pramanik C., Heinz O., Ding Y., Mishra R.K., Marchon D., Flatt R.J., Estrela-Lopis I., Llop J., Moya S., Ziolo R.F., February 2017. Nanoparticle decoration with surfactants: Molecular interactions, assembly, and applications, Surface Science Reports, Vol 72, Issue 1, Pg 1-58
Figure 2: Maeda H. et al., January 2013. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Advanced Drug Delivery Reviews, Volume 65, Issue 1, Pg. 71-79
Figure 3: Lee J. et al., May 2014. Gold nanoparticles in breast cancer treatment: Promise and potential pitfalls, Cancer letters, Vol. 347, 46-53
Figure 4: Jokerst J.V. et al., June 3011. Nanoparticle PEGylation for imaging and therapy. Nanomedicine (Lond), 6(4): 715-728
Figure 5: Yin H., Liao H., Fang J., January 2014. Enhanced Permeability and Retention (EPR) Effect Based Tumor Targeting: The Concept, Application, and Prospect, JSM Clin Oncol Res 2(1): 1010
Figure 6: Austin L.A. et al., August 2014. The optical, photothermal, and facile surface chemical properties of gold and silver nanoparticles in biodiagnostics, therapy, and drug delivery, Molecules, 22(9), 1445
Figure 7: Popovtzer R. et al., 2008. Targeted gold nanoparticles enable molecular CT imaging of cancer. Nano letters, 8(12), 4593-4596
Figure 8: Singh P. et al, July 6, 2018. Gold Nanoparticles in Diagnostics and Therapeutics for Human Cancer, International Journal of Molecular Science, Vol. 19, Issue 7
About the author
Cindy is currently a student studying in the UK, with a strong interest in oncology and the methods behind diagnosing and curing cancer. Hoping to pursue a career in science, she is working hard on researching in depth in the fields of genetic engineering and gene expression.