New drug delivery method promises long-lasting glaucoma relief

Researchers at the University of Toronto see a future where a single injection under the eyelid could replace months of daily eye drops to treat glaucoma, a leading cause of blindness.

A team led by Molly Shoichet, a professor in the department of chemical engineering and applied chemistry and the Institute of Biomedical Engineering, used colloidal drug aggregates (CDAs) to modify the effects of a small-molecule glaucoma drug.

This new approach, described in a paper in the journal Advanced Materials, prolongs the drug’s effect from six hours when it is delivered via an eye drop to up to seven weeks with a single, non-invasive injection under the eyelid.

“Eye drops are the most common treatment for glaucoma, but they come with issues regarding efficacy and patient compliance, especially since the disease is more common in older adults,” says Ph.D. alumnus Mickaël Dang, a postdoctoral fellow in Shoichet’s lab and the first author of the study.

“Self-administering drops perfectly can be difficult and their effects are transient, requiring administration on a precise, interval-based schedule.

“There are also laser therapies and surgical treatments that require an injection inside the eye every few months. But these come with risks of complications such as infection, inflammation or vision loss.”

Glaucoma is a group of eye diseases characterized by an increase in eye pressure, leading to damage of the optic nerve essential for vision. Currently, there are no clinical cures—only treatments that can slow the progression of the disease.

The research team’s new method delivers timolol prodrug colloids dispersed in a hydrogel, demonstrating for the first time that a non-colloid forming drug can be chemically modified into a colloid-forming prodrug.

CDAs are drug molecules that can spontaneously self-assemble into nano-scale particles. Traditionally, they have been seen as a hindrance in drug development research. This is due to CDAs creating false positive and false negative results in enzyme- and cell-based assays, respectively, which are commonly used to screen and characterize drug candidates in the early stages of development.

“We showed that delivery of this colloidal drug aggregate could be dispersed in an in situ-forming hydrogel into the subconjunctival space,” says Shoichet.

“The colloidal drug enabled the slow release over several weeks, leading to a 200-fold increase in efficacy and the hydrogel resulted in the formulation staying in the subconjunctival space after injection. The control—without the hydrogel—mostly leaked out of that space.”

Shoichet’s lab collaborated with Jeremy Sivak, the glaucoma research chair at the Krembil Research Institute, part of the University Health Network, and an associate professor in U of T’s department of ophthalmology and vision science in the Temerty Faculty of Medicine.

Given the success of their preclinical research, the researchers are now working towards optimizing their formulation for ultimate clinical use.

“We envision a future where this non-invasive injection can be administered once every month or two in a medical office,” says Dang, who is also at Synakis, a spinoff biotechnology company founded from research in Shoichet’s lab.

“We invented this novel hydrogel as a vitreous substitute for vitreoretinal surgery, and here we show its versatility to encapsulate and release small molecule drugs.”

“There is a lot of work ahead,” adds Shoichet. “We are focused on the stability and manufacturability of our product while at the same time looking to raise funds to advance it more quickly to the clinic.”

Researchers at the University of Toronto see a future where a single injection under the eyelid could replace months of daily eye drops to treat glaucoma, a leading cause of blindness.

A team led by Molly Shoichet, a professor in the department of chemical engineering and applied chemistry and the Institute of Biomedical Engineering, used colloidal drug aggregates (CDAs) to modify the effects of a small-molecule glaucoma drug.

This new approach, described in a paper in the journal Advanced Materials, prolongs the drug’s effect from six hours when it is delivered via an eye drop to up to seven weeks with a single, non-invasive injection under the eyelid.

“Eye drops are the most common treatment for glaucoma, but they come with issues regarding efficacy and patient compliance, especially since the disease is more common in older adults,” says Ph.D. alumnus Mickaël Dang, a postdoctoral fellow in Shoichet’s lab and the first author of the study.

“Self-administering drops perfectly can be difficult and their effects are transient, requiring administration on a precise, interval-based schedule.

“There are also laser therapies and surgical treatments that require an injection inside the eye every few months. But these come with risks of complications such as infection, inflammation or vision loss.”

Glaucoma is a group of eye diseases characterized by an increase in eye pressure, leading to damage of the optic nerve essential for vision. Currently, there are no clinical cures—only treatments that can slow the progression of the disease.

The research team’s new method delivers timolol prodrug colloids dispersed in a hydrogel, demonstrating for the first time that a non-colloid forming drug can be chemically modified into a colloid-forming prodrug.

CDAs are drug molecules that can spontaneously self-assemble into nano-scale particles. Traditionally, they have been seen as a hindrance in drug development research. This is due to CDAs creating false positive and false negative results in enzyme- and cell-based assays, respectively, which are commonly used to screen and characterize drug candidates in the early stages of development.

“We showed that delivery of this colloidal drug aggregate could be dispersed in an in situ-forming hydrogel into the subconjunctival space,” says Shoichet.

“The colloidal drug enabled the slow release over several weeks, leading to a 200-fold increase in efficacy and the hydrogel resulted in the formulation staying in the subconjunctival space after injection. The control—without the hydrogel—mostly leaked out of that space.”

Shoichet’s lab collaborated with Jeremy Sivak, the glaucoma research chair at the Krembil Research Institute, part of the University Health Network, and an associate professor in U of T’s department of ophthalmology and vision science in the Temerty Faculty of Medicine.

Given the success of their preclinical research, the researchers are now working towards optimizing their formulation for ultimate clinical use.

“We envision a future where this non-invasive injection can be administered once every month or two in a medical office,” says Dang, who is also at Synakis, a spinoff biotechnology company founded from research in Shoichet’s lab.

“We invented this novel hydrogel as a vitreous substitute for vitreoretinal surgery, and here we show its versatility to encapsulate and release small molecule drugs.”

“There is a lot of work ahead,” adds Shoichet. “We are focused on the stability and manufacturability of our product while at the same time looking to raise funds to advance it more quickly to the clinic.”