Biodistribution of Polymeric Nanoparticles following in utero Delivery to a Nonhuman Primate

David A Eaton; Anna Y Lynn; Juliana M Surprenant; Emily I Deschenes; Mary Elizabeth Guerra; Rachel Rivero; Nicholas K Yung; Merissa O'Connor; Peter M Glazer; Mert Ozan Bahtiyar; W Mark Saltzman; David H Stitelman

doi:10.1159/000543138

Biodistribution of Polymeric Nanoparticles following in utero Delivery to a Nonhuman Primate

Biomed Hub. 2024 Dec 12;10(1):23-32. doi: 10.1159/000543138. eCollection 2025 Jan-Dec.

Authors

David A Eaton^{1

2}, Anna Y Lynn¹, Juliana M Surprenant¹, Emily I Deschenes^{1

2}, Mary Elizabeth Guerra¹, Rachel Rivero¹, Nicholas K Yung¹, Merissa O'Connor³, Peter M Glazer^{4

5}, Mert Ozan Bahtiyar⁶, W Mark Saltzman^{2

7

8

9}, David H Stitelman^{1

6}

Affiliations

¹ Departments of Surgery, Yale School of Medicine, New Haven, CT, USA.
² Departments of Biomedical Engineering, Yale University, New Haven, CT, USA.
³ Virscio, Inc, New Haven, CT, USA.
⁴ Departments of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
⁵ Departments of Genetics, Yale School of Medicine, New Haven, CT, USA.
⁶ Departments of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
⁷ Departments of Chemical and Environmental Engineering, Yale University, New Haven, CT, USA.
⁸ Departments of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA.
⁹ Departments of Dermatology, Yale University, New Haven, CT, USA.

Abstract

Introduction: Monogenic diseases can be diagnosed before birth. Systemic fetal administration of nanoparticles (NPs) grants therapeutic access to developing stem cell populations impacted by these classes of disease. Delivery of editing reagents in these NPs administered before birth has yielded encouraging results in preclinical mouse models of monogenic diseases.

Methods: To translate this strategy clinically, the safety and efficacy of this strategy in larger animals will be necessary. We performed a pilot biodistribution study in 3 fetal nonhuman primates (NHPs) in mid-gestation examining systemic delivery of polymeric NPs loaded with fluorescent dye.

Results: We found several similarities in distribution to our experience in mice, namely, extensive uptake in fetal liver and spleen. A striking finding that is not recapitulated in the mouse was the accumulation of NPs in the zones of proliferation and ossification of the fetal bone. Of great importance, there did not appear to be NP accumulation in the fetal male or female germline zones or maternal tissue.

Conclusion: These studies were vital to the next step of testing editing reagents in the fetal NHP with a goal of treating monogenic diseases before birth.

Keywords: Biodistribution; Fetal therapy; Nonviral vehicles; Polymeric nanoparticles; Quantitative microscopy.

Grants and funding

This work was supported by a grant from the National Institutes of Health (NIH R01 EB032791). D.H.S. was supported by a grant from the American Surgical Association Foundation Award (AWD0003330). A.Y.L. was supported by an F30 Individual Predoctoral Fellowship from the NIH NICHD (F30 HD106692) and the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM13665. The funders had no role in the design, data collection, data analysis, and reporting of this study.