This week we profile a recent publication in Small from the laboratories of Drs. Dominik Witzigmann
(pictured, top center) and Pieter Cullis (bottom left) at UBC and Dr. Dirk Trauner (bottom right) at New York University.
The lead authors are Nisha Chander (top right) and Dr. Johannes Morstein (top left).
Can you provide a brief overview of your lab’s current research focus?
The Nanomedicines Research Group at the University of British Columbia (UBC) focuses on the design and development of lipid nanoparticle (LNP) systems to deliver small molecule, peptide, or nucleic acid drugs. Our interest in LNP systems can be divided into two parts: (1) The delivery of cancer chemotherapeutics with the aim of increasing efficacy and reducing toxicity. (2) The design of LNP systems capable of effectively delivering nucleic acids (DNA/RNA) to silence pathogenic genes, express therapeutic proteins, or correct genetic defects. To stimulate release of encapsulated drugs or activate gene therapies locally in response to external triggers, this project is based on a strong collaboration with the Trauner Research Group at New York University (NYU) with expertise in the chemical synthesis of new lipids enabling light triggered release.
What is the significance of the findings in this publication?
The large majority of commonly used pharmaceuticals are small molecule drugs that are administered systemically. Among other issues, such drugs suffer from one major limitation in that very little of the administered dose gets to where it is needed. For anticancer drugs, for example, less than 0.1% of the drug arrives at a tumour site. The other 99.9% distributes through the rest of the body, often inducing toxic, dose limiting side effects (that can be life-threatening) in healthy tissue. Encapsulation and delivery of anticancer drugs in clinically approved nanomedicines, such as liposomes, improves this situation somewhat by avoiding some sensitive tissues and enhancing tumour delivery by up to a factor of 10, with attendant therapeutic benefits. However, there is a critical need to develop more targeted delivery systems that maximize exposure of target tissue to the encapsulated drug, and minimize exposure to sensitive tissues. In order to improve local delivery, our teams at UBC and NYU develop new approaches to stimulate release of encapsulated drug in response to a light trigger.
In our research article, we demonstrate that incorporating photoswitchable phosphatidylcholine-derivatives into conventional lipid nanoparticles (LNPs) generates photoactivatable LNPs (paLNPs). We show that upon irradiation with red light ~70% drug is released which induces cytotoxic effects in human cancer cells. In vivo studies in zebrafish embryos confirm that paLNPs have similar blood circulation properties as clinically approved LNPs with added benefits of light-induced drug release based on trans-to-cis azobenzene isomerization.
What are the next steps for this research?
This proof-of-concept study, and in particular the tools and methods employed, will be applied towards the rational design of new, simple and effective cancer therapeutics. The approach pursued here offers the opportunity for not only dramatically enhancing the potency of the drug by increasing the amount delivered to the tumour site but also decreasing the toxicity of the drug by reducing exposure to sensitive, healthy tissues. The potential is therefore to develop a highly potent but non-toxic cancer therapy. Next steps are (i) further optimization of the delivery systems to allow rapid release within seconds and (ii) proof-of-principle studies in cancer models. The significance of this opportunity is clear, triggered release of anticancer drugs in the vicinity of a tumour could revolutionize cancer therapy.
This research was funded by:
NanoMedicines Innovation Network (NMIN, a Canadian Networks of Centres of Excellence (NCE) Program in Nanomedicines) National Cancer Institute, and Swiss National Science Foundation
