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Welcome to the Canadian Chapter of the
Controlled Release Society
CANADIAN RESEARCH FOCUS
June 20, 2010
Kang, C., Tator, C., and Shoichet, M. just published a new study
"Poly(ethylene glycol) modification enhances penetration of fibroblast growth factor 2 to injured spinal cord tissue from an intrathecal delivery system”, J. Contr. Rel. 144, 25-31 (2010).
Interview with co-author Dr. Molly Shoichet
After obtaining her PhD in Polymer Science and Engineering from the University of Massachusetts (Amhert, MA), Dr. Shoichet was a lecturer and Adjunct Assistant Professor in the Department of Molecular Pharmacology & Biotechnology at Brown University (Providence, RI). A few years later she joined the Department of Pharmacology at the University of Toronto (Toronto, Ontario) as a Visiting Scientist. After 2 months in this position she was promoted to Assistant Professor in the Department of Chemical Engineering & Applied Chemistry and the Department of Chemistry, and is currently a full Professor in both of these departments as well as in the Faculty of Medicine and the Program in Neuroscience. Dr. Shoichet has also served as the Director of the Bioengineering Minor Program (2005-2008) and Associate Director of the Institute of Biomaterials & Biomedical Engineering (2000-2001) at the University of Toronto, as well as the Vice President, Founding Scientist and Director of the Bonetec Corporation (Toronto, Ontario; 1998-2003), a Director and consultant of Chemical Engineering Research Consultants Limited (Toronto, Ontario; 1996-present), and as the President and Founding Scientist of matREGEN Corporation (Toronto, Ontario; 2002-present). She currently heads a team of 25 students and researchers specializing in multidisciplinary projects of regenerative medicine including drug delivery to stimulate endogenous cells, stem cell delivery, tissue engineered scaffold design, and targeted delivery in cancer. Her team designs, synthesizes and modifies polymers for application in medicine that are primarily biodegradable polymers and include naturally-based polysaccharides (e.g. hyaluronan, methyl cellulose, agarose) and synthetic polyester-peg copolymers designed to self-assemble to nanospheres for applications in cancer. To find out more about Dr. Shoichet’s research interests please visit her home page at www.ecf.toronto.edu/~molly/
Dr. Shoichet has been the recipient of many awards as a result of her leading research, including being selected as a Fellow of the American Institute for Medical and Biological Engineering (2006-present) and of Biomaterials Science and Engineering (2008-present), as well as holding the Canada Research Chair in Tissue Engineering since 2001. She also has the prestige of being selected as one of Canada’s Top 40 under 40 in 2001 for innovation and leadership in her field of research.
The blood-spinal cord barrier, as well as the dura and arachnoid membranes that surround the cord, make it very difficult to deliver drugs to the central nervous system and treat spinal cord injuries. The traditional treatment strategies consist of intravenous and oral delivery – both of which typically require high doses for penetration and may lead to undesirable side effects. 
Dr. Shoichet’s lab has developed a minimally invasive, injectable drug delivery system consisting of a biopolymer blend of hyaluronan and methylcellulose (HAMC) in order to achieve sustained intrathecal delivery of up to 24hr (as shown in Figure 1). In her most recent published article in the Journal of Controlled Release, Dr. Shoichet investigates the conjugation of poly(ethylene glycol) (PEG) to FGF2 - with PEG used to enhance tissue penetration and increase local concentrations, and FGF2 used for its previously shown neuroprotective properties. The penetration and distribution of PEG conjugated FGF2 in the spinal cord is studied relative to unmodified FGF2.
Figure 1: Injectable Delivery Strategy to the Intrathecal Space of the Spinal Cord. (Reproduced with permission, copyright Michael Corrin, 2005; Molly Shoichet, 2010).
CC-CRS:
Why was maleimide used to functionalize PEG as opposed to other moieties? Is there any significance to this choice?
Professor Shoichet:
There are free thiol groups on FGF2 that are outside the active binding site. These groups will selectively react with maleimide-PEG, resulting int FGF2-PEG, without side products. Thus we did not have to change FGF2 prior to covalent modification with PEG. And because we took advantage of orthogonal chemistry, we did not have to worry about other reactive functional groups on FGF2 reacting with maleimide-PEG. Importantly, this water-based chemistry is selective and has a high yield of reaction.
CC-CRS:
What is the significance of four free cysteine residues in conjugation? How selective is PEG conjugation to each site?
Professor Shoichet:
We were able to control the PEG conjugation to a certain extent, mostly through reaction conditions. Our modification chemistry resulted in a mixed population of mono- and di-PEG FGF2.
CC-CRS:
Is there a limit to the degree of PEGylation that can occur before bioactivity is lost?
Professor Shoichet:
We focused on mono- and di-PEGylation so that loss of bioactivity would be minimized. Any protein modification comes with the risk of lost bioactivity; however we were able to modify the FGF2 without loss of bioactivity. This probably reflects the water-based reaction conditions and the lack of side products formed.
CC-CRS:
What is the relevance of the target tissue to FGF2? Is there a certain cell type that is expected to respond?
Professor Shoichet:.
FGF2 has been shown to promote angiogenesis and promote healing of leaky blood vessels. This is particularly important after spinal cord injury where the injured tissue becomes ischemic resulting in further cell death (this is often termed the secondary injury response, which follows the primary traumatic injury).
CC-CRS:
What is the loading capacity of HAMC? Are we correct in thinking this gel degrades by dissolution? Will the spinal cord present a challenge for metabolism of degradation products?
Professor Shoichet:.
HAMC allows high loading capacity. We have been limited by the injection of small volumes, but know that we can at least double the injection volume. HA degrades enzymatically and MC dissolves. We have not observed any deleterious effects of the degradation/dissolution products in the injured cord. In fact, we have observed the reverse - that is the HAMC alone has shown reduced cavitation and an attenuated inflammatory response and even improved functional recovery at early time points, relative to the injection of an artificial cerebral spinal fluid (basically a salt solution).
CC-CRS:
Over what time period should FGF2 delivery be sustained? Do you plan to combine FGF2 with any other molecules (whether neuroprotective or neuroregenerative)?
Professor Shoichet:.
FGF2 is considered to be a neuroprotective molecule and thus we were interested in releasing it over the first week following injury in an attempt to reduce the loss of neurons. Combining FGF2 with other regenerative and protective molecules makes a lot of sense. We know that there is "no magic bullet" - that is no single strategy - that will overcome spinal cord injury.
CC-CRS:
Could this delivery system be applied in the brain or to other tissue?
Professor Shoichet:.
Yes, we are currently investigating this delivery system to the brain and for stem cell delivery as well to the retina.
CC-CRS:
What future work do you have planned? How soon do you predict that this delivery system can be used clinically to treat spinal cord injury?
Professor Shoichet:.
CCCRS:
Thank you for the interview!