The wet form of age-related macular degeneration (AMD) accounts for 90% of all AMD-related blindness and affects 1.5 million people with 200,000 new cases each year in the US. Minimally invasive and selective drug delivery to the eye still remains an open challenge; the current standard of care involves delivery of anti- vascular endothelial growth factor (anti-VEGF) drugs via intraocular injection. For patients refractory to anti- VEGF drugs, photodynamic therapy (PDT) is the standard of care. Clinical efficacy of PDT depends on significant accumulation of the photosensitizer (PS) at the choroid neovasculature (CNV), availability of oxygen near the PS, and effective dosing of the drug-light combination. Our new platform for delivery and imaging of PS, entitled the Photodynamic therapy NanoDroplet (PtND) will enhance all three of these areas, raising PDT's therapeutic index and enabling PDT to become a frontline clinical wet AMD therapy. PtND comprises a core of oxygen-rich liquid perfluorocarbon (PFC) containing indocyanine green (ICG) dye stabilized by a lipid shell which both houses the photosensitizer (PS) and provides binding sites for conjugating choroid targeting moieties. Following intravitreal injection, PtND will transcytose through the retinal pigment epithelium, bind with choroid neovessels, and undergo receptor-mediated endocytosis. Interestingly, the ICG dye is used to trigger a liquid to gas phase change of the PFC which serves two purposes: (1) it delivers PS and additional O2 to the cell cytosol and (2) the vaporization event creates a giant acoustic transient which can be used in combined photoacoustic and ultrasound (PAUS) imaging to visualize the distribution of drug delivery at the CNV. From the rich spatial information received by PAUS imaging of the drug distribution, light intensity and duration dosimetry for the choroid region can be calculated. This personalized dosimetry will ensure patients receive the correct dose for their disease burden. The promise of PDT to provide localized therapy with minimal residual damage or systemic side effects is remarkable. The proposed PtND platform is poised to enhance delivery of PS to CNV, increase efficacy of PDT through companion O2 delivery, and ultimately deliver a personalized patient specific dose enabled by PAUS imaging. The overall goal of our project is to demonstrate that PtND can raise the therapeutic index of PDT in vivo, leading to a decrease in required treatments for wet AMD, and ultimately replace the need for anti-VEGF drugs which carry a risk of systemic side effects. Overall we are excited to develop this nanoplatform for PDT that will remove the roadblocks to widespread use of this important clinical treatment.
Project Terms: Acids; Acoustics; Adverse effects; Affect; Age; Age related macular degeneration; antiangiogenesis therapy; Area; base; bevacizumab; Binding; Binding Sites; Blindness; Blood Vessels; burden of illness; Cells; Choroid; Clinical; clinical development; clinical efficacy; Clinical Treatment; commercialization; Companions; Custom; Cytosol; Developed Countries; Dose; dosimetry; Drug Delivery Systems; drug distribution; Dyes; Endothelial Cells; Ensure; Event; experience; Eye; Fluorocarbons; Future; Gases; Goals; Growth; Human; Image; improved; In Vitro; in vivo; Indocyanine Green; Injections; intravitreal injection; Laboratories; Letters; Light; light intensity; Lipids; Liquid substance; Local Therapy; macula; minimally invasive; mouse model; nanoDroplet; nanoformulation; nanoparticle; nanoproducts; neovasculature; Ophthalmology; Oxygen; Patients; Pharmaceutical Preparations; Phase; phase change; photoacoustic imaging; Photosensitization; Provider; PUVA Photochemotherapy; receptor mediated endocytosis; Recombinants; Refractory; Residual state; Retinal; RGD (sequence); Risk; standard of care; Structure of retinal pigment epithelium; Testing; Therapeutic Index; therapy outcome; Ultrasonography; vaporization; Vascular Endothelial Growth Factors; Vision; Work;
