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NANYANG INSTITUTE OF TECHNOLOGY IN HEALTH & MEDICINE Ph. D Project Proposal for IGS @ NITHM Each proposal must satisfy the following requirements: 1) One Supervisor and one Co-Supervisor (Co-Supervisor must be from another School; can be Adjuncts) 2) One clinician collaborator is highly recommended 3) Length of proposal should be capped within 2 pages Programme: Diagnostic Medical Devices X-omics Therapeutic Medical Devices Medical Imaging and Signal Analysis x Nanomedicine Tissue Engineering Drug Discovery, Systems Biology and Synthetic Biology Health Systems Complexity Project Topic: Bioactivity and controlled release studies of proteins in nanocarriers Supervisor: Subbu Venkatraman School/College: MSE Co-Supervisor: Peter Preiser School/College: SBS Clinician Collaborator: Tina Wong Institution: SERI Is research funding available for the project? x Yes No SCOPE OF THE PROJECT Present scope of the project that the student will address For retinal diseases, included macular degeneration, anti -angiogenesis factors are injected intravitreally to the back of the eye, using a painful inject ion that sometimes also leads to infections. Our approach is to use nanocarriers encapsulating the anti -angiogenesis factor, as a sub-conjuctival injection, followed by transport across the sclera to the back of the eye. While other researchers will focus on trans-scleral transport studies, this student will work on maximizing the loading of the protein into the nanocarriers, as well as controlling the release of the protein from the carriers. This is to be accomplished by enhancing the interaction of the protein with the carrier molecules; such interactions include electrostatic, hydrogen -bonding as well as hydrophobic interactions. As the carriers are based on liposomes, and polyelectrolyte coated nanoparticles, the composition of the liposomal molecules as well as of the polyelectrolyte will be varied to maximize the interactions, which could also be influenced by the pH. Active methods of loading the proteins into the core of the liposome will be explored. For the nanoparticles, we will attempt to load t he core using double-emulsion methods. Both of these approaches will have different effects on the protein bioactivity, which will be assessed by existing methods. Factors affecting the release of the encapsulated protein will be studied using standard in vitro methodologies. We will also assess the bioactivity of the released protein. Based on the compositions and the interactions (assessed via iso -thermal calorimetry) we will formulate a model to predict the release behaviour. STATAMENT OF NEED Describe medical problem that the project will attempt to address Age-related macular degeneration is characterized by the growth of unwanted blood vessels in the retina, in the case of the so-called wet version of AMD. This is the predominant version, and is currently treated with intra-vitreal injections of anti-angiogenesis factors (bevacizumab and ranibizumab; which are vastly different in molar mass). The intra-vitreal injections are painful and not patient-friendly, and need to be repeated at 3-month intervals. There is a clear need for a less-invasive option for the patient, which also needs to be a sustained therapy (not daily administration). The availability of this option for the patients will in all likelihood increase the number of patients opting for treatment of the condition, even if it means somewhat more frequent doctor visits. PROPOSED SOLUTION Describe proposed solution to the medical problem Our proposed solution is a formulation of the anti -angiogenesis factor that may be delivered via the more friendly, less invasive sub-conjuctival injection. The approach is to encapsulate the protein into nano-sized carriers for sub-conjuctival injection. The carriers may release some of their payload in the sub-conjuctival space and the released protein can be transported trans-sclerally into the posterior segment of the eye. It is also likely that some of the carriers are transported trans-sclerally with intact payload. For the purposes of the therapeutic benefit, either way of getting the protein to the back of the eye is acceptable. However, the duration of the therapeutic effect will vary depending on how the protein is transported across the sclera (ie, as a protein molecule or encapsulated). This project will study the release kinetics and bioactiv ity of the released protein from various carriers, and correlate them to trans -scleral transport kinetics.