Comprehensive ocular and systemic safety evaluation of polysialic acid-decorated immune modulating therapeutic nanoparticles (PolySia-NPs) to support entry into first-in-human clinical trials

Anitha Krishnan, David G Callanan, Victor G Sendra, Amit Lad, Sunny Christian, Ravinder Earla, Ali Khanehzar, Andrew J Tolentino, Valory Anne Sarmiento Vailoces, Michelle K Greene, Christopher J Scott, Derek Y Kunimoto, Tarek S Hassan, Mohamed A Genead, Michael J Tolentino

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Abstract

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using strains and , with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation.
Original languageEnglish
Article number481
Number of pages21
JournalPharmaceuticals (Basel, Switzerland)
Volume17
Issue number4
DOIs
Publication statusPublished - 09 Apr 2024

Keywords

  • macular degeneration
  • polysialic acid
  • toxicity
  • geographic atrophy
  • nanoparticle
  • intravenous administration
  • intravitreal administration

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