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CANADIAN RESEARCH FOCUS

Interview with Dr. Molly Shoichet

“Poly(ethylene glycol) modification enhances penetration of fibroblast growth factor 2 to injured spinal cord tissue from an intrathecal delivery

system”, J. Control. Release (2010).doi:10.1016/j.j.conrel.2010.01.029

June 22nd, 2010

conducted by Patricia Comeau

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Presentation Contents

Brief background on article Slides 3 - 5 Interview with Dr. Shoichet Slides 6 - 19 Dr. Shoichet’s Biography Slides 20 - 23

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PEG modification enhances penetration of FGF2 to injured spinal cord tissue from an

intrathecal delivery system

• Poly(ethylene glycol) (PEG) was conjugated to fibroblast growth factor (FGF2)– PEG used to enhance tissue penetration and increase

local concentrations, and – FGF2 used for its previously shown neuroprotective

properties

• Main objective was to investigate the penetration and distribution of PEG conjugated FGF2 in the spinal cord relative to unmodified FGF2

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Figure 1: Injectable Delivery Strategy to the Intrathecal Space of the Spinal Cord

Image reproduced with permission, copyright Michael Corrin, 2005; Molly Shoichet, 2010

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• 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.

• 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.

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Interview with Dr. Shoichet

Terrence Donnelly Centre for Cellular & Biomolecular Research,

Department of Chemical Engineering & Applied Chemistry,Institute of Biomaterials & Biomedical Engineering,

Department of Chemistry

University of Toronto

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Why was maleimide used to functionalize PEG? Is there any

significance in this choice?

There are free thiol groups on FGF2 that are outside

the active binding site.  These groups will selectively

react with maleimide-PEG, resulting in FGF2-PEG,

without side products.  Thus we did not have to

change FGF2 prior to covalent modification with

PEG. 

…continued on next slide →

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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.

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How selective is PEG conjugation to each conjugation site?

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.

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Is there a limit to the degree of PEGylation that can occur before

bioactivity is lost?

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.

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What is the relevance of the target tissue to FGF2?  Is there a certain cell

type that is expected to respond?

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).

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What is the loading capacity of HAMC?  How does this gel degrade?

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. 

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Will the spinal cord present a challenge for metabolism of degradation

products?

We have not observed any deleterious effects of the

degradation/dissolution products in the injured cord. 

In fact, we have observed the reverse - the HAMC

alone has shown reduced cavitation and an

attenuated inflammatory and even improved

functional recovery at early time points, relative to the

injection of an artificial cerebral spinal fluid (basically

a salt solution).

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Over what time period should FGF2 delivery be sustained? 

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.

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Do you plan to combine FGF2 with any other molecules? 

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

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Could this delivery system be applied in the brain or to other tissue?

Yes, we are currently investigating this delivery

system to the brain and for stem cell delivery as well

to the retina.

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What future work do you have planned?

We have several ongoing studies with HAMC for both

local delivery to the spinal cord and brain; and stem

cell delivery to the spinal cord, brain and retina.  We

are optimistic about HAMC and have patented the

composition of matter and its use in several different

contexts. 

…continued on next slide →

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We are actively seeking commercialization

partners (in collaboration with MaRS Innovation) so

that we can realize the potential that HAMC has for

use in diseases and disorders of the central nervous

system.

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CC-CRS Question #8

Thank you for the interview!

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Dr. Molly Shoichet

Biography of

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• 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.

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• 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).

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• 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.

 

…continued on next slide →

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• 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.