Project 4

Ocular Drug Delivery Study

Head of Project: Mark Kester Ph.D.

 

Specific Aims:

The overall goal of this Ocular Drug Delivery Technology Project is to develop improved means to deliver minimally- or non-invasive controlled-release and/or targeted drug therapies to the eye. The specific objective of this project is to develop subconjunctivally implantable hydrogels for sustained release of neuroprotective insulin, and subconjunctivally/topically administrated nanoliposomes for targeted release of anti-inflammatory dexamethasone, and neuroprotective and anti-inflammatory (bifunctional) doxycycline, to retard the development and progression of early diabetic retinopathy.

 

Accomplishments:

To this end, we previously achieved our first milestone in designing and synthesizing hydrogels with thermoresponsive and biodegradable properties that can load insulin with above 50% loading efficiency and can sustain insulin release for two months and even longer (=5 months). We now report that, we have achieved our first milestone in designing and synthesizing hydrogels with thermoresponsive and biodegradable properties that can load intact insulin with above 50% loading efficiency. The hydrogels can sustain insulin release for two months and even longer (=5 months) in vitro and at least one week with detectable insulin amount in the retinas after subconjunctival implantation. Importantly, the developed hydrogels not only are well tolerated by animals for at least 2 months after subconjunctival implantation, but also release biologically active insulin that can increase Akt phosphorylation, insulin receptor and insulin like growth factor I receptor tyrosine phosphorylation of normal ex vivo retinas, and dramatically decrease the DNA fragmentation of the retinas of diabetic rats for at least one week after subconjunctival implantation without changing the blood glucose level. The results clearly indicate that our hydrogel/insulin systems have strong potential as therapeutics to treat diabetic retinopathy.

 

Moreover, we have also met the first milestone for the nanoliposome project. We have conclusively demonstrated that 70nm-sized highly pegylated nanoliposomes can target the peripheral segments of the rat eye. We demonstrated that subconjunctival and, more importantly, topical administration of fluorescent nanoliposomes intercolate within retinal neurons, capillaries and pigmented epithelial cells. Over the last year, we now demonstrate that we can encapsulate the anti-inflammatory agent doxycycline within nanoliposomes at therapeutic concentrations. Using retinal neuronal cell lines, we now demonstrate that our doxycycline-loaded nanoliposomes are non-toxic at the in vivo dosages administered.

 

Who benefits from this research?:

  This project is innovative and highly translational. The developed insulin-impregnated hydrogels and doxycycline/dexamethasone-encapsulated nanoliposomes will have great potential to be transferred into a novel, clinically useful and minimally invasive therapy to reduce the risk of diabetic retinopathy in type 1 diabetes— bench to bedside.

 

Future Plans:

In the future, we will continue our efforts on optimizing the hydrogels, and assessing in vitro and in vivo effects of insulin-loaded hydrogels on retinal cell survival and vascular permeability of diabetic rats after subconjunctival implantation to achieve our milestones of the hydrogel-insulin project.

 

Similarly for the nanoliposome project, we are presently designing experiments to evaluate the mechanism by which nanoliposomes can deliver therapeutics to retinal tissues via topical administration. We are also formulating nanoliposomes that contain maleimide-linked phospholipids that will be to create immunoliposomes for more specific cellular targeting. Finally, we have begun to assess the efficacy of doxycycline-loaded nanoliposomes after topical or subconjunctival administration in models of diabetic retinopathy.