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Drug Delivery

Drug Delivery - Poster Session D

Poster X12 - A peptide-sunitinib conjugate provides sustained retinal neuroprotection with topical administration

Friday, October 25, 2024
3:30 PM – 4:30 PM EST
Location: Exhibit Hall E, F & G

Introduction:  Delivery of therapeutics to the posterior segment of the eye is usually done via injections, such as intravitreal or intracameral. However, topical administration is the most common ocular delivery system due to its ease-of-use; but steps need to be taken to improve its bioavailability in the posterior segment. We previously engineered a hypotonic thermo-sensitive gel using F127, designed to gel on the surface of the eye. We have shown that this gelling system can successfully deliver sunitinib to the posterior segment of the eye and protect retinal ganglion cells from damage. To further extend the effect of sunitinib, we conjugated it to our previously engineered multifunctional peptide, HR97. This peptide is capable of melanin binding, high cell penetration, and low toxicity. We combined these two technologies into a simple sustained release system to assess its retinal neuroprotective function.

Materials and

Methods:  The multifunctional peptide (HR97) was conjugated to sunitinib (HR97-sunitinib) via a traceless linker. The conjugate was evaluated in vitro for its multifunctional properties. The conjugate was then loaded into the thermo-sensitive gel. Finally, the conjugate-gel was topically administered to Brown Norway rats daily for a week after an optic nerve head crush, after which the retinal ganglion cells (RGCs) were collected at various timepoints and counted using a TensorFlow Object Detection program.

Results, Conclusions, and Discussions: In vitro experiments revealed that the conjugate amplified the melanin binding and cellular penetration of sunitinib. Concerning melanin binding, the HR97-sunitinib conjugate amplified the melanin binding capacity of sunitinib with a Kd of 7.30×10^(-6)M compared to one of 5.51×10^(-6)M. In vivo trials in Brown Norway rats showed the HR97-sunitinib gel-forming eye drop protected RGC density for up to 2 weeks after administration compared to controls.
The results indicate that the combination of the multifunctional peptide and the hypotonic gelling system allowed sunitinib to reach the posterior segment of the eye and protect RGC density for an extended period of time. Additionally, we learned that amplifying the melanin binding of sunitinib was vital to create a drug depot in the posterior region of the eye and maintain the neuroprotective effects for multiple weeks.
Glaucoma affects over 80 million people worldwide and is the leading cause of irreversible blindness globally. The standard of care is eye drops to reduce the intraocular pressure; however, in some cases, RGC damage can proceed independently of ocular hypertension. Therefore, we explored using sunitinib, a DLK inhibitor investigated for its RGC neuroprotective ability. While eyedrops are the standard of care for both glaucoma and many ocular diseases, the limited bioavailability and adherence from patients reduces its effectiveness. To keep the simplicity of eyedrops while increasing the bioavailability of the therapeutic and extending its effect, a sunitinib-HR97 conjugate was loaded into a thermo-sensitive gel. Understanding the therapeutic efficacy of this system is limited by in vivo studies in rats, but future studies in larger animals will help understand the translatability of the system.

Acknowledgements (Optional):  This work was supported by the National Institutes of Health (R01EY026578, R01EY031041).