This is a topic that I’ve been extremely interested in lately, prompting me to dig deeper, research more and write a blog post about it. Without further ado, let’s get started with a brief introduction on what exactly nanoparticles are…
Introduction & History
When it comes to combating diseases like cancer, new drugs are in constant development. Yet, there are challenges in how to best deliver these drugs in order to mitigate side effects and maximize the effectiveness of the treatment. In recent years, nanoparticles have been developed for the application of drug delivery; these systems would carry drugs into the bloodstream and to their destination, improving efficiency and reducing the likelihood of a drug affecting other parts of the body.
Nanomaterials refer to materials with a dimension in the nanoscale (100 nm). Nanoparticles are most commonly used in drug delivery and are a subset of nanomaterials with all dimensions in the nanoscale (Murthy). Nanoparticle development for drug delivery is a relatively new field, with development of metal and lipid nanoparticles accelerating in the 1970s. In fact, in 1990, Sigma-Tau Pharmaceuticals released Adagen – the first nanomedicine to use PEGylated synthetic nanoparticles for the treatment of severe combined immunodeficiency disease (SCID) (Salmaso and Caliceti).
Today we’ll focus on how nanoparticles are developed for this application, with an emphasis on how the chemistry of the nanoparticles could be engineered to yield better results. Further, this review will analyze the application of some nanoparticles to recent therapies.
Metal Nanoparticles for Drug Delivery Purposes
One subset of nanoparticles includes metal nanoparticles, which encompasses metal nanospheres and nanorods that release a drug payload. (Mitchell et al.). Common metal nanoparticles are synthesized out of metals such as silver, platinum, and gold. However, gold nanoparticles are particularly desirable due to their positive charge, as they are able to be internalized through endocytosis.
A common method of gold nanoparticle synthesis is the bottom-up method, or condensation. Nanostructures are fabricated atom by atom; they are in a supersaturated solution, and nuclei growth follows after a certain period of time. (Chandrakala et al.). Often, nuclei form from a compound containing a gold ion, such as tetrachloroauric acid (HAuCl4). The gold ion is reduced to a zero charge using sodium citrate; this process occurs at extremely high temperatures, and one paper reported it occurring at 343 K. Nucleation then follows, and this is when a discrete particle of a new phase is formed.
Brief Steps of Nanoparticle Synthesis. Demonstrates the process of nucleation, stabilization and then growth. (Chandrakala et al.).
In order to form stable, nanoparticle clusters in the growth and stabilization stage, a radius and energy barrier must be surpassed, requiring the high temperature for the process to occur. In addition, using water as a solvent for the process and surfactants helps control crystal growth and modulate the size of gold nanoparticles (Suárez-López et al.).
Recent studies have examined applying green chemistry concepts in the synthesis of nanoparticles, as the reaction between HAuCl4 and citric acid can be harmful to the environment. Using plant extract as a biological reducing agent has been proposed (Lee and Lee).
Photothermal Therapy Using Gold Nanoparticles. Demonstrates the steps and how membrane wrapped nanoparticles are more effective. Aboeleneen et al.
Another aspect that makes gold nanoparticles desirable is its photothermal properties, which can be used in photothermal cancer therapy. For instance, in photothermal cancer therapy, gold nanoparticles accumulate at the tumor site; after, a laser causes them to heat which prompts the release of the drug payload and cancer cell death. However, coating gold nanoparticles with a membrane that mimics that of a tumor cell leads to better accumulation at the tumor site, as demonstrated in Figure 2 (Aboeleneen et al.).
Specifically, transferrin, a type of serum glycoprotein, transports iron into cells; transferrin receptors are overexpressed in tumor cells and are expressed at low levels in normal cells; thus, transferrin-conjugated nanoparticles can be used as a targeting method to deliver drugs for cancer treatment (Yao et al.).
Applying capping agents to nanoparticles is another technique to improve circulation. Capping agents provide colloidal stability, along with preventing agglomeration (accumulation & grouping of nanoparticles) and stopping the uncontrolled growth of synthesized nanoparticles. (Sidhu et al.)
Polyethylene glycol (PEG) is a common capping agent used. Adding PEG improves uptake by the desired target and decreases uptake by the liver and mononuclear phagocyte system (MPS), which is part of the immune system and has the ability to internalize particles. In addition, PEG increases the molecular weight of the molecule, therefore increasing its half life and circulation. Further, adding PEG coatings improves solubility of hydrophilic drugs. (Swierczewska et al).
Demonstrates how PEGylated Nanoparticles are more effective. (Hadjesfandiari and Parambath).
Research in Lipid Nanoparticles
Another class of nanoparticles includes lipid nanoparticles (LNPs). These are nanoparticles composed of lipids (fatty acids insoluble in water), and are considered to be a novel pharmaceutical formulation and drug delivery system, and the first LNP drug delivery vehicle was approved in 2018 for the siRNA (small interfering RNA) drug Onpattro. (Akinc et al.).
In order to produce lipid nanoparticles, solid lipids and hydrophobic drugs are dissolved in a water-immiscible organic solvent such as cyclohexane. This is then dispersed in an aqueous solution to form oil-in-water emulsions. The lipid nanoparticles are generated as a result of the evaporation of the organic solvent, and temperature sensitive drugs are able to be encapsulated due to this method.
The most frequently used types of nanoparticles are solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). SLNs were developed in 1990 as an alternative carrier system to emulsions, liposomes, and polymeric nanoparticles, which can be toxic (Müller et al.). NLCs are a more novel development, and consist of both solid and liquid lipids in a core matrix (Azhar et al.). They hold several advantages, as it has increased solubility, the ability to enhance storage ability, improved permeability and prolonged half life. Furthermore, the blend of solid and liquid lipids allows for an unstructured matrix with imperfections that holds a greater number of drug molecules. They are therefore superior to SLNs (Garg et al.).
As demonstrated in Figure 4, the inner core of an NLC consists of liquid and solid lipids, with drug dispersed throughout. The NLC is surrounded by surfactant, which helps promote stability of the nanoparticle.
Illustration of nanostructured lipid carrier (Haider et al.)
Similar to metal nanoparticles, nanostructured lipid carriers can also be PEGylated to improve circulation time (Wang et al.).
Research & Future Directions
Future research in the nanoparticle drug delivery space includes determining the effectiveness of drug release both in vitro and in vivo. Currently, the concentration of nanoparticles is measured in the blood, and there exists opportunities to determine how nanoparticles accumulate in tumors and their targeted sites. In addition, as NLCs are novel, more research can be done in their optimization, especially when experimenting with what types of fatty acids to use in their development (“Nanostructured Lipid Carriers (NLCs) for Drug Delivery and Targeting”).
A growing application for nanoparticle drug delivery is in cancer therapy. Through being able to accumulate in tumors, nanoparticles are particularly valuable in targeting certain tumor types. However, research has to be done to identify certain receptors on tumor cells, so that nanoparticles could be conjugated accordingly.
Another new area of research includes using drug delivery systems for RNA therapeutics, where the RNA molecule modulates the expression of its target molecule in order to treat a certain condition, which could be useful in treating genetic disorders. Such a therapy requires that RNA function inside target cells without eliciting unwanted immune responses. These RNA molecules can be encapsulated in lipid nanoparticles for selective targeting (Paunovska et al.).
Moreover, recent research at the Massachusetts Institute of Technology (MIT) has unveiled the creation of bottlebrush-shaped nanoparticles that could be loaded with multiple drugs in easily controllable ratios. The researchers formed monomers with certain drugs, and then polymerized them; this formed polymer nanoparticles (“Targeting Cancer With a Multidrug Nanoparticle”). This research builds upon basic nanoparticle research, but also helps solve the existing problem of effectively delivering multiple drugs, which is often needed in the treatment of cancer.
Conclusion
In summary, nanoparticle drug delivery is an emerging field with the potential to yield new therapies for devastating diseases such as cancer. This review summarized some common methods for synthesizing nanoparticles, as well as current research in the field.
Unlike many drugs on the market, nanoparticles are selective and can result in fewer drug-related side effects – supporting further research in the field. Furthermore, nanoparticles could be used in conjunction with other known cancer therapies, such as radiotherapy and surgery in order to directly deliver drugs to the tumor site. In-vivo and clinical studies would have to be conducted to determine the effectiveness of such approaches.
Yet, questions still remain about its toxicity and overall accumulation in the body; because the research is fairly recent, long term effects of nanoparticle accumulation are still being studied. Nonetheless, the continuation of research into nanoparticle drug delivery can help save lives.
Well that was interesting! I still have a bunch of questions after compiling this post, and maybe you do too. I think it’s quite amazing how applicable engineering is to medicine, and this is a field I hope to explore further. Continue to grow that curiosity and research more; leave your thoughts, ideas, questions & knowledge in the comments below, and let’s continue learning more.
And if you’re interested in learning more about STEM, visit the Parea column of my blog!
Sources (in case you want to learn more…):
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