TY - JOUR
T1 - Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles
AU - Swart, Laura E
AU - Fens, Marcel H A M
AU - van Oort, Anita
AU - Waranecki, Piotr
AU - Mata Casimiro, L Daniel
AU - Tuk, David
AU - Hendriksen, Martijn
AU - van den Brink, Luca
AU - Schweighart, Elizabeth
AU - Seinen, Cor
AU - Nelson, Ryan
AU - Krippner-Heidenreich, Anja
AU - O'Toole, Tom
AU - Schiffelers, Raymond M
AU - Kooijmans, Sander
AU - Heidenreich, Olaf
PY - 2023/5/27
Y1 - 2023/5/27
N2 - 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.
AB - 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.
U2 - 10.3390/pharmaceutics15061603
DO - 10.3390/pharmaceutics15061603
M3 - Article
C2 - 37376052
SN - 1999-4923
VL - 15
JO - Pharmaceutics
JF - Pharmaceutics
IS - 6
ER -