Periodic Reporting for period 1 - Light4Sight (Light-activated carriers for the controlled delivery of therapeutic peptides in posterior segment eye diseases)
Reporting period: 2019-11-01 to 2021-10-31
Recent report from the Global Health Commission estimated that in 2020 596 million people around the world had distance vision impairment and the number is expected to increase to 895 million by 2050. Ocular diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR) and glaucoma, pose a serious threat to vision as structures of the back of the eye, such as retina, choroid or macula, are affected in these diseases. Current therapies to treat posterior eye diseases require long-term treatments and invasive methods to ensure that adequate drug levels reach the back of the eye, while causing patients’ discomfort and risk of inflammation. Hence, the development of safe and efficient therapies to treat these diseases is crucial to improve patient’s quality of life and decrease the burden in healthcare systems. In the Light4Sight project, a delivery system was developed for the release of therapeutics in the vitreous humour for the treatment of posterior segment ocular disorders. Hyaluronic acid, the main component of the vitreous, was used and modified with light sensitive small molecules to produce a supramolecular hydrogel that disassembles and releases the cargo upon light irradiation. The overarching goal on the hydrogel design is to control and predict the release of different molecular therapeutics (e.g. macromolecules and small molecules) by light stimulation, as well as to provide an intra-ocular drug delivery platform for potential clinical applications.
Work performed from the beginning of the project to the end of the period:
Light sensitive supramolecular hydrogels, that allow long-term and on-demand release of therapeutics into the vitreous for the treatment of posterior eye disorders, were designed, synthesized and characterized. The properties of the light sensitive supramolecular hydrogels, including microstructure, rheology, stability, injectability and ability to controllably release loaded cargos, were confirmed and the bioactivity (therapeutic effect) of the loaded cargos was assessed in an in vitro model of angiogenesis. Therapeutic peptides with reported anti-angiogenic activity were synthesized and modified to drive their self-assembly into stable nanostructures. Their integration in light sensitive supramolecular hydrogels was attained by investigating their interaction with the hydrogel components. Using an established in vitro model of angiogenesis, the anti-angiogenic effect of the hydrogels containing therapeutic peptides was investigated.
Description of main results achieved so far:
A light-sensitive supramolecular hydrogel was successfully developed as designed and its rheological properties, injectability, both in solution and in an ex vivo ocular model, were characterized. The hydrogel can be easily injected, being stable in both phosphate buffer saline solution (pH 7.4) and in the vitreous humour. The supramolecular hydrogel was shown to have a high loading capacity for a model protein and its light sensitivity is able to regulate the release of the model protein up to 30 days. This result indicates the possibility to use this hydrogel for the delivery of other macromolecular proteins, such as antibodies used clinically. In addition, a series of anti-angiogenic peptides, as well some peptide variations, were successfully synthesized and their interactions with the hydrogel components studied. Peptides with aromatic residues were found to generate stronger interactions with the hydrogel components. The interaction between hydrogel component and the peptides was shown to be beneficial, not only by reducing their cytotoxicity, but their combination in the hydrogel also generated a stronger anti-angiogenic effect compared to the peptide alone. These results show that the interaction between hydrogel component and peptides can affect the way in which these peptides originally act on cells, which is worthy for further research to develop new clinical treatment methods with small molecules.
We have attended several workshops and international conference to introduce our ocular delivery platform. In addition, a review paper entitled Supramolecular Hydrogels for Protein Delivery in Tissue Engineering was published to discuss the importance of supramolecular hydrogels as delivery system.
Light sensitive supramolecular hydrogels, that allow long-term and on-demand release of therapeutics into the vitreous for the treatment of posterior eye disorders, were designed, synthesized and characterized. The properties of the light sensitive supramolecular hydrogels, including microstructure, rheology, stability, injectability and ability to controllably release loaded cargos, were confirmed and the bioactivity (therapeutic effect) of the loaded cargos was assessed in an in vitro model of angiogenesis. Therapeutic peptides with reported anti-angiogenic activity were synthesized and modified to drive their self-assembly into stable nanostructures. Their integration in light sensitive supramolecular hydrogels was attained by investigating their interaction with the hydrogel components. Using an established in vitro model of angiogenesis, the anti-angiogenic effect of the hydrogels containing therapeutic peptides was investigated.
Description of main results achieved so far:
A light-sensitive supramolecular hydrogel was successfully developed as designed and its rheological properties, injectability, both in solution and in an ex vivo ocular model, were characterized. The hydrogel can be easily injected, being stable in both phosphate buffer saline solution (pH 7.4) and in the vitreous humour. The supramolecular hydrogel was shown to have a high loading capacity for a model protein and its light sensitivity is able to regulate the release of the model protein up to 30 days. This result indicates the possibility to use this hydrogel for the delivery of other macromolecular proteins, such as antibodies used clinically. In addition, a series of anti-angiogenic peptides, as well some peptide variations, were successfully synthesized and their interactions with the hydrogel components studied. Peptides with aromatic residues were found to generate stronger interactions with the hydrogel components. The interaction between hydrogel component and the peptides was shown to be beneficial, not only by reducing their cytotoxicity, but their combination in the hydrogel also generated a stronger anti-angiogenic effect compared to the peptide alone. These results show that the interaction between hydrogel component and peptides can affect the way in which these peptides originally act on cells, which is worthy for further research to develop new clinical treatment methods with small molecules.
We have attended several workshops and international conference to introduce our ocular delivery platform. In addition, a review paper entitled Supramolecular Hydrogels for Protein Delivery in Tissue Engineering was published to discuss the importance of supramolecular hydrogels as delivery system.
Currently, intravitreal injection is the most effective method to treat posterior ocular diseases by delivering drugs closer to their target. In fact, intravitreal injection of anti-VEGF (vascular endothelial growth factor) agents has become the first-line treatment used clinically. Current marketed biologics for retina diseases are antibodies, which are proteins with relatively longer half-life compared to small molecules. However, multiple dosing is still needed to maintain sufficient drug levels to reach the structures at the back of the eye. Treatment with small molecules is not easily achieved since their half-life is much shorter than proteins (usually less than 10 hours), requiring dosing intervals that are too short to be clinically acceptable. Here, a light-responsive supramolecular hydrogel with high drug loading capacity for a model protein was developed. The hydrogel would enable the administration of higher doses in a single injection, for long term sustained release, while preventing rapid clearance of the protein drugs in the vitreous humour. In addition, the light sensitivity of the hydrogel provides the possibility for on-demand release of the protein cargo, enabling more precise control overdosing. The hydrogel delivery system can also be used to deliver small molecules, such as anti-angiogenic peptides, which are simpler molecular therapeutics. The interaction between the hydrogel components and the peptides reduced the toxicity of positively charged peptides and the anti-angiogenic activity was observed for 3 weeks in an in vitro model of angiogenesis. The ultimate goal is to provide a light responsive system for intra-ocular delivery of various types of drugs where higher amounts of therapeutics can be loaded to achieve extended release for several weeks or months and minimize patient’s noncompliance with medical treatments. Findings in this project demonstrate the possibility to engineer interactions between small peptide molecules and hydrogel components to provide a robust and effective strategy for their long-term delivery in the vitreous. Overall, this project developed a new delivery system expected to improve the intraocular delivery of therapeutics for treating a number of diseases affecting the back of the eye and patient’s compliance.