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

doi:10.3390/ph17040481

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

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

43 Downloads (Pure)

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 language	English
Article number	481
Number of pages	21
Journal	Pharmaceuticals (Basel, Switzerland)
Volume	17
Issue number	4
DOIs	https://doi.org/10.3390/ph17040481
Publication status	Published - 09 Apr 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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10.3390/ph17040481Licence: CC BY

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
Copyright 2024 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 5.25 MBLicence: CC BY

Cite this

Krishnan, A., Callanan, D. G., Sendra, V. G., Lad, A., Christian, S., Earla, R., Khanehzar, A., Tolentino, A. J., Vailoces, V. A. S., Greene, M. K., Scott, C. J., Kunimoto, D. Y., Hassan, T. S., Genead, M. A., & Tolentino, M. J. (2024). 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. Pharmaceuticals (Basel, Switzerland), 17(4), Article 481. https://doi.org/10.3390/ph17040481

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title = "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",

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.",

keywords = "macular degeneration, polysialic acid, toxicity, geographic atrophy, nanoparticle, intravenous administration, intravitreal administration",

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

year = "2024",

month = apr,

day = "9",

doi = "10.3390/ph17040481",

language = "English",

volume = "17",

journal = "Pharmaceuticals (Basel, Switzerland)",

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Krishnan, A, Callanan, DG, Sendra, VG, Lad, A, Christian, S, Earla, R, Khanehzar, A, Tolentino, AJ, Vailoces, VAS, Greene, MK , Scott, CJ, Kunimoto, DY, Hassan, TS, Genead, MA & Tolentino, MJ 2024, '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', Pharmaceuticals (Basel, Switzerland), vol. 17, no. 4, 481. https://doi.org/10.3390/ph17040481

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. / Krishnan, Anitha; Callanan, David G; Sendra, Victor G et al.
In: Pharmaceuticals (Basel, Switzerland), Vol. 17, No. 4, 481, 09.04.2024.

Research output: Contribution to journal › Article › peer-review

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T1 - 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

AU - Krishnan, Anitha

AU - Callanan, David G

AU - Sendra, Victor G

AU - Lad, Amit

AU - Christian, Sunny

AU - Earla, Ravinder

AU - Khanehzar, Ali

AU - Tolentino, Andrew J

AU - Vailoces, Valory Anne Sarmiento

AU - Greene, Michelle K

AU - Scott, Christopher J

AU - Kunimoto, Derek Y

AU - Hassan, Tarek S

AU - Genead, Mohamed A

AU - Tolentino, Michael J

PY - 2024/4/9

Y1 - 2024/4/9

N2 - 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.

AB - 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.

KW - macular degeneration

KW - polysialic acid

KW - toxicity

KW - geographic atrophy

KW - nanoparticle

KW - intravenous administration

KW - intravitreal administration

U2 - 10.3390/ph17040481

DO - 10.3390/ph17040481

M3 - Article

C2 - 38675441

SN - 1424-8247

VL - 17

JO - Pharmaceuticals (Basel, Switzerland)

JF - Pharmaceuticals (Basel, Switzerland)

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M1 - 481

ER -

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

Abstract

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Keywords

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