A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells

Kim, Yoo Chun; Hsueh, Henry T.; Shin, Moon L.; Berlinicke, Cynthia; Han, Hyounkoo; Anders, Nicole M.; Hemingway, Avelina; Leo, Kirby T.; Chou, Renee Ti; Kwon, Han Sung; Appell, Matthew B.; Rai, Usha; Kolodziejski, Patricia; Eberhart, Charles G.; Pitha, Ian; Zack, Donald J.; Ensign, Laura M.

doi:10.1007/s13346-021-00987-6

Cited by 12 publications

(13 citation statements)

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“…We next characterized how the predicted cell-penetrating properties of the peptides affected cell uptake in a retinal pigment epithelium cell line (ARPE-19). ARPE-19 cells were cultured using standard methods (non-induced, n = 3) and using culture conditions that induce melanin production (induced, n = 3) 20 . A positive correlation was observed between the measured in vitro melanin binding of the peptides and the intracellular peptide concentrations in melanin-induced cells for cell-penetrating peptides ( r = 0.77, p < 2.2 × 10 −16 ) but not non-cell-penetrating peptides ( r = 0.28, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Due to the low turnover rate of ocular melanin, a drug that can bind to melanin may accumulate in pigmented eye tissues, leading to drug toxicity or drug sequestration 18 , 19 . However, with the right balance of melanin-binding affinity and capacity, melanin may act as a sustained-release drug depot in the eye that results in prolonged therapeutic action 20 . Several drugs have been demonstrated to have intrinsic melanin binding properties due to particular physicochemical properties, which in some cases, prolongs the pharmacologic activity in the eye 20 – 22 .…”

Section: Introductionmentioning

confidence: 99%

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Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery

et al. 2023

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Sustained drug delivery strategies have many potential benefits for treating a range of diseases, particularly chronic diseases that require treatment for years. For many chronic ocular diseases, patient adherence to eye drop dosing regimens and the need for frequent intraocular injections are significant barriers to effective disease management. Here, we utilize peptide engineering to impart melanin binding properties to peptide-drug conjugates to act as a sustained-release depot in the eye. We develop a super learning-based methodology to engineer multifunctional peptides that efficiently enter cells, bind to melanin, and have low cytotoxicity. When the lead multifunctional peptide (HR97) is conjugated to brimonidine, an intraocular pressure lowering drug that is prescribed for three times per day topical dosing, intraocular pressure reduction is observed for up to 18 days after a single intracameral injection in rabbits. Further, the cumulative intraocular pressure lowering effect increases ~17-fold compared to free brimonidine injection. Engineered multifunctional peptide-drug conjugates are a promising approach for providing sustained therapeutic delivery in the eye and beyond.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery

et al. 2023

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“…While they still face significant challenges in successful implementation and translation from laboratory to clinical use, several preclinical studies are making use of gelling systems to improve drug delivery efficiency through eyedrops. One interesting recent development has been investigation into thermosensitive polymers that form gels at physiologic temperatures (207,214). These polymers could allow future eyedrops to be administered in solution at room temperature, then form a hydrogel reservoir on contact with the warmer tissue of the eye, providing an easily administered long-lasting form of ocular drug delivery.…”

Section: Eyedrop Deliverymentioning

confidence: 99%

Considerations for Polymers Used in Ocular Drug Delivery

et al. 2022

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PurposeAge-related eye diseases are becoming more prevalent. A notable increase has been seen in the most common causes including glaucoma, age-related macular degeneration (AMD), and cataract. Current clinical treatments vary from tissue replacement with polymers to topical eye drops and intravitreal injections. Research and development efforts have increased using polymers for sustained release to the eye to overcome treatment challenges, showing promise in improving drug release and delivery, patient experience, and treatment compliance. Polymers provide unique properties that allow for specific engineered devices to provide improved treatment options. Recent work has shown the utilization of synthetic and biopolymer derived biomaterials in various forms, with this review containing a focus on polymers Food and Drug Administration (FDA) approved for ocular use.MethodsThis provides an overview of some prevalent synthetic polymers and biopolymers used in ocular delivery and their benefits, brief discussion of the various types and synthesis methods used, and administration techniques. Polymers approved by the FDA for different applications in the eye are listed and compared to new polymers being explored in the literature. This article summarizes research findings using polymers for ocular drug delivery from various stages: laboratory, preclinical studies, clinical trials, and currently approved. This review also focuses on some of the challenges to bringing these new innovations to the clinic, including limited selection of approved polymers.ResultsPolymers help improve drug delivery by increasing solubility, controlling pharmacokinetics, and extending release. Several polymer classes including synthetic, biopolymer, and combinations were discussed along with the benefits and challenges of each class. The ways both polymer synthesis and processing techniques can influence drug release in the eye were discussed.ConclusionThe use of biomaterials, specifically polymers, is a well-studied field for drug delivery, and polymers have been used as implants in the eye for over 75 years. Promising new ocular drug delivery systems are emerging using polymers an innovative option for treating ocular diseases because of their tunable properties. This review touches on important considerations and challenges of using polymers for sustained ocular drug delivery with the goal translating research to the clinic.

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“…LBPs have little research on the drug delivery system for retinal diseases, and their application is limited. The methods of ocular drug delivery methods include common ophthalmic liquid/solid preparations, including gel [ 117 ], nanoparticles [ 118 ], lyophilized powder, ocular inserts, and medical contact lenses [ 119 ], which may become the direction of LBPs’ preparation development and can be actively promoted for further application research. However, the problems of drug residence time and drug permeability in the eye still need to be further explored.…”

Section: Application Prospectmentioning

confidence: 99%

Effects of Lycium barbarum L. Polysaccharides on Vascular Retinopathy: An Insight Review

Yang

Zhao

et al. 2022

Molecules

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Vascular retinopathy is a pathological change in the retina caused by ocular or systemic vascular diseases that can lead to blurred vision and the risk of blindness. Lycium barbarum polysaccharides (LBPs) are extracted from the fruit of traditional Chinese medicine, L. barbarum. They have strong biological activities, including immune regulation, antioxidation, and neuroprotection, and have been shown to improve vision in numerous studies. At present, there is no systematic literature review of LBPs on vascular retinal prevention and treatment. We review the structural characterization and extraction methods of LBPs, focus on the mechanism and pharmacokinetics of LBPs in improving vascular retinopathy, and discuss the future clinical application and lack of work. LBPs are involved in the regulation of VEGF, Rho/ROCK, PI3K/Akt/mTOR, Nrf2/HO-1, AGEs/RAGE signaling pathways, which can alleviate the occurrence and development of vascular retinal diseases in an inflammatory response, oxidative stress, apoptosis, autophagy, and neuroprotection. LBPs are mainly absorbed by the small intestine and stomach and excreted through urine and feces. Their low bioavailability in vivo has led to the development of novel dosage forms, including multicompartment delivery systems and scaffolds. Data from the literature confirm the medicinal potential of LBPs as a new direction for the prevention and complementary treatment of vascular retinopathy.

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A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells

Cited by 12 publications

References 54 publications

Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery

Machine learning-driven multifunctional peptide engineering for sustained ocular drug delivery

Considerations for Polymers Used in Ocular Drug Delivery

Effects of Lycium barbarum L. Polysaccharides on Vascular Retinopathy: An Insight Review

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