This week we profile a recent publication in Nanoscale from Dr. Souvik Biswas (pictured) during his time as a postdoctoral
scientist in the laboratory of Dr. Pieter Cullis at the University of British Columbia.
Can you provide a brief overview of your lab’s current research focus?
I am an organic synthetic chemist, and my research interest is in the interface of chemistry, nanotechnology and the life sciences. I have always been attracted to the field of non-viral gene delivery using nanoparticles, and I was a postdoctoral scientist in Professor Pieter Cullis’s NanoMedicine laboratory at the Life Sciences Institute at the University of British Columbia while conducting the above research that is featured in this article. My Ph.D. thesis research in Chemistry (University of Louisville, Louisville, KY, USA) was focused on synthesis of iron oxide and lipid-based magnetic nanoparticles (typically 10-20 nm in diameter) for therapeutics and diagnostics. At the National Cancer Institute (Frederick, MD, USA) I developed carbohydrate antigen-conjugated gold nanoparticles which showed promising anti-tumor effects in animal studies. At present, I am working as a Scientist at Moderna Therapeutics (Cambridge, MA, USA) to develop mRNA drugs.
Professor Cullis and his research group has pioneered the art of synthesizing lipid nanoparticles or LNPs (lipid nanoparticles are vesicles from 30-100 nm in diameter) for encapsulating and delivering genetic and small molecule drugs. These lipid-based delivery systems or LNPs are capable of encapsulating multiple copies of drugs within each LNP resulting in protection of the drug from degradation, decreased side effects and increased circulation time, which enhances the therapeutic effect of the drug many folds compared to the free drug. Dr. Cullis’ research programs range from the purely academic quest of understanding the biophysical behavior of drug loaded LNPs, to the translation of this knowledge into the most advanced LNP drug delivery systems in FDA approved nano-formulations. At present, his research team is developing a next generation LNP system that could carry an inorganic nanoparticle (such as gold or iron oxide) and a therapeutic molecule at the same time. Gold or iron oxide nanoparticles could work as imaging agents as well as acting as a triggering agent to release the drug from the LNP more efficiently at the desired site of therapy when stimulated by an external force (such as an electromagnetic field). Professor Cullis is also interested in small-interfering RNAs (siRNAs) therapeutics. RNA interference (RNAi) is a very attractive strategy for the treatment of human disease, however the therapeutic applicability of siRNA has been hampered by the inability to deliver it to the disease site and the ineffective intracellular delivery of functional siRNAs to target cells in vivo.
A focus of our laboratory is the design of LNP systems that are able to effectively deliver their contents intracellularly following systemic administration, thus enabling the therapeutic use of siRNA. The challenge in this work is to develop potent LNP systems that are well tolerated, able to evade the immune system and remain stable in the circulation. Patisiran®, an LNP encapsulating siRNA for hepatic gene silencing, is currently in Phase III clinical trials for treatment of Transthyretin amyloidosis as are several other siRNA products employing this delivery technology. Dr. Cullis is also interested in applications of the LNP platform in the rapidly growing new field of mRNA therapeutics where it shows real promise.
What is the significance of the findings in this publication?
Due to their unique optical and electromagnetic properties, inorganic nanoparticles are extremely promising for therapeutics as well as diagnostics (theranostics: therapeutic + diagnostic). For example, iron oxide nanoparticles can be used as an MRI contrast agent but also can generate heat when stimulated by an external electromagnetic and can be used to destroy cancer cells. However, due to solubility and stability issues the clinical utility of these nanoparticles is limited. In this manuscript, we have described a simple controlled and rapid mixing formulation technique to encapsulate hydrophobic inorganic nanoparticles (iron oxide, gold and quantum dots) inside of a LNP system to overcome the above challenges. As a result of the perfect encapsulation in our LNP, the water solubility of these hydrophobic inorganic nanoparticles (HNP) was enhanced many fold and they became biocompatible. These LNPs consist of hydrophobic “core” lipids such as triolein surrounded by a monolayer of amphipathic “surface” lipids, such as phosphatidylcholine and polyethylene-glycol-lipid. It is shown that rapid, controlled mixing of HNPs, core lipids and surface lipids in an organic solvent with an aqueous phase resulted in stable, monodisperse LNPs containing inorganic nanoparticles. This method allows 40-fold more hydrophobic iron oxide nanoparticles to be entrapped within an LNP than previous methods and can be a universal method to entrap other HNPs. We have demonstrated that the diameter of the LNP loaded with HNP can be modulated very easily by varying the flow rate during particle synthesis or by varying the core-to-surface lipid ratio.
Finally, we have shown that LNP containing iron oxide nanoparticles are non- toxic and accumulated in the liver, resulting in enhanced contrast for in vivo MRI. In summary, our bottom-up approach for encapsulating HNPs within LNPs has advantages of homogeneity, reproducibility and stability required for biomedical applications. This simple formulation technology is a significant step forward to entrap inorganic nanoparticles within LNP for various biomedical applications.
What are the next steps for this research?
It is expected that this formulation technique will be useful to entrap a wide variety of inorganic nanoparticles to achieve LNP systems with a wide spectrum of diagnostic and/or therapeutic properties. At present, we are in the process of developing a LNP system carrying a therapeutic effector and gold or iron oxide nanoparticles together to achieve a next generation stimuli-responsive drug delivery system.
This work was funded by:
This research was funded by the Canadian Institutes of Health Research (CIHR FRN148469).
