Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2023 Jun 28

PMID 37376052

Authors

Laura E Swart

Marcel H A M Fens

Anita van Oort

Piotr Waranecki

L Daniel Mata Casimiro

David Tuk

Martijn Hendriksen

Luca van den Brink

Elizabeth Schweighart

Cor Seinen

Ryan Nelson

Anja Krippner-Heidenreich

Tom OToole

Raymond M Schiffelers

Sander Kooijmans

Olaf Heidenreich

Affiliations

Soon will be listed here.

Abstract

Lipid nanoparticles (LNPs) have evolved rapidly as promising delivery systems for oligonucleotides, including siRNAs. However, current clinical LNP formulations show high liver accumulation after systemic administration, which is unfavorable for the treatment of extrahepatic diseases, such as hematological disorders. Here we describe the specific targeting of LNPs to hematopoietic progenitor cells in the bone marrow. Functionalization of the LNPs with a modified Leu-Asp-Val tripeptide, a specific ligand for the very-late antigen 4 resulted in an improved uptake and functional siRNA delivery in patient-derived leukemia cells when compared to their non-targeted counterparts. Moreover, surface-modified LNPs displayed significantly improved bone-marrow accumulation and retention. These were associated with increased LNP uptake by immature hematopoietic progenitor cells, also suggesting similarly improved uptake by leukemic stem cells. In summary, we describe an LNP formulation that successfully targets the bone marrow including leukemic stem cells. Our results thereby support the further development of LNPs for targeted therapeutic interventions for leukemia and other hematological disorders.

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