The Science of Nanoparticles

The fascinating world of nanoparticles!

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Magnetic Nanoparticles in Cancer

When hearing the term “nanoparticles,”; you may think of computers, cosmetics, paints, and even medicine; have you ever heard of magnetic nanoparticles? What are they used for? Magnetic nanoparticles (MNPs) are usually produced from pure metals or a mixture of metals and polymers. In medicine, magnetic nanoparticles are used primarily in cancer treatments associated with hyperthermia, controlled drug delivery, and magnetic resonance imaging (MRI). In addition, they are considered a promising alternative for fluorescent and optical labels in biosensors. Magnetic nanoparticles have a crucial advantage over other types of nanoparticles: their ability to be magnetically manipulated from an external magnetic field. Magnetic nanoparticles’ biomedical applications are determined by the particle’s size, shape, morphology, and magnetic behaviour. 

 Back in the 19th century, it was shown that fever caused cancerous and non-cancerous cells to behave differently. Under hyperthermia conditions, the temperature of a specific tissue or the entire body increases above normal physiological temperatures; non-cancerous cells tolerate these conditions for a short period, while the cancerous cells experience apoptosis. This indicated that cancerous cells are more sensitive to hyperthermia than normal cells due to the lower pH in the cancerous tissue due to glycolysis used to obtain extra energy, resulting in decreased thermotolerance. Therefore, it was hypnotized that maintaining the hyperthermia temperature of the cellular environment could represent an effective method of treating cancer with fewer side effects. Magnetic nanoparticles are used to produce heat under an applied magnetic field. Therefore, they are considered a promising method to promote the temperature of the cancerous tumour. Magnetic nanoparticles are currently employed to produce hyperthermia in cancerous tumours and are used to treat prostate, uterine, lung and neck cancers. 

 Magnetic nanoparticles are classified into five different types: ferromagnetic, paramagnetic, diamagnetic, antiferromagnetic, and ferrimagnetic. Magnetic nanoparticles have exceptional superparamagnetism, magnetic susceptibility, and low Curie temperature, the temperature when magnetic material changes its magnetic properties. Magnetic nanoparticles are synthesized via top-down or bottom-up techniques. The top-down approach involves high-energy ball crushing magnetic metals. The bottom-up strategy includes multiple approaches such as co-precipitation, hydrothermal synthesis, thermal decomposition, etc. A magnetic nanoparticle has a straightforward structure indicated below. 

Figure 1: Simplified illustration of a magnetic nanoparticle’s structure. The structure shows the magnetic ability to deliver drugs to the target cell.

Magnetic nanoparticles can be delivered through the direct injection method by injection MNPs using catheters or hypodermic needles directly into the cancerous site. Then an external magnetic field is used to manage and localize the magnetic nanoparticles in the cancerous site. This method is commonly used in vivo clinical studies. Another advantage of this method is the controllability of magnetic nanoparticles concentration in the cancerous area. Nevertheless, this technique is successful only when there is easy access to the tumour. Additionally, magnetic nanoparticles tend to combine into groups after injection, which would negatively affect the homogeneity in the tumour, affecting the temperature distribution across the tumour. Therefore, this approach is limited to specific types of cancers.

 Oppositely, systematic delivery is injecting magnetic nanoparticles intravenously. The MNPs concentration will increase in the bloodstream due to the enhanced permeability and retention. As known, tumours contain a defective vasculature compared to normal tissue. Still, the damaged vasculature can enable nutrients and oxygen supply to the tumour cells; this can ease the entrance of nanoparticles into a tumour site. Furthermore, the increase in retaining time and the ease of transportation of Magnetic nanoparticles prevent the accumulation of MNPs in the bloodstream. This allows for a faster and easier reach of the MNPs to the cancerous cells. 

Figure 2. Illustration of magnetic nanoparticles' migration through the bloodstream reaches the cancerous target cells. Agglomeration represents the accumulation of magnetic nanoparticles after direct injection into the cancerous area. The red circle represents the migration of magnetic nanoparticles to the cancerous cells throughout breaks in the damaged blood vessels due to the stimulation of the external magnetic field.

The hydrophobic properties of drugs lead to a reduction in the bioavailability of the drug within the bloodstream. Encapsulating drugs in a polymer structure improves the drug’s bioavailability in the body. Magnetic nanoparticles are considered one of the most promising approaches for drug delivery because they are responsive to external stimuli, allowing for the localization of the MNPs encapsulated drugs. Additionally, Magnetic nanoparticles can amalgamate hyperthermia therapy and sustainable drug release. Magnetic nanoparticles attain controlled and specific drug release by attaching to drug molecules via a polymeric shell created with the ability to release the encapsulated drugs. The release occurs due to either enzymatic cleavage or modifications in the physiological environment, such as temperature or pH.

Magnetic nanoparticles application is associated with a significant issue: the depth in which the magnetic field can infiltrate. The magnetic field can infiltrate up to two centimetres throughout the body. However, penetrating the body past two centimetres is difficult because the magnetic field reduces with distance. Previous studies have shown interactions between magnetic nanoparticles and magnetic field stimulations that enabled drug delivery. However, there are issues relating to the data from animal models. Multiple physiological measures differ between the human body and an animal model, such as weight and cardiac output variations. In addition, another issue that is frequently forgotten in the literature is the long-term effects of magnetic nanoparticles once they have accomplished their role within the body. It is critical to understand magnetic nanoparticles’ interactions and behaviour within the human body after achieving their function. Likewise, it is necessary to know where the nanoparticles finally end up and how they exit the body if so.

Magnetic nanoparticles hold great potential for cancer treatments like hyperthermia and drug release methods. In addition, they are also used in cancer diagnostic as biosensors, and they are used in MRI imaging applications. MNPs’ magnetization behaviour can be affected by their size, shape, and morphology. Magnetic nanoparticles are widely expanding in different studies, but none of their long-term side effects are studied or considered. However, clinical trials show great results using this methodology. Magnetic nanoparticles are vital for decreasing cancerous patients’ pain, enhancing life expectancy, and improving cancer therapies.

Zhang H, Liu XL, Zhang YF, Gao F, Li GL, He Y, Peng ML, Fan HM. Magnetic nanoparticles based cancer therapy: current status and applications. Sci China Life Sci. 2018 Apr;61(4):400-414. doi: 10.1007/s11427-017-9271-1. Epub 2018 Apr 3. PMID: 29675551.

Farzin, A., Etesami, S. A., Quint, J., Memic, A., & Tamayol, A. (2020). Magnetic Nanoparticles in Cancer Therapy and Diagnosis. Advanced healthcare materials, 9(9), e1901058. https://doi.org/10.1002/adhm.201901058

Yigit, M. V., Moore, A., & Medarova, Z. (2012). Magnetic nanoparticles for cancer diagnosis and therapy. Pharmaceutical research, 29(5), 1180–1188. https://doi.org/10.1007/s11095-012-0679-7

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Nanoparticles for Cancer Therapeutic

There is no scarier diagnosis in most peoples’ minds than that of cancer. Cancer is often thought of as an untreatable, unbearably painful disease with no cure besides surgery and chemotherapy. At the same time, Cancer is one of the critical public health problems globally and is the second leading cause of death.  Traditional cancer therapies include surgery, chemotherapy, radiation, targeted therapy, and immunotherapy. However, those conventional therapies are associated with limitations such as lack of specificity, cytotoxicity, and multidrug resistance, which pose a massive challenge. Nanoparticles (NPs) have transformed the arena of cancer diagnosis and treatment. Nanoparticles not only solved the limitations of conventional cancer treatment but also overcame multidrug resistance.

Nanoparticle-based drug delivery systems have displayed benefits in cancer therapy and management by demonstrating good pharmacokinetics, accurate targeting, reduced side effects, and drug resistance. In addition, Nanotherapeutic drugs have shown promising results in the delivery system and anti-tumour multidrug resistance (MDR), providing an opportunity for drug recombination therapy and inhibition of resistance drug mechanism. Nanoparticles’ delivery systems are approved to increase drug stability by preventing the degradation of the encapsulated cargo. In addition, large volumes of drugs can be encapsulated without any chemical reactions. Another advantage is that nanoparticles have a high surface-to-volume ratio and intracellular uptake, allowing administered in many ways, including oral, nasal, parenteral, and intra-ocular. Nanoparticles should maintain specific essential characteristics such as the ability to remain stable in the vascular system until reaching the target (TME), escape the reticuloendothelial system (RES) clearance, escape mononuclear phagocyte system (MPS), accumulate in TME via tumour vasculature, high-pressure diffusion into the tumour fluid, and reach the target and only interact with tumour cells.

Nanoparticles can have different shapes, sizes, and structures. Therefore, the synthesis of nanoparticles can be characterized mainly into two main approaches: 1) bottom-up approach, building nanoparticles from atoms to clusters than to NPs, hence known as constructive method 2) top-down approach, also known as a destructive method which involves the breakdown or decomposes of large molecules into smaller units that are converted to NPs. These approaches can be classified into different subclasses based on reaction conditions and operation. Nanoparticles contain broadly classified two different targeting mechanisms: passive and active. The passive targeting mechanism mainly relies on the vascularity and leakiness of the tumour biology and carrier characteristics such as size and circulation time. This type of tumour-targeting does not require a specific ligand for certain types of tumour cells. The active targeting depends on specific ligands or molecules such as transferrin and folate, which bind to molecules or receptors mainly expressed or over-expressed on the targeted cells. Nanoparticles used in drug delivery systems include organic, inorganic, and hybrid NPs. The image below indicates different examples of nanoparticles used in the delivery systems.

Figure 1: Nanoparticles extensively used in drug delivery systems include organic, inorganic, and hybrid nanoparticles.

The amount of knowledge and research put into nanoparticles has steeply raised. But only a few of them make it up to clinical trials. This is because nanoparticles are associated with clinical challenges that can be divided into biological and technological and study-design-related challenges. The biological challenges include lack of routes of administration, tempering biodistribution, the channel of NPs across the biological barriers, NPs degradation, and NPs toxicity. Technological challenges involve scale-up synthesis, equal optimization, and performance predictions. The study-design challenges such as study size, intent, and timing of NP therapies during the therapy are affected significantly during clinical studies. Although nanoparticles showed a promising new era of cancer treatment, there are still many obstacles to overcome.

“Cancer is a journey, but you walk the road mostly alone. There are many places to stop along the way and get nourishment- you just have to be willing to take it.” In 2020, it was estimated that about 1.8 million people were diagnosed with cancer in the united state alone. COVID-19 pandemic stole the world’s attention for the past few years when cancer and other disease were nearly ignored. However, many studies showed promising results of using nanoparticles in cancer therapy as a delivery system. In addition, Nanoparticles were used in cancer therapy multidrug resistance due to the NP’s ability to co-encapsulate multiple therapeutic agents.

 Gavas, Shreelaxmi et al. “Nanoparticles for Cancer Therapy: Current Progress and Challenges.” Nanoscale research letters vol. 16,1 173. 5 Dec. 2021, doi:10.1186/s11671-021-03628-6

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Why are nanoparticles used in mRNA vaccines?

Many vaccines inject a weakened or inactivated microorganism into our bodies to trigger an immune response, but not messenger RNA, mRNA, vaccines. Instead, mRNA vaccines use laboratory-made mRNA to teach cells how to make a protein or even a part of a protein that would trigger an immune response inside our bodies.   mRNA vaccines benefit people who get vaccinated by giving them protection against diseases like COVID-19 without risking the potentially severe consequences of getting sick. Nevertheless, for the mRNA vaccines to achieve therapeutic effects, mRNA molecules must reach specific target cells and produce sufficient proteins of interest. However, targeted delivery and endosomal escape remain the main challenges for mRNA delivery systems. Those challenges highlight the need for safe and effective mRNA delivery materials. Lipid nanoparticles, LNP, have successfully been used as the delivery system of mRNA. However, the mRNA vaccines compromise mRNA encoding the SARS-Cov-2 spike region as the antigen, encapsulated in Lipid NPs. You might be asking yourself, how would very tiny particles be used as a delivery system? Furthermore, how would they approve the efficiency of mRNA molecules? First, however, let us grasp what a coronavirus is and why it impacted human lives harshly?  

The Coronavirus family contains alpha, beta, gamma, and delta classes featuring a single-stranded positive-sense RNA genome. SARS-CoV-2 is the virus that is responsible for the COVID-19 outbreak. It belongs to the beta class. Beta class is responsible for severe acute respiratory syndrome and the Middle East respiratory syndrome. SARS-CoV-2 particles have four structural proteins. The spike (S) protein is the recognition site and membrane fusion; it contains S1 and S2. The S1 subunit houses the receptor-binding domains. It forms a protein composed of three identical polypeptide units on the viral surface. The spike protein enables the attachment of the virus to the host cells followed by membrane fusion, promoting the migration of the viral particle into the host cell. The membrane (M) protein plays a vital role in assembling the virus protein-protein interactions and the viral infectivity through binding to the viral S protein and the host surface receptors. Thus, this promotes membrane fusion. The envelope (E) protein plays a structural role and helps in the assembly and budding of the viral particles. Finally, the nucleocapsid (N) protein binds to the RNA to support nucleocapsid formation, and it protects the RNA of the virus by keeping it intact and stable within the virus.

Figure 1: SARS-Cov-2 structure shows the location of each protein within the SARS-Cov-2.

The figure above also shows that SARS-CoV-2 spike protein binding to the angiotensin-converting enzyme 2 (ACE2) to enter the host cell. Polar interactions facilitate the contact between SARS-CoV-2 spike protein and ACE2. SARS-CoV-2 mainly affects the respiratory system because ACE2 is highly expressed in the lungs and bronchial branches cells. The bronchial branch cells served as the primary entry and binding sites for SARS-CoV-2. This makes the alveolar epithelial cells more accessible for SARS-CoV-2. It is worth mentioning that the ACE2 receptors are also expressed in the cardiovascular system, central nervous system, and GI tract. Interestingly, ACE2 is highly expressed in the female reproductive system, especially in pregnant women's placenta, uterus, and fetal interface. This provides an excellent target site for CoV-2 binding. You are probably wondering whether this has to do with mRNA vaccines and Lipid nanoparticles.

Several vaccines are being given out at this time, but there are many concerns about their safety. The targeting strategy for most of the development of the SAR-Cov-2 vaccine is to induce neutralizing antibodies against the spike protein, preventing the ACE2-mediated host uptake. Another is targeting the SARS-CoV-2 RNA genome using RNA interference (RNAi) or antisense oligonucleotides. Early research on mRNA vaccines has determined that naked mRNA is quickly degraded after administration. mRNA vaccines have many advantages over other types of vaccines. A general advantage of mRNA vaccines is that their development is relatively fast compared to other vaccines that take 5 to 10 years. However, the most significant challenge when developing mRNA vaccines is their poor stability. This is because naked mRNA is quickly degraded upon injection by ribonucleases (RNase). Secondly, the internalization of mRNA inside the cell is identified by intracellular RNA sensors. The binding of mRNA to the intracellular RNA sensors activates innate immune pathways, leading to the expression of hundreds of genes. This may deliver an adjuvant effect on the vaccine potency, and it establishes an antiviral state in cells, which strongly reduces the mRNA intracellular stability and translation. Thus, nanoparticle vaccines provide a unique opportunity to advance vaccine science and offer tractable solutions to the COVID-19 pandemic.

Nanoparticles are nanoscale-sized and adjustable particulate structures that mimic structural features of natural viruses. They are utilized as a delivery vehicle for vaccines. This makes them an up-and-coming platform for next-generation vaccine development, which provides pathways to drive strong antibody responses or broader antibody-based immunity that might better account for the variation and evolution of viral pathogens. The LNPs in mRNA COVID-19 vaccines consist of four main components: a neutral phospholipid, cholesterol, a polyethylene-glycol (PEG)-lipid, and an ionizable cationic lipid. Cationic lipids are the most significant component in formulating the LNPs. Cationic lipids have two key roles: first, encapsulating the negative charged nucleic acids into nanoparticles via forming an electrostatic complex; second, facilitating the intracellular release of the cargo into the cytoplasm. Neutral phospholipids are incorporated in the LNP formulation as helper lipids to enhance particle stability and increase membrane LNPs fusing with the membranes of target cells. Cholesterol enhances the bilayer stability by improving its rigidity and preventing the therapeutic ingredient or mRNA leakage. PEG-lipids are used to provide a hydrophilic steric barrier and prevent inter-particle fusion during LNP manufacturing, also to reduce the in vivo binding of plasma proteins.

Figure 2: Lipid nanoparticles, LNP, structure encapsulating mRNA.

Nanoparticles surround the naked mRNA as a layer of protection and are then used as a delivery system to ensure the entrance of the naked mRNA into the cell reaching the target site. It has been reported encapsulated mRNA recognized the ACE2 receptor on the surface of the target cell membrane. Once the S protein link to the receptor, the encapsulated mRNA will enter the cell via endocytosis, the process of actively transporting molecules into the cell by engulfing it with its membrane. At this point, the naked mRNA is inside the cells but surrounded by two barriers, the lipid nanoparticles layer and the endosome compartment membrane. The challenge for the mRNA now is to escape both membrane layers to reach the cytoplasm, and then it is used as a template to make proteins. The endosomal compartments maintain a characteristic PH for their functionality. Acidification of the endosomal lumen leads to the release of mRNA from LNP and escape from the endosomal lumen into the cytoplasm. In other words, LNPs are ionizable lipid, which is positively charged at low pH to allow encapsulation of negatively charged mRNA. While being neutral at physiological pH, LNPs enter cells via endocytosis, and within the low pH of endosomes, the ionizable lipid becomes positively charged and can disrupt endosomal membranes. This allows mRNA cargo release into the cytoplasm for protein translation.

Figure 3: The lipid-nanoparticles protection mechanism for the naked mRNA to reach its target site. The top right shows a demonstration of naked mRNA degradation via RNase. A shows the migration of the encapsulated naked mRNA with lipid-nanoparticles into the cytoplasm of a cell via endocytosis, resulting in a double membrane surrounding the naked mRNA, lipid nanoparticles, and the endosomal membrane. B shows the escape of the naked mRNA from the encapsulation and the endosomal membrane due to the acidification. Finally, C indicates the migration and translation of naked mRNA in the endogenous antigen.

The COVID-19 pandemic has harshly impacted human lives, and desperate efforts are put into controlling and eliminating the spread; however, the evolution of variants for SARS-Con-2 demands developing an effective vaccine strategy. A successful and widely used approach in mRNA vaccines is encapsulating and protecting the naked mRNA in Lipid-nanoparticles, LNPs. Both Moderna and BioNTech/Pfizer mRNA-LNP vaccines demonstrate efficacy more significant than 90% against Wuhan-Hu-1 SARS-CoV-2. Lipid-nanoparticles served as a delivery vehicle and a protection layer for the naked to establish a safer and more effective vaccine. Nanotechnology is a field that shows tremendous potential for future work in various areas, including medicine, vaccinations, and others.

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Nanoparticles and Scaffolds are delivery vehicles for mesenchymal stem cells

The use of mesenchymal stem cells encapsulated within tiny particles or scaffolds enables the replacement, engineering, or regenerating of human cells, tissues, or organs lost or injured due to multiple reasons, including age, disease, or congenital disabilities, to restore or establish normal function. Mesenchymal stem cells are multipotent cells that can differentiate into various cell types, including bone cells, cartilage cells, muscle cells, and fat cells, which give rise to marrow adipose tissue. Mesenchymal stem cells also can be self-renewal. This might sound great to you, but there are a few significant challenges with using those cells. The main challenges when using mesenchymal stem cells are that most cells are either unable to migrate to the site of injury and get trapped within the capillary network or that mesenchymal stem cells have a short life span. Thus, mesenchymal stem cells get cleared from the hematopoietic system before reaching the target site.

 To circumvent these significant challenges and ensure maximum mesenchymal stem cells migrate to the target site. Let us think of an example of our everyday life if you want to take ice to the beach. You always make sure to keep the ice in a cold container or a cooler. Otherwise, the ice will melt and will become liquid before reaching your destination, the beach. It is the same for mesenchymal stem cells. If they are not contained or kept under the right conditions, they will get trapped or cleared out of the circulation system. Here nanoparticles and scaffolds come to play. Nanoparticles usually act as a delivery vehicle for drugs, gene therapy, and others. Therefore, nanoparticles will be the container or the vehicle that will encapsulate the mesenchymal stem cells. Nanoparticles are ultrafine particles that find various applications due to their tunable optical, electrical, magnetic, and mechanical properties that can be manipulated via controlling certain factors including surface chemistry (hydrophobic/hydrophilic), surface charge to determine the NP-cellular interaction, and NP size, which defines their membrane permeability.

 Please click the link below to learn more about the different types of nanoparticles and scaffolds used to help deliver the mesenchymal stem cells and the benefits and consequences of using each.

 The source:

Pawan Kumar Raghav, Zoya Mann, Swati Ahlawat, Sujata Mohanty, Mesenchymal stem cell-based nanoparticles and scaffolds in regenerative medicine, European Journal of Pharmacology, 2021, 174657, ISSN 0014-2999,  https://doi.org/10.1016/j.ejphar.2021.174657.

(https://www.sciencedirect.com/science/article/pii/S001429992100813X)

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Meet me

Welcome to my blog; my name is Ali Abu Zeid. I am currently a fourth-year Biology-chemistry student at the University of New Brunswick Fredericton, UNB. The biology-chemistry allowed me to understand how the human body works. My degree also allowed me to understand every critical and complex interaction and the mechanisms used within the human body. During my time at UNB, I had the opportunity to work in microbiology labs, organic and inorganic chemistry labs, biology labs, and physics labs. Also, I had a chance to present some topics of interest, such as the study of mRNA vaccines and SARS-Cov 2. My dream has always been to be a cardiothoracic surgeon, but as I am finishing my degree, I realize that I am more interested in microbiology and laboratory work. Therefore, currently, I am fascinated and interested in becoming a clinical pathologist.

With this blog, I am aiming to achieve a few different goals. I want to communicate some scientific papers more straightforwardly using more accessible language and diagrams if needed. Also, I would like to provide the utmost accuracy about my topic, which is nanoparticles.

My blog will introduce you to nanoparticles, their functions, uses, and more. Nanoparticles have received intensive attention and are classified as the most studied topic regarding therapeutics and diagnosis. This is due to their unique physicochemical properties that make medical treatments more potent and less toxic. COVID-19 outbreak involved the use of nanoparticles. Nanoparticles were used to develop vaccines and cures throughout multiple studies and research. Another significant benefit of the nanoparticles is creating fluorescent biological labels for necessary biological markers and molecules in research. At the end of this term, my goal is to provide a deeper understanding of nanoparticles and their use in medicine and the human body.

I am looking forward to sharing my blogs about nanoparticles with you!

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