{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:14:56Z","timestamp":1780107296843,"version":"3.54.0"},"reference-count":88,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Domp\u00e9 Pharmaceutics"},{"name":"Levy-Longenbaugh Donor-Advised Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Nerve growth factor (NGF) plays a critical neuroprotective role in retinal health, supporting neuronal survival and regeneration. Recombinant human NGF (rhNGF) holds promise for treating retinal degenerative diseases such as glaucoma, retinitis pigmentosa, and optic neuropathies. However, efficient retinal delivery of rhNGF remains a major challenge due to anatomical barriers and rapid clearance from conventional routes. Here, we integrate in vivo experimentation with mathematical modeling to identify and validate optimized delivery strategies for rhNGF. By using stable isotope-labeled rhNGF, we quantified ocular biodistribution in rats and rabbits following topical eye drops, intravitreal (IVT) injections, and sustained-release formulations. Eye drop administration resulted in negligible retinal exposure (&amp;lt;0.04% of instilled dose), while IVT injection achieved \u223c34% vitreous retention with sustained delivery to the retina and optic nerve over 60 days. A mechanistic compartmental model was developed and validated against the in vivo data to simulate route-specific drug transport and estimate delivery losses via a penalty factor (fB). The model identified key parameters governing retinal exposure and guided the design of dose-release profiles to sustain therapeutic concentrations. Controlled-release platforms, such as bioadhesive tablets and gels, exhibited in vitro release rates (0.002\u20130.015\u2005h\u207b\u00b9) aligned with model-predicted requirements for prolonged exposure. Together, these results highlight the importance of route-specific delivery design and demonstrate that combining isotope tracing with mechanistic modeling can quantitatively guide development of long-acting retinal therapeutics. This platform provides a translational framework for optimizing macromolecular drug delivery to the posterior eye.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgaf250","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T23:06:08Z","timestamp":1755039968000},"source":"Crossref","is-referenced-by-count":2,"title":["Human nerve growth factor delivery to the retina: Quantitative methodology and mathematical modeling in preclinical settings"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1691-6115","authenticated-orcid":false,"given":"Simone L","family":"Mattioli","sequence":"first","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , Napoli, Campania 80131 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6722-7371","authenticated-orcid":false,"given":"Prashant","family":"Dogra","sequence":"additional","affiliation":[{"name":"Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute , Houston, TX 77030 ,","place":["USA"]},{"name":"Department of Physiology & Biophysics, Weill Cornell Medical College , New York, NY 10021 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1939-4137","authenticated-orcid":false,"given":"Francesco","family":"Longobardi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Bari Aldo Moro , Bari, Puglia 70121 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Casiello","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Bari Aldo Moro , Bari, Puglia 70121 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Apparente","sequence":"additional","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , Napoli, Campania 80131 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Detta","sequence":"additional","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , Napoli, Campania 80131 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubina","family":"Novelli","sequence":"additional","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , Milan, Lombardy 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Aramini","sequence":"additional","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , L\u2019Aquila, Abruzzo 67100 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franca","family":"Cattani","sequence":"additional","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , L\u2019Aquila, Abruzzo 67100 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria I","family":"Antonangeli","sequence":"additional","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , L\u2019Aquila, Abruzzo 67100 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Romeo","sequence":"additional","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , L\u2019Aquila, Abruzzo 67100 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-0233","authenticated-orcid":false,"given":"Marcello","family":"Allegretti","sequence":"additional","affiliation":[{"name":"Research & Development, Domp\u00e9 Pharmaceutics , L\u2019Aquila, Abruzzo 67100 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6262-700X","authenticated-orcid":false,"given":"Zhihui","family":"Wang","sequence":"additional","affiliation":[{"name":"Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute , Houston, TX 77030 ,","place":["USA"]},{"name":"Department of Physiology & Biophysics, Weill Cornell Medical College , New York, NY 10021 ,","place":["USA"]},{"name":"Neal Cancer Center, Houston Methodist Research Institute , Houston, TX 77030 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9819-2597","authenticated-orcid":false,"given":"Cleide G","family":"Machado","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of S\u00e3o Paulo Medical School , S\u00e3o Paulo, SP 054003 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4155-9324","authenticated-orcid":false,"given":"Renata","family":"Pasqualini","sequence":"additional","affiliation":[{"name":"Rutgers Cancer Institute , Newark, NJ 07101 ,","place":["USA"]},{"name":"Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School , Newark, NJ 07103 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8686-4584","authenticated-orcid":false,"given":"Wadih","family":"Arap","sequence":"additional","affiliation":[{"name":"Rutgers Cancer Institute , Newark, NJ 07101 ,","place":["USA"]},{"name":"Division of Hematology\/Oncology, Department of Medicine, Rutgers New Jersey Medical School , Newark, NJ 07103 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7909-4278","authenticated-orcid":false,"given":"Vittorio","family":"Cristini","sequence":"additional","affiliation":[{"name":"Mathematics in Medicine Program, Department of Medicine, Houston Methodist Research Institute , Houston, TX 77030 ,","place":["USA"]},{"name":"Neal Cancer Center, Houston Methodist Research Institute , Houston, TX 77030 ,","place":["USA"]},{"name":"Physiology, Biophysics, & Systems Biology Program, Graduate School of Medical Sciences, Weill Cornell Medicine , New York, NY 10021 ,","place":["USA"]},{"name":"Department of Imaging Physics, University of Texas M.D. Anderson Cancer Center , Houston, TX 77030 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