TY - JOUR
T1 - Controlled delivery of gold nanoparticle-coupled miRNA therapeutics via an injectable self-healing hydrogel
AU - van der Ven, Casper F T
AU - Tibbitt, Mark W
AU - Conde, João
AU - van Mil, Alain
AU - Hjortnaes, Jesper
AU - Doevendans, Pieter A
AU - Sluijter, Joost P G
AU - Aikawa, Elena
AU - Langer, Robert S
N1 - Funding Information:
This research was funded by the National Institutes of Health (NIH) R01 grants R01HL 141719, R01HL136431 and R01HL147095 (E.A.); the National Institutes of Health grant EB000244 (to R.L.); the Netherlands CardioVascular Research Initiative (CVON: The Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Science) and Vrienden UMC Utrecht (C.V., J.S.); an unrestricted grant from CELLINK to Vrienden UMC Utrecht (C.V., J.S.); the Harvard Catalyst Advanced Microscopy Pilot grants (C.V., E.A.); and the NIH Ruth L. Kirschstein National Research Service Award F32HL122009 (M.W.T.). J.C. acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers. We thank the Harvard Center for Biological Imaging for infrastructure and support, in particular Dr D. Richardson and S. Terclavers. The authors would like to thank Elia Guzzi for assistance with hydrogel preparation.
Publisher Copyright:
© 2021 The Royal Society of Chemistry.
PY - 2021/12/28
Y1 - 2021/12/28
N2 - Differential expression of microRNAs (miRNAs) plays a role in many diseases, including cancer and cardiovascular diseases. Potentially, miRNAs could be targeted with miRNA-therapeutics. Sustained delivery of these therapeutics remains challenging. This study couples miR-mimics to PEG-peptide gold nanoparticles (AuNP) and loads these AuNP-miRNAs in an injectable, shear thinning, self-assembling polymer nanoparticle (PNP) hydrogel drug delivery platform to improve delivery. Spherical AuNPs coated with fluorescently labelled miR-214 are loaded into an HPMC-PEG-b-PLA PNP hydrogel. Release of AuNP/miRNAs is quantified, AuNP-miR-214 functionality is shown in vitro in HEK293 cells, and AuNP-miRNAs are tracked in a 3D bioprinted human model of calcific aortic valve disease (CAVD). Lastly, biodistribution of PNP-AuNP-miR-67 is assessed after subcutaneous injection in C57BL/6 mice. AuNP-miRNA release from the PNP hydrogel in vitro demonstrates a linear pattern over 5 days up to 20%. AuNP-miR-214 transfection in HEK293 results in 33% decrease of Luciferase reporter activity. In the CAVD model, AuNP-miR-214 are tracked into the cytoplasm of human aortic valve interstitial cells. Lastly, 11 days after subcutaneous injection, AuNP-miR-67 predominantly clears via the liver and kidneys, and fluorescence levels are again comparable to control animals. Thus, the PNP-AuNP-miRNA drug delivery platform provides linear release of functional miRNAs in vitro and has potential for in vivo applications.
AB - Differential expression of microRNAs (miRNAs) plays a role in many diseases, including cancer and cardiovascular diseases. Potentially, miRNAs could be targeted with miRNA-therapeutics. Sustained delivery of these therapeutics remains challenging. This study couples miR-mimics to PEG-peptide gold nanoparticles (AuNP) and loads these AuNP-miRNAs in an injectable, shear thinning, self-assembling polymer nanoparticle (PNP) hydrogel drug delivery platform to improve delivery. Spherical AuNPs coated with fluorescently labelled miR-214 are loaded into an HPMC-PEG-b-PLA PNP hydrogel. Release of AuNP/miRNAs is quantified, AuNP-miR-214 functionality is shown in vitro in HEK293 cells, and AuNP-miRNAs are tracked in a 3D bioprinted human model of calcific aortic valve disease (CAVD). Lastly, biodistribution of PNP-AuNP-miR-67 is assessed after subcutaneous injection in C57BL/6 mice. AuNP-miRNA release from the PNP hydrogel in vitro demonstrates a linear pattern over 5 days up to 20%. AuNP-miR-214 transfection in HEK293 results in 33% decrease of Luciferase reporter activity. In the CAVD model, AuNP-miR-214 are tracked into the cytoplasm of human aortic valve interstitial cells. Lastly, 11 days after subcutaneous injection, AuNP-miR-67 predominantly clears via the liver and kidneys, and fluorescence levels are again comparable to control animals. Thus, the PNP-AuNP-miRNA drug delivery platform provides linear release of functional miRNAs in vitro and has potential for in vivo applications.
UR - https://www.scopus.com/pages/publications/85121671354
U2 - 10.1039/d1nr04973a
DO - 10.1039/d1nr04973a
M3 - Article
C2 - 34817483
SN - 2040-3364
VL - 13
SP - 20451
EP - 20461
JO - Nanoscale
JF - Nanoscale
IS - 48
ER -