By Tim Sandle, Ph.D.
Over the past two decades, nanotechnology has promised a revolution in medicine, particularly by creating “smart” ways to deliver drugs to specific targets for more effective treatments. Scientists are working on different types of nanoparticles, in particular to diagnose and treat cancer. This article examines some of the key innovations in the field over the past year and promising future developments.
What is nanomedicine?
Nanomedicine refers to any medicine that includes an artificially constructed component of nanotechnology (“artificial” differentiates science from bacteria and viruses). Nanotechnology is a size-based concept describing technologies measured below 1,000 nanometers (one nanometer equals one millionth of a millimeter). The application is based on the empirical benefits of nanoparticles, which can be manipulated to improve the behavior of drug substances.
These benefits manifest themselves in better drug delivery. This overcomes three obstacles encountered by conventional medicine:
- Several types of drugs have low water solubility and the human body finds it difficult to absorb enough of them to treat disease.
- While some drug molecules are well absorbed, often the body clears the drug before it has had enough time to provide benefit or side effects are more likely to develop.
- Drugs often miss their intended target, or the drug is delivered to the intended target and to healthy cells, causing unintended damage to other parts of the body.
Nanotechnology overcomes absorption problems due to the size of the drug and because nanoparticles can contain drugs that would otherwise become insoluble or rapidly degrade in the blood tightly on the surface of the particle. Additionally, due to their small size, nanoparticles can overcome biological barriers such as membranes, skin, and the small intestine, which would typically prevent the drug from reaching its target.1
In terms of timely drug delivery, the use of a nano-engineered drug carrier allows for the slow release of the active ingredient. Nanotechnology also allows drugs to be delivered with greater precision, with the drug specifically targeting areas of the body that need treatment.
Nanoparticles of an active ingredient are usually coated with a biomolecular multilayer (such as a protein crown). This outer layer alters the physiochemical properties, pharmacokinetics and toxicity profile of the nanoparticles, allowing targeted delivery and increased survival time in the body.2
The chicken or the egg: do we need innovations in nanostructures or suitable drug candidates first?
Despite the benefits described above, nanomedicine has failed to treat cancer. This is largely due to poor clinical translation of preclinical models to cancer patients.3 To overcome this, nanoparticles need to be further enhanced to protect the pathways that nanomedicines have to take in the human body.
Scientists at Harvard’s Wyss Institute have created more stable nanostructures capable of assembling biomolecules with different functions. The aim is to develop DNA nanostructures capable of binding and assembling biomolecules into multifunctional structures. The specially developed “DNA origami” is programmed to fit together in rigid square lattice blocks. Such a DNA nanostructure was shaped to create a four-ended branched structure. The researchers managed to bind and collect different antibodies that can guide T cells in the body to attack cancer cells more intensively.4 The DNA nanostructure is made sufficiently stable by coating the DNA with a discrete, small-molecule neutralizing agent called PEG-oligolysin. This positively charged chemical covers several negative charges of DNA at once to create a stable “electrostatic net”. Stability is further enhanced by applying glutaraldehyde as a chemical crosslinking reagent.
An alternative to DNA is artificial oligonucleotides, which can be modified to form the nanostructure. An example comes from the University of Aarhus, using the acyclic L-threoninol nucleic acid (aTNA). This is created when a natural sugar molecule (deoxyribose) is replaced with an artificial sugar molecule (acyclic L-threoninol). This strengthens the overall structure and minimizes the potential for the molecule to break down in the blood. Another advantage is that these oligonucleotides do not provoke an immune response. Trials are underway using artificial oligonucleotides with a high specificity biomolecule for breast cancer cells.5
Improving the robustness of nanostructures remains academic until new drug candidates are developed. This area of research is gaining momentum, notably at the University of Arkansas, which has developed a drug candidate that kills triple-negative breast cancer cells (an aggressive form of cancer that cannot be treated with therapy targeted to receptors). It involves a compound co-formation of a relatively new class of nanomaterials, called metal-organic frameworks, with a photodynamic therapy drug. The resulting compound is a nanoporous material that targets and kills tumor cells.6
Photodynamic therapy uses a photosensitizer which, upon irradiation with light, generates toxic reactive oxygen species that kill cancer cells. The critical step is the bio-conjugation of the nanomaterials with the ligands (binding molecules) of the drug.
New FDA guidelines will help move the field forward
As with any new medical innovation, a regulatory framework is needed and the FDA has recently issued guidanceseven for the development of nanotechnology for use as active ingredients or inactive ingredients, including carriers loaded with an active ingredient. The guidelines require taking a risk-based approach to drive safety and efficacy, as well as defining requirements for each drug application. There are three important areas of risk assessment:
- Product stability: Here, the developer is asked to identify potential factors that could impact product performance, including interactions of nanomaterial properties. This requires a scientific evaluation of the physical and chemical changes in the material during handling and storage.
- Security: Often the safety of the nanomaterial cannot be fully demonstrated by existing safety data. Therefore, further assessment is required regarding level of exposure, duration of exposure and route of administration.
- Efficiency: In particular for nanomaterials formed of complex structures involving several components or compartments, ligands and coatings.
Nanoparticle-based drug delivery systems show promising therapeutic efficacy in cancer. To increase tumor targetability, nanoparticles must be robust enough to survive the human body, hit the right target, and be functionalized with an appropriate drug. To ensure specificity and protect patients from any negative influence of the delivery mechanism, a strong regulatory framework is timely and necessary.
- Ma, W., Saccardo, A., Roccatano, D., Animal-Mensah, D. et al Modular assembly of proteins on nanoparticles. Nature Communication, 2018; 9 (1) DOI: 10.1038/s41467-018-03931-4
- Berger, S., Berger, M., Bantz, C., Maskos, M., Wagner, E. Performance of nanoparticles for biomedical applications: the in vitro/in vivo gap. Biophysics journals, 2022; 3 (1): 011303 DOI: 10.1063/5.0073494
- Song, S., Bugada, L., Li, R. et al An albumin nanoparticle containing a PI3Kγ inhibitor and paclitaxel associated with α-PD1 induces tumor remission of breast cancer in mice. Science Translational Medicine, 2022; 14 (643) DOI: 10.1126/scitranslmed.abl3649
- Anastassacos, F., Zhao, Z., Zeng, Y., Shih. W. Glutaraldehyde cross-linking of oligolysines encasing DNA origami dramatically reduces susceptibility to nuclease degradation, Jam. Chem. soc. 2020, 142, 7, 3311–3315
- Marcher, A., Kumar, V., Andersen, V. et al. Four-way junction of functionalized acyclic (l)-threoninol nucleic acid with high stability in vitro and in vivo. International Edition of Applied Chemistry, 2022; DOI: 10.1002/anie.202115275
- Sakamaki, Y., Ozdemir, J., Perez, A. et al Maltotriose-conjugated metal-organic frameworks for the selective targeting and photodynamic therapy of triple-negative breast cancer cells and tumor-associated macrophages. Advanced therapy, 2020; 2000029 DOI: 10.1002/adtp.202000029
- FDA. Drug Products, including Biological Products, that Contain Nanomaterials Guidance for Industry, US Department of Health and Human Services, April 2022: https://www.fda.gov/media/157812/download
About the Author:
Tim Sandle, Ph.D., is a pharmaceutical professional with extensive experience in microbiology and quality assurance. He is the author of over 30 books on pharmaceuticals, healthcare and life sciences, as well as over 170 peer-reviewed articles and some 500 technical articles. Sandle has presented over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant for the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.
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