In what ways do quantum dots play a crucial role in advancing the field of medicine, specifically in the diagnoses and treatment of cancer?

This project will explore the application of quantum dots in diagnosing and treating cancer. We will begin by understanding what quantum dots are, their basic properties and applications, and the advantages and disadvantages they provide. We will then transition to specifically explore how quantum dots can be used to treat one of the most common diseases in the world: cancer. This project will explore the three most common ways quantum dots can be applied in the biomedical field to treat cancer: discovery of biomarkers, delivering drugs, and improving photodynamic therapy. In each of these sections, a brief overview will be provided as the background information on the topic along with how each of these are currently being done in the medical world. We will then look into how each of these methods can be used with quantum dots by understanding the mechanism behind their application, the advantages and disadvantages that exist and taking a look at studies that have been conducted that support the arguments being made in this project. Lastly, a conclusion will be provided which will analyze the challenges that exist that prevent quantum dots from being widely used, the potential solutions to these challenges presented and, finally, how to incorporate quantum dots more into our healthcare system to ultimately revolutionize the world of medicine.

Quantum Dots

What are Quantum Dots?

Nanomaterial can be classified based on the number of degrees of freedom the electrons experience. 

Quantum wells are a two dimensional nanomaterial in which the electrons are confined in only one direction. Quantum wires are a one dimensional nanostructure with its electrons confined in two directions. And lastly, quantum dots are zero dimensional nanocrystals in which the electrons are confined in all three directions.

 

Quantum dots (QD) are nanocrystals with semiconducting properties. Despite their small size, they do not always consist of a singular atom; usually QDs are created by a cluster of atoms in a crystal-like structure, ranging a total between 2-10 nm in diameter (ie. 10 - 50 atoms).  They are mainly made from elements in Group II-VI or III-V on the periodic table such as cadmium selenide (CdSe) or indium arsenide (InAs). These elements are used to make the outer shell and the inner core of the QD. 

The increasing interest in QD for various applications is due to their unique optical and electrical properties because of the quantum effects they produce from having the electron’s motions confined in all three dimensions. 

 

How Quantum Dots are Made

There are four main ways of preparing QD:

1. Colloidal Synthesis: This is a process that requires heating a precursor solution to transform it into nucleated monomers. These monomers - under high temperatures - cause nanocrystals to grow.
2. Fabrication: This process is simply used to make existing QDs stronger by adding an outer shell to them.
3. Viral Assembly: This process requires genetically engineered bacteriophage viruses to be exposed to precursor solutions. This helps form nanocrystals via the nucleation between the proteins in the virus and the precursor solution. 
4. Electrochemical Assembly: This process requires an ionic reaction between a metal and an electrolyte to take place. This reaction generates a spontaneous formation of QD.

 

When making QDs, it is possible to control the diameter of the core and the thickness of the shells. The process of making QDs usually involves growing them in a nucleation site or making them on a metal dish using an electrochemical approach. This allows engineers to control how large the QD will be by adjusting the flow of gas or the temperature of the site/dish. The elements on the dish are then excited by a laser, causing them to glow different colours. The colours emitted are based on the elements used and the size of the QD being produced. The outer shell of the QD is made from heavy or inorganic materials such as cadmium, selenium, zinc oxide, silica, etc. These are then coated with a special shell material that allows the QD to later conjugate to other materials and reduces the toxicity of the outer shell. 

 

Classification of Quantum Dots

Depending on the size, the material used for preparation, the composition and the structure, quantum dots can be classified into three main types:

1. Core-Type Quantum Dots: These QD are made of a single type of element with a uniformly composed internal structure. The properties of these can be manipulated by changing the size of the crystals. 
2. Core-Shell Quantum Dots: These QDs are coated with shells that are made of semiconducting material which have a higher band gap than the core. This improves the efficiency and the brightness of the dots made.
3. Alloyed Quantum Dots: In some applications, changing the crystal’s size to obtain different properties could be problematic due to size restrictions. Because of this, alloyed QDs would be used since the composition and internal structure of the crystals can be changed without altering the overall size of the QD. Alloyed QDs will still result in different properties that would be beneficial for its targeted application. 

 

Another aspect of classifying QDs is by their size. Larger QDs are those with diameters of 5-6 nm. They emit longer wavelengths of red and orange. On the other hand, smaller QDs are those with diameters of 2-3 nm. Their resulting emissions are of shorter wavelengths of blue and green. 

 

Knowing the different methods for making quantum dots can help us choose the appropriate method that will result in the desired properties needed for a specific application.

 

Properties of Quantum Dots

Quantum dots hold many unique and useful properties. Not all quantum dots are the same which results in their properties differing based on their size, shape and the material used. However, all quantum dots hold unique optical, absorption and photoluminescent properties because of their small size. These properties are different from large, bulky semiconductors because of the high surface area to volume ratio that QDs have. The consequence of this ratio is most apparent in the colours the dots display which is based on the size of the particles. This quality is called quantum confinement.

 

To understand the many unique optical and electronic properties of quantum dots, it is essential to understand what quantum confinement is. 

A characteristic of each semiconductor is the Bohr radius. The Bohr radius is the distance between the electrons in the conduction band (the place the electrons bounce up to when excited) and their corresponding hole in the valence band (where the valence electron’s resting energy level is at). The effects of quantum confinement can only occur in dimensions smaller than the Bohr radius. Since large semiconducting materials are larger than the Bohr radius, they do not experience quantum confinement and instead have continuous electronic energy levels. However, quantum dots are small enough to experience quantum confinement.

 

When a QD is excited by a photon, the electrons in the valence shell gain energy and form an exciton. An exciton is the combination of an electron and the hole-pair that is free to move around. The size of the exciton is equivalent to the size of the QD which already has discrete atomic-like energy levels. This causes the exciton to also be confined in all three dimensions to also display discrete atomic-like energy levels, resulting in the first main property of quantum dots: their long life durations in an excited state.

The atoms within the QD that gained the photon’s energy get “excited”, meaning their electrons went up to the conduction band. Eventually, when the electrons go back down to the valence band, they will “give away” that excitation energy they had previously gained, resulting in the QD emitting a photon of a slightly lower energy but a longer wavelength than what it had initially absorbed. The wavelength and frequency of light emitted by the QD results in different colour emissions. This equates to the other main property of quantum dots: that different types of quantum dots can emit different colours. Because the dots are so small, the energy released from the electrons stays consistent, meaning that the emissions are of the exact same colour.

 

One way to determine the colours the atoms emit is by knowing the ways their energy levels are arranged. Energy levels in an atom have set values to them, making them quantized. This means that the energy levels of a quantum dot are also quantized, resulting in their quantized energy level behaviour. However, the material used for a QD (ex. silicon) can produce different colours based on the size of the QD. This results in another essential property of quantum dots: their tunable light emission property. Generally, smaller QD requires more energy to be excited which results in more energy released when returning to a resting state. This is why smaller QDs tend to emit higher frequency colours like blue. Similarly, larger QDs require less energy to be excited which is why the energy released from them tends to be of lower frequency, resulting in colours like red to be emitted. By knowing that QD can emit any colour light from the same material by simply changing the dot’s size, it gives engineers control over the optical and electrical properties by only changing the size of the dots when manufacturing. 

 

It is also possible to change the emission spectra by manipulating the core composition of the dot. For example, QDs with CdS cores with an average diameter of 1-6 nm would have an emission spectra in the ultraviolet-visible range depending on the particle’s exact size. QDs with InAs cores that also are 1-6 nm in diameter would instead have emission spectra in the infrared range. 

 

The quantum confinement effect also results in other incredible optical properties such as:

• High quantum yield (ie. more light emitted than absorbed)
• High brightness 
• High extinction coefficient (how much light it absorbed and reflected of a specific wavelength)
• High stability against photobleaching (when a chemical reaction occurs between a fluorophore and its immediate environment, causing the fluorophore to degrade and lose its ability to fluoresce. QD have a high resist against this phenomenon)
• Blinking (randomly switching between On (bright) and Off (dark) states)

 

Many of these properties can be proven as an advantage for certain applications, whereas certain qualities of QDs can be a form of disadvantage.

 

Advantages and Disadvantages of Quantum Dots

Quantum dots provide many advantages based on their specific application, their composition, their structure, etc. However, overall, all quantum dots hold a general set of advantages and disadvantages that allow for engineers and scientists to determine if they are the best material to use for a specific application. Many of these advantages are what is attracting researchers and engineers to study quantum dots more and begin implementing them in various fields. To better understand the increasing interest in quantum dot technology and the need to implement them more, it is important to compare the advantages and disadvantages of this much needed and emerging technology.

 

Advantages

• Manufacturing process requires considerably less energy: Since we can easily control the size of the dot produced, we can indirectly control the wavelengths of the re-emitted photons as well. This means that it is possible to manipulate the light that is emitted without significant cost going into other forms of high-end technology to make that happen. This property allows a full range of QDs to be made, each with distinct emission spectrums.
• Can be excited with very little energy: To excite a QD, only a single beam of light of a specific wavelength is required, no matter the size of the QD. This lowers cost by only using a small amount of light to excite many QDs. 
• Can be used in various forms: QDs could be used as crystals dissolved in a liquid-based solution, as quantum dust particles, as beads, etc. This makes their range of potential applications even wider.
• Multiple manufacturing methods which are all easy and cost effective (ex. Colloidal synthesis)
• Can easily be modified to have different shapes, sizes, coating, etc: The modifications to QDs changes the charge, solubility and size of the particles. These modifications can make the particles more suitable for biological systems (e.g coating a bioactive molecule to allow safe entry into the body)
• QDs are 10-20 times brighter and have longer/higher photostability than organic dyes: This makes them great candidates for high sensitivity applications.
• Good flowability
• Can produce a wider range of colours than other conventional dyes
• Energy efficient: Almost all the light that QDs absorb is emitted right back as light energy. This efficiency of light emission shows that QDs do not consume much power.
• Highly durable with less degradation over time: materials that are made with QD technology have longer lifespans
• Reduced environmental impact: by having a high energy efficiency with longer lifespans of the materials produced, this would indirectly reduce carbon emissions in terms of manufacturing.

 

Disadvantages

• Cost: QD may be expensive to implement which initially would make the products very expensive
• Toxicity: This is the biggest concern on QD applications. Some QDs are made of toxic metals such as cadmium which could be an environmental and health concern if not handled and disposed of properly.
• Limited research: As this is still a relatively new technology, more research is required to understand all the risks and benefits of quantum dots.
• Could blink and become invisible: Although quantum dots’ blinking property may be beneficial, they still hold the potential of blinking “Off” and then simply never turning back “On”. This could be caused by quantum yield distortion (ie. the ratio of emitted to absorbed energy is rather low) and would require high-sensitivity detection systems to detect the low transmittance.

 

Applications of Quantum Dots

Despite the cons, quantum dots are still an extremely versatile and flexible form of material. Because of their unique properties and the advantages they provide, quantum dots hold promise in advancing many different fields. Such fields include: 

 

• Televisions and Display Systems: The application of quantum dots in this area will enhance the colour and brightness of TVs, resulting in brighter and higher quality displays.
• Energy storage: Quantum dots would improve supercapacitors and batteries’ performance by speeding up charging time, increasing their capacity and increasing energy density since the energy is stored at a nanoscale.
• Security: Quantum dots will help combat counterfeits by creating more authentic and secure tags, each having their own unique fluorescent markers.
• Quantum Computing: Because of the dots’ size, electrons do not have to travel so far. This results in faster electrical signals being sent for computers, which would result in increased computer calculations. 
• Optoelectronic devices: Quantum dots have the ability to improve solar cell efficiency since they would be able to capture broader rays of light wavelengths than traditional solar cells.
• Environmental monitoring: Water and air qualities can be monitored more accurately by quantum dots since they would be able to provide real time information on pH, temperature, pollutants and other environmental parameters.
• Biological applications: Quantum dots hold the power to revolutionize many areas in medicine. They can provide more precise and accurate visualization on biological processes and drug development because of their stability, brightness and resistance to photobleaching. They also can improve treatment and detection of various conditions, ultimately speeding up the recovery process for the patients.

 

• Global cancer statistic: 10 million cancer deaths worldwide in 2020

For the purpose of this project, we will focus on the medical aspect and application of quantum dots, specifically for the diagnosis and treatment of cancer. 

 

Cancer is a collection of diseases characterized by the abnormal and uncontrollable growth of body cells. These abnormal cancerous cells are caused by a genetic mutation within normal tissues. Cancerous cells can begin anywhere and they have the ability to destroy healthy cells and spread to other areas of the body. This devastating disease is the leading cause of death in Canada and was responsible for 10 million deaths worldwide in 2020. Cancer research and the need for a potential cure has been a top priority for decades. Unfortunately, despite all efforts, no definite cure as such exists. There are only treatments to slow down and control the spread of cancer, medications to relieve some of the symptoms, and procedures to remove and kill the cancerous tissues. However, the current treatments and procedures available hold many significant side effects and do not provide a guarantee that the cancer may not emerge again many years later. By improving the treatments available or introducing new ones, we can provide a form of cure for cancer and improve the quality of life of millions of patients. 

 

Quantum dot technology has recently been gaining popularity as a potential method for battling cancer. Because of their unique properties and various biological applications, researchers are delving into the numerous ways quantum dots can be used to improve cancer diagnosis and treatments. This project will dive into the three areas of biomedical applications that quantum dots have the ability to revolutionize for cancer research. These areas are:

1. Biomarkers
2. Drug delivery
3. Photodynamic therapy 

 

Biomarkers

Prevention is always better than cure. Detecting diseases is necessary in beginning the treatment process for patients. Earlier detection of diseases will lead to faster and more cost effective treatments, and will reduce the trauma and pain for patients. Diagnostics of conditions in their earlier stages of development are dependent on the detection of biomarkers. In this section, we will take a look into how quantum dots can improve the detection of biomarkers to ultimately provide earlier diagnoses of diseases like cancer. 

 

What are Biomarkers?

Biomarkers - short for biological markers - are any characteristic of the body that can be measured. These measurable traits provide doctors an insight into the individual’s health. Biomarkers can be in the form of molecular or cellular matter such as DNA, RNA, proteins, molecules made by tumors that are related to cancer, etc. or even qualitative and quantitative factors such as blood pressure, pulse, CAT scan results, and X-ray results. These biomarkers are usually collected and measured from body tissues or from a liquid biopsy (ie. blood, urine, saliva, etc.) 

Each body system - such as the cardiovascular, immune and metabolic system - have different sets of biomarkers. These biomarkers are used to show signs of conditions, normal body functions or help identify if something is going wrong to make a more specific diagnosis. They can also be used to monitor the progression of a condition by reviewing the set of biomarkers over time to see whether or not the condition improves, worsens or stays the same. Biomarkers also help in determining if certain treatments will be efficient or not for a particular individual, help monitor healthy individuals for potential signs of a disease, observe the potential progression of a disease in a lab setting, and provide researchers with a global view of the processes that occur within a cell. Biomarkers are especially important in the clinical development of drugs. This is because they provide a means of measuring the effect that experimental drugs have on people during trials, allowing researchers to predict the drug’s risk and effects earlier on to be able to put safer drugs out onto the market. Knowing the effect of drugs requires seeing the effect the drug has on biomarkers. This makes it necessary to have a wide range of biomarkers for use to know the full effect the drug can have on the human body.

However, not any measurable factor of the body can be used as a biomarker. Ideal biomarkers are those that are safe and easy to measure, cost efficient to follow up, modifiable, and consistent across genders and ethnic groups. 

 

Biomarkers for Cancers

For cancer, biomarkers like proteins, genes and other molecules can provide a variety of information and insight into the condition. Such biomarkers can: 

• Detect early-stage cancers. This early detection can allow for better and faster treatments and recoveries. 
• Predict how serious a cancer is (ie. how far along the cancer is).
• See how an individual will respond to a cancer treatment to be able to find the most appropriate treatment for them. Observing the biomarkers in a lab can also show how the treatment may work for the patient over time.
• Monitor and predict the likelihood of the cancer reoccuring. In some cases, doctors can take cells from the tumor, observe the biomarkers and give a recurrence risk score from there (the score shows how likely the cancer is to return).

 

The development into making and using more biomarkers for cancers has become increasingly popular. Usually, most anti-cancer drugs kill not only the cancerous cells, but also the healthy cells. Targeted therapy is becoming more popular as it provides a way to only kill cancer cells. For targeted therapy, researchers need to find and use the most common types of biomarkers found in a particular type of cancer. This allows the therapy to only target the cancer cells since those would match the biomarkers that are used. Quantum dots have the ability to provide targeted therapy to cancer cells with the use of biomarkers.

 

Quantum Dots as Biomarkers

The fundamentals of quantum dots’ application in identifying biomarkers is in their ability to be conjugated to target ligands. Ligands are molecules that bind to other - usually larger - molecules. These ligands in biomedical applications would include small molecules like antibodies, peptides, etc. When trying to identify biomarkers in a tissue or liquid sample, the targeted molecules of the sample will be immobilized on paper strips, membranes, gels or in cells. These target molecules in terms of cancer would be the biomarkers that doctors try to identify to determine if an individual is potentially developing a cancer, what type of cancer is developing, or how much the cancer has spread. The QD-ligand conjugate will then be used to label the target molecules in these samples. Molecular recognition will occur when the target molecule and its ligand interact as would happen in antibody and antigen pairs or complementary DNA strands. When the ligand in the QD-ligand conjugate and the target molecule interact, the target location and the amount of the target molecule will be revealed by the QD’s fluorescent property. 

 

Quantum dots can also provide a means of analyzing single cancerous cells at a time. This could be in terms of analyzing a single tumor cell circulating throughout the body or observing one cancerous cell at a time in a tumor tissue or biological fluid. This would allow medical professionals to identify the development of a cancer before the whole area is affected and the classical signs and symptoms of the cancer begin to arise. QDs hold an advantage compared to other methods when analyzing distinct regions as they allow molecular and morphological data to be extracted without physically removing the area of interest  Studies have been done to test QDs ability in single-cell analysis. Liu et al.¹ conducted a study in which they used quantum dots to identify a single cancerous cell in the prostate gland before the whole gland was affected. 

 

Another significant study carried out by Liu et al. was for Reed-Sternberg cells in Hodgkin’s lymphoma ². Reed-Sternberg (RS) cells, which are large abnormal lymphocytes, are the hallmarks of Hodgkin’s lymphoma, a type of cancer that affects the lymphatic system. Despite RS cells being the hallmark tumor cell in Hodgkin’s lymphoma, they are only in 1% of the affected cells in the lymph nodes. Thus, identifying these cells to give a confirmed diagnosis of Hodgkin’s lymphoma is extremely difficult, especially in the earlier stages of the cancer. However, quantum dot probes have the ability to identify the few individual RS cells that are present and differentiate them from other immune cells with the use of four biomarkers: CD15, CD30, CD45, and Pax5. In the study, they had brought in individuals who were confirmed with having the disease, those who were simply “suspected” to have it, and those with reactive lymph nodes. After they had stained the patient’s tissue samples with QD, Liu et al. compared the QD staining results with the pathological examination results. What they found was that the QD-based method was able to quickly identify those who were confirmed with the disease along with showing the presence of the disease in the previously “suspected” patients. The RS cell count in the “suspected” patients was so low that the pathological examinations did not pick it up. However, the QD probes did and confirmed the disease in those such patients. The probes also found no RS cells in the patients with reactive lymph nodes, showing that they did not have the disease at all. This study's results show QDs’ sensitivity and their potential to improve therapeutic success by identifying diseases earlier on than other methods with the help of biomarkers.

 

Just like with Hodgkin’s lymphoma, many complex diseases like cancers have more than one biomarker that becomes an identifying factor of the disease. Being able to observe more than one biomarker at a time is traditionally difficult to do without the use of quantum dots. One of the ways targeted therapy is done conventionally is with organic dyes. However, the drawback with organic dyes is that only a few of them can be used at once because many of their emission spectrums tend to overlap. This overlap makes it difficult to distinguish the different colours apart which are used to represent the different biomarkers being identified. However, quantum dots do not pose this problem. Quantum dots’ easily modifiable properties along with their tunable emission spectrums prevents this overlapping from occurring so that each fluorescent signal for each biomarker can be easily identified. This phenomenon was proven in Yezhelyez et al. study on molecular profiling of breast cancer biomarkers with the use of QD³. In the study, they found that the QD-based method’s results matched closely with the results of other methods for identifying biomarkers. The advantage that QD held though was that more than five quantum dot colours could be used at once on a tissue specimen. These five colours corresponded to the five unique biomarkers of breast cancer tissues: ER, mTOR, PR, EGFR, Her1. This study proved that quantum dots have a high molecular profiling ability which yields accurate and precise results. By using multiple quantum dots to identify multiple biomarkers at a time for a cancer, we can speed up the identification and diagnosis time to be able to quickly start treatment for patients if a cancer is found. 

 

Advantages and Disadvantages of Using QD for Identifying Biomarkers

There are currently 32 valid biomarkers listed by the FDA across a spectrum of therapeutic areas with cancer being the one with the most biomarkers. There are many cancer treatments that are prescribed to many patients despite the uncertainty in the degree of the patient’s response to the therapy. An example of this is chemotherapy. Chemotherapy carries many side effects, lacks precision as it affects the whole body, could cause potential progression of the disease, and is very expensive. By using biomarkers when analyzing individual patient’s samples, doctors can make appropriate decisions on whether or not a treatment like chemotherapy would be the best for a patient. By improving the detection, diagnosis and analysis of cancer with quantum dots, we can improve the therapeutic process for the patients and would not have to necessarily go to extreme treatments like chemotherapy if the cancer can be detected and treated earlier on. 

 

Overall, quantum dots in their identification of biomarkers hold many advantages such as:

• Size: quantum dots are small enough to diffuse into the cancer cells to find the specific biomarkers
• High detection and sensitivity 
• Increased accuracy in locating the biomarkers and the cancer cells
• Reduce overall cost of treatment
• Helps identify more subgroups of biomarkers than organic dyes can to improve diagnostics. This means that more people will be able to be diagnosed sooner than later
• Can stain 5-10 colours at a time to help detect multiple disease markers in a single sample slide
• Preserves the morphology of tissues which is important for making many diagnoses 
• Toxicity is also not a concern for in vitro and ex-vivo samples.

 

Despite the advantages, quantum dots are not on the market yet for the purposes of identifying biomarkers. Potential reasons for this could be: 

• The identification of 5-10 colours is still not enough to give comprehensive molecular profiling 
• It is still a relatively new technology so there is more reluctance to implement it
• Organic dyes are comparatively cheaper
• Toxicity of the material: quantum dots made from heavy metals could leak when illuminating or on oxidation. It is necessary to apply coating to heavy metal QD if they are used so that they meet biocompatibility requirements.
• Toxicity accumulation in the body: QD are 2-10 nm in diameter while organic dyes are 0.5 nm in diameter. There is a potential risk that the kidneys may not be able to filter the QDs out due to their relatively larger size. 

 

Drug Delivery

As much as medicine attempts to prevent certain conditions and diseases from arising, there is only so much doctors and researchers can do. Once someone is diagnosed with a disease like cancer, treatment immediately begins. Treatment goals usually involve delivering medication to the body to either allow the immune system to have the power to overtake the illness or to let the medication do the work in killing off the disease. Drug delivery is an area in science that is continuously being researched and improved. One way drug delivery is being studied to take it to the next level is with quantum dot technology. 

 

What is Drug Delivery?

Drug delivery is any form of technology that carries drugs into and throughout the body. It can include various methods such as pills, vaccines or “packaged” drugs such as michelle or quantum dots which protect the drug from degeneration as it travels inside the body. 

 

There are two main ways of delivering drugs to the body: routes of delivery and delivery vehicles. Routes of delivery refers to the method in which medications are taken. This can include methods like inhaling, swallowing, injecting, or absorption of medication through the skin. There are advantages and disadvantages to each method; the most suitable method is one that will optimize the drug’s ability. Drug delivery vehicles is the method used in which medications are packaged to allow the drug to travel into the body safely. Research is being done to find different ways to package drugs, specifically drugs that are hard to use based on reasons such as size and fragility. 

 

Whenever administering any form of drug, it is important to know the time it would take for the drug to be released into the body to control its effect and modify the drug accordingly. Proper delivery methods can enhance the performance of drugs by increasing their effectiveness, safety and their patient compliance.

There are four main drug delivery control times to consider when making the dosages and the release mechanisms of drugs:

Immediate release is when the dosage used makes sure that the drug is released completely and rapidly for immediate reaction. 

Non-Immediate release is that the dosage form does not fully release the drug upon administration. 

Sustained release is the dosage form that continually releases a drug into the body in slow and controlled amounts for over a prolonged period of time.

Site-specific release is when the dosage form offers targeted delivery of the drug to the specific location it needs to be administered to. This is the type of release method used with quantum dots.

 

Despite the different methods available to optimize the drug’s effects and safely transport it into the body, many drugs still hold significant side effects. Although drugs are administered to treat the infected or damaged area, many drugs will still interact with the healthy organs and tissues. This limits doctors' abilities in treating conditions such as cancer if the side effects experienced from a drug are too severe, making it dangerous or detrimental for the patient to use it. 

 

Because of this drawback, targeted drug delivery is being looked at as a potential solution to these problems. Targeted drug delivery is a method of delivering drugs that enhances the concentration of the drug to a particular part of the body. This increases efficacy and reduces the off-target side effects experienced with other drug delivery methods. Depending on the drug and the location that needs to be administered to, there are two main mechanisms of doing targeted drug delivery. 

 

Drug Delivery with Quantum Dots

Many of the anti-tumor drugs that are created remain in clinical trials because of the side effects associated with them such as non-selectivity, toxicity, or poor targeting. Those drugs that do pass clinical trials and are put onto the market still have severe side effects to the patient due to their non-specific nature. This means that they not only affect cancer cells but also non-cancerous cells. These side effects are associated with the high toxicity in the non-cancerous cells which continue to divide in the body. Targeted drug delivery prevents these unwanted side effects from arising, however, target therapy is difficult to implement. The main reason for this is because it is difficult to exactly locate tumors in the body and remove them without affecting the healthy surrounding cells - especially with deep, small-scaled tumors. To counteract these limitations, the goal becomes finding a method of targeted drug delivery that can image the tumors in the organism and target the tumor cells with high specificity at the same time.

 

These two reasons are what makes quantum dots excellent candidates for targeted drug delivery.  

 

QD nano-carriers for drugs can enhance the efficacy of the drug (since the drug is affecting the cancer directly) and reduce the side effects of the body’s reaction to the drug. This would result in improved therapeutic results of the drug. Quantum dots can also help visualize the drug being delivered, the tumor itself, and the drug being released because of their incredible optical properties to act as luminescent nanoprobes. QD’s rigid structure and large surface area is necessary to allow for drugs to be conjugated to the surface. QDs are usually designed to also conjugate to various tumor markers. Tumor markers are substances that are found on body tissues that can be found in elevated amounts in cancerous cells. These help doctors recognize the cancerous cells and the type of cancer it may be. For example, CA 15-3 is a tumor marker for breast cancer. By designing nanoparticles like QD to bind with these tumor markers, it allows the QD to be accepted by the cancer cell and be able to enter inside it. 

 

Once researchers have modified the surface of the QD to be able to conjugate to the tumor cell and have also encapsulated the drug inside the QD, they will release it into the body. 

The targeted drug delivery process of the QD will occur as followed:

1. The QD travels through the bloodstream.
2. It then binds to the target receptors on the cancer cell because of the tumor markers on its surface.
3. The cell membrane forms a vesicle around the QD to let it enter inside the cell (endocytosis).
4. Once inside the cancer cell, cellular proteins will wrap around the vesicle and take deeper into the cell. These proteins take the vesicle (which contains the QD) to the center of the cell.
5. Once they reach the center, the proteins will leave and the vesicles will continue to travel deeper into the cell to fuse with the endosome. The endosome is the digestive system of the cell as it contains acids that digest incoming material.
6. The vesicle will release the QD.
7. The QD will degrade inside the endosome due to the digestive acids. As a result, the drug that was inside the QD will be exposed.
8. The drug then kills the cancer cell.

 

The process of drug delivery with QDs has been studied and research has gone into seeing the effectiveness and potential of QDs as drug delivery systems. A study done by Abdellatif et al. involved coating Cd/Se QDs with vapreotide to act as a somatostatin receptor agonist⁴. Their research demonstrated that QDs as a vapreotide drug-carrier holds strong potential in treating blood cancer as they observed reduced side effects and increased drug delivery to the cancerous tissues via this method.

Another study done by Liu et al. tried to trace the delivery of doxorubicin to cancer cells⁵. They prepared doxorubicin-loaded MoS₂ QDs and injected them into the bloodstream. They noted that MoS₂ QDs had blue photoluminescence and had a pH-responsive drug release, meaning that their pH changed to indicate the successful release of the drug in the cell. The whole process demonstrated good stability of the QD and the drug itself and biological safety in terms of side effects and potential toxication. 

 

Advantages and Disadvantages of Quantums Dots for Drug Delivery

Quantum dots hold many advantages for delivering drugs which is what makes drug delivery one of the most popular uses of QD in the medical field. 

 

Some of these advantages include: 

• The capacity to be conjugated to many different types of drugs
• Unique optical properties to allow for traceable drug delivery
• Physical and chemical properties can be modified for the type of cancer cell they have to infiltrate and the drug being conjugated to them. 
• Modifiable properties can help optimize the QDs bioavailability, decrease clearance so they can reach the cell and deliver the drug completely, and increase stability within the body. These properties make them ideal carriers for delivering drugs to target-tissues. 
• Good solubility
• Small size but large surface area which increases their bioavailability 
• Have the ability to cross the blood-brain barrier, allowing them to enter the pulmonary system or pass through tight junctions between neurons for the delivery of specific neurotransmitters
• Can prevent the drug being rapidly degraded by the body’s digestive enzymes to increase effectiveness of the drug
• Can deliver lower doses of the drug with increased effectiveness. Along with its specific targeting mechanism, the side effects experienced with the drug can be greatly reduced

 

Because of all these advantages, QDs drug delivery has the potential for early detection of tumors (thanks to their bioluminescence), monitoring  of the tumors, and localized treatment. 

 

However, more research still needs to be done into all the properties of QD and their potential usage for delivering drugs. 

The major concern for QD as drug carriers is the QD’s potential toxicity. 

There is still also limited knowledge on all the bioconjugation strategies, especially for conjugating antibodies onto QD. There also needs to be more protocols established for the manufacturing of QD, the acceptable dosages to be administered into the body, the types of drugs that can be conjugated to QDs, etc. 

There is also a concern that due to their relatively large physical size, the QD may not be able to diffuse through the cell membrane, ultimately making drug delivery difficult. 

 

Photodynamic Therapy

Photodynamic therapy (PDT) is a promising technique for treating many localized forms of cancer such as pancreatic cancer, bile duct cancer, esophageal cancer, certain skin cancers like precancerous skin changes or non-melanoma skin cancer, and lung cancer. This light based treatment holds many advantages and benefits compared to other cancer treatments, making it an excellent candidate for treating certain cases. The potential use of quantum dots in photodynamic therapy is gaining popularity as quantum dots can counteract the few drawbacks that conventional PDT has. By improving PDT with the use of QD, the methods and technology for treating cancer can be revolutionized. 

 

What is Photodynamic Therapy?

Photodynamic therapy is a form of treatment that uses special drugs called the photosensitizer (PS) to kill cancer cells. The drug is non toxic and harmless and only begins to work once it is activated by light. The type of light used for PDT comes from LEDs or certain lasers. The light source and the wavelengths of light used is dependent on the type of cancer being treated and its location in the body. 

Depending on the location of the body that needs to be treated, the photosensitizer can either be injected into the bloodstream via a vein or placed directly onto the skin as a form of topical cream. Once inside the body, the drug is absorbed by the cancer cells. When light is applied to the area, the photosensitizer absorbs the photons from the light and gets excited to a higher energy level. The excited electrons of the photosensitizer can then do two things:

1. It can emit the light back out to return to its resting, ground state. Emitting the light back out will illuminate the photosensitizer and thus, the cancer cell as well.
2. More commonly, the electrons instead will relax back down to a ground state by transferring its energy to a nearby oxygen. When the oxygen absorbs the energy, it gets converted into a singlet oxygen species (¹O₂). It is also called the reactive oxygen species because once made, it readily oxidizes biomolecules like proteins, lipids, DNA, RNA, etc. By oxidizing all the biomolecules within the cancer cell, the cancer cell begins to die. 

 

However, depending on factors such as the type of photosensitizer used, the amount of it, the light source, tissue type, and the availability of oxygen, the way cell death is triggered by PDT varies. One way cell death can be triggered is by the PDT causing vascular constriction and platelet aggregation to the area, depriving the cancer of nutrients and oxygen. Another way already mentioned above is by causing direct cellular oxidation. This oxidation causes apoptosis (programmed cell death) or necrosis (the death of a tissue due to the lack of blood flow and oxygen supply to the area). The final way cell death can occur is that the reaction occuring within the cancer cell by the photosensitizer and the oxygen can stimulate an inflammatory response to the area, allowing the body’s immune system to attack the cell. 

 

PDT holds many advantages compared to other cancer drugs. Most anti-cancer drugs have severe side effects because the drug molecules continue to circulate throughout the body, affecting healthy cells as well. However, PDT does not pose this problem. Some of PDT’s advantages compared to other cancer treatments are as followed:

• PDT does not have long term effects when properly used.
• It is less invasive than other treatments.
• It takes a short time to complete treatment and is often done as an outpatient procedure.
• It can be repeated multiple times on the same site, unlike certain treatments like radiation therapy.
• It usually results in little to no scarring after the area heals.
• PDT costs less than other cancer treatments.
• It can be localized at the tumor site which reduces systemic toxicity.

 

Despite these advantages, photodynamic therapy still holds certain drawbacks which prevent it from being used to treat every cancer case. Some of these drawbacks are as followed:

• PDT can only treat areas that light can reach, such as areas that are on or just under the skin or the lining of organs. It cannot be used to treat cancers that are deep within the body.
• It can not treat large cancers that have spread to many places in the body. Large cancers would require other treatments like chemotherapy.
• Photosensitizing drugs can cause people to become very sensitive to light for some time so it is advised to take certain precautions after the procedure.
• PDT cannot be used on patients with certain blood diseases as there is a chance of potentially aggravating the disease with PDT’s vascular constriction and platelet aggregation potential.

 

PDT with Quantum Dots

Ideal photosensitizers (PS) are ones that are:

• Chemically pure
• Easy to synthesize
• Have long shelf life 
• Have a strong absorption capacity, preferably between 600-800 nm to have enough energy to cause singlet oxygen excitation
• Have minimum dark toxicity (ie. the photosensitizer will not start affecting the cell in any way until it is activated with light) 
• Have high renal clearance rate (ie. it can be easily filtered through the kidneys) to prevent toxicity and accumulation in the body
• Able to selectively localize at tumor tissues

 

These ideal parameters allow researchers to continue improving the PS that they put onto the market and create new generations of PS that are more advanced than the previous ones. Currently, there are three generations of PS with the third generation being the most advanced one. The third generation consists of PS being conjugated to specific proteins, amino acids, antibodies, and carbohydrates to allow specific targeting. The problem with the current second generation of PS is that they are not fully tumor selective since they tend to accumulate in the skin and eyes, causing phototoxicity and photosensitivity in those areas for a long time. Most of them also have hydrophobic tendencies which cause them to agglomerate in aqueous solutions. The second generation has also not shown much success in treating deep/bulky tumors or tumors that have spread to multiple organs. 

Research is being focused on third generation PS to potentially overcome the drawbacks experienced with the second generation. One of the materials being researched for the third generation of PS are nanoparticles like quantum dots. 

 

Quantum dots have the ability to:

1. Be the PS or
2. The energy donor for other PS

 

Quantum Dots in Being the PS

The first aspect to observe for QDs role in PDT is how they will penetrate into the tumor cells. Cellular uptake of QD is dependent on their size, composition, surface modification, and charge. By altering the surface modification by conjugating it with the proteins found in the tumor, it will guarantee that the QD will only go to the cancer cells, not the healthy cells. The QD conjugate then penetrates the cancer cell via endocytosis. Once inside, the QD tends to accumulate in the cytoplasm but can be made to target other cellular organelles if needed. Many studies have been done to see the localization of different types of QDs in different cellular organelles. The studies found that most QDs tend to localize in the lysosomes, with some concentrations in the mitochondria and endoplasmic reticulum. It was reported that exocytosis of the internalized QD occurred very fast but only 40% of the internalized QD were discharged out of the cell. The studies also looked into the various types of QDs such as metallic QD, graphene QD and carbon QD. Metallic QDs are to be avoided for biological applications because of their risk of toxicity. However, graphene QDs were reported to be non toxic and biocompatible and were observed to localize in the nucleus and cytoplasm of cells. Carbon based QDs were also well tolerated by the body and showed very little toxicity risk. Because of their biocompatibility and safety in terms of reduced toxicity, carbon and graphene based QDs are being explored the most for clinical applications, including for photodynamic therapy. These studies demonstrate the highly specific targeting capacity of QD which is vital in successful PDT. By directly affecting the vital organelles that the cell would need for survival, QDs can more effectively kill the cancer cells. 

 

Compared to traditional photosensitizers, QDs have the ability to penetrate and target deeper tumors. This is due to their tunable emission spectra. By modifying the emission spectra by changing the QD’s size, the QD can emit wavelengths that are between the UV range to the near infrared regions. This is more than what conventional photosensitizers can emit because they can only emit light in the visible range. Near infrared wavelengths are useful as they can diffuse quickly and deeper into tissues than the visible range can. This allows the QD to target deeper rooted tumors. 

QDs can also induce ¹O₂  production by transferring the energy they gain from being excited to a nearby ground-state oxygen. In a sense, by being able to absorb energy from the near infrared region, QDs can transfer more energy to the nearby oxygens, resulting in faster and higher production of ¹O₂  to induce faster cell death. Certain studies were done to prove this phenomenon and observe how some QD can cross over from being antioxidant in nature to proxidant when stimulated by light. Christensen et al. conducted a study using bimetallic and carbon dots in in vitro samples⁶. They reported that the QD initially inhibited oxidation from occurring but upon irradiation with blue light, started a cascade of oxidation reactions within the cell. As a result, a large number of ¹O₂ were generated. They concluded by saying that QDs behave like “oxygen scavengers” in the dark but when shone with a blue light, induced the production of the reactive oxygen species. Another study done by Chong et al. used graphene quantum dots to observe QD’s antioxidant and prooxidant properties⁷. In this study, they observed that when light was absent, the graphene QD seemed to be protecting the cell from potential oxidation damage. However, when irradiated by blue light, the QD began generating a lot of reactive oxygen species. These two studies show that it is possible to make QDs that first protect the cell but then later kill it all by controlling their exposure to light. Along with conjugating the QD to the cancer cell’s biomarkers, it will provide a guarantee that the QD photosensitizer will be easily accepted into the cancer cell, be able to infiltrate the organelles within it, and then kill the whole cell once it is activated by light. 

 

Quantum Dots in Being the Energy Donor for PS

Fluorescence resonance energy transfer (FRET) can be a method of using QD to enhance photodynamic therapy’s actions. FRET is the coupling of acceptor and donor dipoles. When the donor is excited by a photon, it wants to relax back down to its lowest energy level. If an acceptor is close by, the energy that the donor releases to go to its ground state will be absorbed by the acceptor. As a result, the acceptor will get excited. This energy exchange is called resonance. If the acceptor molecule happens to be fluorescent, upon excitation, the acceptor’s fluorescence will be enhanced. FRET can allow the QD to enhance the fluorescence emissions of the PS drug it is conjugated to. The QD-PS conjugates would be synthesized in such a way that the QD’s emissions overlap with the PS’s excitation. This means that the excitation of the PS can be at a lower wavelength but the emission of those wavelengths will be amplified to enhance the fluorescence of the PS. This would make it easier for doctors to see where the cancer is located even if it is deeper in the body. 

 

Advantages and Disadvantages of Using QD for PDT

Quantum dots have the ability to transform cancer therapy and imaging. By using QDs in photodynamic therapy, we can eliminate most of the drawbacks experienced with the current methods for PDT.

 

QDs’ advantages compared to organic photosensitizers are as followed: 

• Stronger emissions 
• Higher photostability 
• Higher water solubility to combat aggregation issues
• Tunable optical properties
• High tissue accumulation
• Can target tumor cells more effectively because of their enhanced permeability and retention properties. QDs can also be functionalized to specific antibodies/proteins to cause site specific localization of PS, allowing for more targeted photodynamic action which limits phototoxicity to healthy cells (something that is usually seen with conventional PS).
• Can delivery higher concentrations of PS to the cancer cell
• With appropriate surface modifications and the material used (eg. Graphene QD or Carbon QD), QD can be more biocompatible than organic dyes which can improve the intracellular delivery of the PS
• Improved therapeutic results because of their ability to be conjugated to conventional PS or target molecules 

 

QDs for the use of PDT are still being explored. There still needs to be more data collected on the pharmacokinetics and pharmacodynamics of QD. More research is still needed to determine the long term toxicity of QD in humans and in the environment, the metabolism and excretion of QD from the body and the lethal doses of each QD. However, besides further research, QDs still hold promise in improving photodynamic therapy and making it a suitable and extremely effective solution for many cancer cases.

Despite the cons, the potential that quantum dots hold for the future in medicine is an undeniable truth. They are a necessary and needed form of technology in our healthcare system, especially for cancer. By having the chance to detect cancer earlier on, treat it immediately and directly, and provide forms of treatments that will have little to no significant side effects, we can improve the lives of millions of people globally. Quantum dots provide a method to achieve all three of these goals. Whether that be by improving our ability to detect biomarkers, providing a form of targeted drug delivery, or enhancing photodynamic therapy, quantum dots can take medicine to another level. 

The potential of quantum dots in our healthcare system can already be seen today.

There are several companies that are dedicated to manufacturing QDs for the healthcare industry. NANOCO™ is a major company for the healthcare market of QDs. They have already done incredible work creating QD-based products such as their marketed product HEATWAVE™. HEATWAVE™ are QD biosensors that work in the electromagnetic spectrum of 100-1650 nm (a very broad range) to allow for a non-invasive quantification of the molecules in the blood. For example, the QDs can detect hemoglobin at 575 nm, bilirubin at 455 nm and glucose at 1650 nm. Another one of their products is VIVODOTS ® where QDs are used to map cancerous cells during surgery to avoid the unnecessary removal of the healthy tissues. 

A Japanese based QD company called QD LASER™ invented VISIRIUM ® Technology. This is a pair of 50 gram weight eyeglasses that can project images directly onto the retina to help those with visual disorders. 

The global market for QD is estimated to be between $4 to 8 billion USD. Despite this incredible revenue along with companies dedicated to the innovation of QD technology, QDs are still not found commonly on the market or in application. This is because the clinical translation of QDs is slow due to certain challenges they face:

1. Pharmaceutical Challenges: 

• QD’s ultra-fine colloidal particles make them susceptible to degradation. 
• Any changes to the physcio-chemical properties of the QD could potentially cause dramatic changes to their optical properties

However, a solution to these two challenges is to improve the stability of the QD. Especially for those QDs that are more susceptible to degradation due to their surface oxidation, we can use certain chemicals for passivation (the process of coating a material so that it less readily reacts to the environment) of the surface. This would protect the QD from oxygen and improve the quantum properties, no matter the particle’s size or original surface ligands. 

 

2. Industrial Challenges:

• The mass production of QD is a very intricate and multi-step process, especially if surface modifications are required.
• Mass-scale production can also make it difficult to maintain the same physico-chemical properties of all the QDs produced.
• Large scale production of QD could pose a potential environmental hazard because of the toxic heavy metals used (eg. Cd and Pb).

A solution to the problems with mass production is by the one-pot strategy. This is a form of making QD that requires mixing all the precursors together at room temperature and letting the reaction compounds that would later become the QDs to be heated uniformly. 

To solve the toxicity issue, cadmium free QDs have been introduced and are hoped to be used more often (eg. carbon QD, graphene QD, silicon QD). There are also green methods of QD production that are being explored such as dry heating, microwave-based synthesis or using recycled components. 

 

3. In-vivo Challenges: 

• In principle, QD are not organ specific and will interact with all cellular membranes in a non-selective manner. To make them more selective, we simply modify the surface with targeting ligands, polymers, antibodies, etc to make them have an increased affinity to certain tissues such as tumors. 
• Most metallic QDs are associated with intracellular toxicity which can damage cellular bodies. A simple solution to this would be to use other materials that are not heavy metals when manufacturing QDs. If metal QDs are used, then certain surface modifications can be done to allow the body to clear the metallic QD that would usually accumulate inside. 

 

As shown, the challenges presented by the application and production of QDs can be counteracted with unique solutions. The benefits and versatility of QDs proves the need to implement QDs into the healthcare industry. These challenges are the only thing holding healthcare professionals and researchers back from applying QDs to the biomedical field. Steps that can be taken to counteract these challenges and improve the clinical transition of QD into the biomedical field are:

• Using environmentally friendly and aqueous-solvent based synthetic methods of making QD. This would reduce the environmental hazards they could have, improve the ability to alter their size, and skip unnecessary post-synthetic modifications that are usually done. This will ultimately decrease the complexity of making QDs and will lower the cost of production.
• Using functional coatings with materials like pH-responsive biomaterials that have a self-homing tissue affinity. This would be to replace ligand-based modifications to improve stability and scalability of the QD.
• Eliminate the use of heavy metals to minimize biosafety hazards such as the accumulations of heavy metals in the body.
• Finding a balance between the body retention and clearance ability of the QD by the kidneys. This can be accomplished by manipulating the particle’s size, charge and surface properties. The goal would be to help the QD stay in the body long enough to complete its intended application but be able to then clear out from the body to avoid potential toxicity. 
• Have enough experimental protocols in place to see all the diverse applications of QD. By expanding their usage, the QDs can have a chance to compete with classical methods which already have well-established protocols and wide commercial availability. 

 

Once all of these steps can be taken and quantum dots can be incorporated into our healthcare system, medicine will be revolutionized in a way it never has before

Studies:

1. Liu et al. study on identifying single cancerous cell in prostate glands  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923482/ 
2. Liu et al. study on the presence of Reed-Sternberg cells in patients with Hodgkin’s lymphoma https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914471/ 
3. Yezhelyez et al. study on molecular profiling of breast cancer biomarkers with the use of QD https://www.academia.edu/download/91916555/AM2007.pdf 
4. Abdellatif et al. study on coating Cd/Se QDs with vapreotide for treating blood cancer https://pubmed.ncbi.nlm.nih.gov/30532637/ 
5. Liu et al. study on traceable and pH-responsive drug delivery using PEGylated MoS₂ QDs https://pubmed.ncbi.nlm.nih.gov/31670002/ 
6. Christensen et al. study in observing carbon dots as antioxidants and prooxidants https://www.ingentaconnect.com/contentone/asp/jbn/2011/00000007/00000005/art00007 
7. Chong et al. study in the antioxidant and prooxidant properties of graphene QD in the absence and presence of light https://pubmed.ncbi.nlm.nih.gov/27584033/ 

 

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