At the Centre for Biologics Evaluation, research on nanoparticles and nanomedicines provides new information and tools for evaluating medicines that are being developed using nanotechnology.
- Why we study nanotechnology and products of nanotechnology
- Concepts regarding nanomedicines and nano-scale drug delivery systems
- How we study nanomedicines
- Research highlight 1: Investigation of production methodology of protein nanoparticles
- Research highlight 2: Investigation of leachates and nano-scale contaminate interaction with vaccine adjuvants
Why we study nanotechnology and products of nanotechnology
Nanotechnology is the manipulation of material resulting in the production of particles generally smaller than 100nm. The resulting nanoparticles, due to their small size, may demonstrate altered physical or chemical properties and/or altered biological behaviour.
One of the most promising avenues for the application of nanotechnology is in the medical field. Nanoparticles are currently being used, or are proposed for use, as an effective means for medical imaging as well as vaccine and drug delivery. Due to the time required for the development of many nanomedicines a number of the delivery systems have, or will have shortly, expired patents. This has led to more interest in the development of generic nanomedicines and it is unknown if current physiochemical methods will be sufficient to establish interchangeability of nanomedicines between two manufactures.
The development and adaptation of methodology to assess nanomedicines as well as developing an understanding of how changes to the manufacturing process and starting materials affect the physical properties of nanomedicines are research priorities for Health Canada.
Concepts regarding nanomedicines and nano-scale drug delivery systems
At the Centre for Biologics Evaluation, scientists use the term “nanoparticles” to refer to particles that have at least one dimension sized between 1 and 100 nanometres. Nanoparticles include a wide range of particle types. Some occur naturally, while others are composed of chemically synthesized material. Their variable and unique properties make nanoparticles very useful as drug delivery systems.
Nanomedicines have the potential to offer many benefits over the conventional delivery of therapies. These include
- Reducing toxicity or adverse effects by decreasing exposure of susceptible tissues
- Improving efficacy by
- targeting disease sites
- improving circulation lifetimes
- controlling drug release
- improving stability of active agents, and
- delivering compounds with poor solubility
- Enabling therapeutic activity of previously inactive agents
- Enabling alternative routes of drug administration and improving compliance by patients
The Nanomedicine Laboratory is primarily interested in liposomes and protein-based nanomedicines:
Lipid nanoparticles are also known as liposomes. These artificial vesicles have one or more lipid bilayers surrounding an aqueous core. Lipid nanoparticles are one of the most widely used drug delivery systems, because they can encapsulate hydrophobic or hydrophilic drugs, show bio-compatibility and be functionally modified on their surface.
Protein-based delivery systems have been the focus of recent studies using albumin as a delivery system for other proteins or small molecule drugs. These albumin-based delivery systems showed improved pharmacokinetic profiles and tumour accumulation for the therapeutically active agent. Some albumin-based delivery systems are in late stage clinical studies or have been approved for use in the clinic.
How we study nanomedicines
Using a wide range of highly specialized scientific equipment the Centre for Biologics Evaluation is investigating techniques to better characterize and understand the properties of nanomedicines. This dedicated equipment includes instruments to measure the size of nanoparticles through single particle tracking analysis, characterize protein/nanomedicine interaction with various types of calorimetry and identify changes in protein structure due to interaction with nanoparticles with circular dichroism spectropolarimetry. Information gained from these studies will provide scientifically relevant experience, advice, and expertise in this critical and rapidly expanding field—both for the centre and the regulatory decision-making process at Health Canada.
Scientists are currently studying a number of different nanoparticle drug delivery systems, including delivery systems based on lipid or protein nanoparticles. This research on nanomedicines provides valuable knowledge for:
- Evaluating both lipid and protein based nanomedicines in terms of current regulations
- Developing or adapting existing techniques to further characterize nanoparticle drug delivery systems
- Examining the effects of nanoparticle association with vaccine adjuvants
- Identifying possible changes to critical attributes of nanomedicines due to alterations in the starting materials and production methods
Research highlight 1: Investigation of production methodology of protein nanoparticles
Due to the concern for potential pathogen contamination and variability in albumin sourced from human serum (HSA) we have investigated the fabrication of albumin nanoparticles using recombinant human serum album (rHSA) expressed in Asian rice (Oryza sativa). When formulating nanoparticles with rHSA expressed in rice we have noted the presence of bound fatty acids increased nanoparticle diameters, polydispersity and interestingly drug loading efficiency. These studies involved small quantities of nanoparticles but it remains to be determined how the presences of protein bound contaminating ligands or therapeutic compounds affect the physical properties of protein nanoparticles at larger fabrication quantities (scale up).
The Nanomedicine Laboratory is currently conducting research to gain an understanding of how scale up protocols influence the physical properties of protein nanoparticles. The information generated will provide further insights to nanomedicine researchers and the larger nanomedicine community; specifically the effects of bound ligands and on scale up production and the effects of drug loading methodology on the physical properties of the nanoparticles. It may also further explain the differences in nanoparticles sizes observed between various studies although all appear to ostensibly use identical or similar fabrication protocols. This is being accomplished by:
- Investigate current fabrication methods with an emphasis on determining their suitability for production of larger quantities of nanoparticles
- Determining how contaminating ligands or therapeutic compounds affect the production of larger quantities of nanoparticles
- Development of novel methods for generation of larger quantities of protein nanoparticles such as micro/nano fluidic devices
Research highlight 2: Investigation of leachates and nano-scale contaminate interaction with vaccine adjuvants
Leachates and nano/micro-scale contaminants in therapeutic products such as silica particles shed from containers, cellulose particles shed from the filters, Teflon® shed from containers or metal particles (stainless steel or titanium) shed from production/filling equipment have been identified and been implicated in the generation of sub-visible particles and have the potential for generating adverse events.
Relatively little is known how these materials interact with nano-scale vaccine adjuvants (e.g. liposomes, nano-scale emulsions of squalene) currently in use or under development. Previous work has shown that metallic nano-particles can influence the physical properties of liposomes with both gold and silver nano-particles increasing the membrane fluidity of dipalmitoylphosphatidylcholine (DPPC) liposomes when incorporated into the lipid bilayer. Changes to membrane fluidity have been shown to alter protein binding and circulation lifetimes of liposomes.
It is conceivable that these leachates and nano-scale contaminates, especially those generated from production machinery could influence critical attributes of both nano-scale adjuvants either pre or post particle fabrication as well as antigen binding. Of particular interest in the effect of these contaminates on adjuvant particle size as numerous studies showing size plays a critical role in the efficacy of nano-scale adjuvants.
The Nanomedicine Laboratory is currently determining how leachates and nano-particle contaminates interact with nano-scale adjuvants used in the clinic or currently under development by:
- Utilize a number of biophysical techniques to determine how leachates and nano-particle contaminates interact with nano-scale adjuvants
- Assess if adjuvants and leachates/contaminates alter a monocyte activation test (MAT) for the detection of pyrogens
For information about the lead scientist of this laboratory, please visit their Directory of Scientists and Professionals profile.