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Polymersomes scalably fabricated via flash nanoprecipitation are non-toxic in non-human primates and associate with leukocytes in the spleen and kidney following intravenous administration

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Abstract

Vesicular nanocarrier formulations confer the ability to deliver hydrophobic and hydrophilic cargos simultaneously to cells of interest in vivo. While liposomal formulations reached the clinic long ago, younger technologies such as polymeric vesicles (polymersomes) have yet to make the transition to clinical approval and use, in part due to difficulties in ensuring their safe and scalable production. In this work, we demonstrate the scalable production of poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-bl-PPS) polymersomes via flash nanoprecipitation, and further show the safe administration of these nanocarriers to mice and non-human primates. In mice, PEG-bl-PPS polymersomes were found to be well tolerated at up to 200 mg/(kg·week). Following the administration of a more relevant 20 mg/(kg·week) dosage in non-human primates, polymersomes were found to associate with numerous phagocytic immune cell populations, including a remarkable 68% of plasmacytoid dendritic cells and > 95% of macrophages in the spleen, while showing no toxicity or abnormalities in the liver, kidney, spleen, or blood. Despite the presence of a dense PEG corona, neither anti-PEG antibodies nor complement activation were detected. This work provides evidence of the translatability of PEG-bl-PPS polymersomes into the clinic for therapeutic applications in humans.

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Acknowledgements

We acknowledge staff and instrumentation support from the Structural Biology Facility at Northwestern University, the Robert H Lurie Comprehensive Cancer Center of Northwestern University and NCI CCSG P30 CA060553. The Gatan K2 direct electron detector was purchased with funds provided by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust. SAXS experiments were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by Northwestern University, E.I. DuPont de Nemours & Co., and The Dow Chemical Company. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02- 06CH11357. This work made use of the EPIC facility of Northwestern University’s NUANCE Center, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN. This work made use of the IMSERC at Northwestern University, which has received support from the NSF (CHE-1048773); Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205); the State of Illinois and International Institute for Nanotechnology (IIN). This work was supported by the Northwestern University–Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI CA060553). Imaging work was performed at the Northwestern University Center for Advanced Molecular Imaging generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. The authors acknowledge Jonathan Remis (Structural Biology Facility, NU) for his contribution to cryoTEM image acquisition. We acknowledge Sierra M. Paxton and Courtney R. Burkett for their excellent technical assistance with the NHP study.

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Authors and Affiliations

  1. Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, 60208, USA

    Sean D. Allen & Evan A. Scott

  2. Department of Biomedical Engineering, Northwestern University, Evanston, 60208, IL, USA

    Yu-Gang Liu, Sharan Bobbala & Evan A. Scott

  3. Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, 40506, USA

    Lei Cai, Peter I. Hecker & Ryan Temel

  4. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, 40506, USA

    Peter I. Hecker & Ryan Temel

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  1. Sean D. Allen
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  2. Yu-Gang Liu
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  3. Sharan Bobbala
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  4. Lei Cai
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  7. Evan A. Scott
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Correspondence to Evan A. Scott.

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Allen, S.D., Liu, YG., Bobbala, S. et al. Polymersomes scalably fabricated via flash nanoprecipitation are non-toxic in non-human primates and associate with leukocytes in the spleen and kidney following intravenous administration. Nano Res. 11, 5689–5703 (2018). https://doi.org/10.1007/s12274-018-2069-x

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