Controlled delivery of gold nanoparticle-coupled miRNA therapeutics via an injectable self-healing hydrogel,Nanoscale

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Controlled delivery of gold nanoparticle-coupled miRNA therapeutics via an injectable self-healing hydrogel
Nanoscale ( IF 5.8 ) Pub Date : 2021-11-24 , DOI: 10.1039/d1nr04973a
Casper F T van der Ven _{1,

2,

3,

4} , Mark W Tibbitt _{4,

5} , João Conde _{6,

7} , Alain van Mil _{1,

2,

8} , Jesper Hjortnaes _{1,

2} , Pieter A Doevendans _{2,

8} , Joost P G Sluijter _{1,

2} , Elena Aikawa _{3,

9} , Robert S Langer _{4,

10}

Affiliation

Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
Department of Cardiology, Experimental Cardiology Laboratory, Circulatory Health Laboratory, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
Center of Excellence in Cardiovascular Biology, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Woman's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston 02115, MA, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge 02142, MA, USA.
Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Sonneggstrasse 3, 8092 Zurich, Switzerland.
NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands.
Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 3 Blackfan Circle, Boston 02115, MA, USA.
Department of Chemical Engineering, Massachusetts Institute of Technology, 25 Ames Street, Cambridge 02142, MA, USA.

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.

中文翻译：

通过可注射的自愈水凝胶控制金纳米颗粒偶联 miRNA 疗法的传递

microRNA (miRNA) 的差异表达在许多疾病中发挥作用，包括癌症和心血管疾病。miRNA 疗法有可能成为靶点。持续提供这些疗法仍然具有挑战性。这项研究将 miR 模拟物与 PEG 肽金纳米颗粒 (AuNP) 结合，并将这些 AuNP-miRNA 加载到可注射、剪切稀化、自组装聚合物纳米颗粒 (PNP) 水凝胶药物递送平台中，以改善递送。将涂有荧光标记的 miR-214 的球形 AuNP 加载到 HPMC-PEG-b-PLA PNP 水凝胶中。对 AuNP/miRNA 的释放进行定量，在 HEK293 细胞中体外显示 AuNP-miR-214 的功能，并在钙化性主动脉瓣疾病 (CAVD) 的 3D 生物打印人类模型中跟踪 AuNP-miRNA。最后，在 C57BL/6 小鼠皮下注射后评估 PNP-AuNP-miR-67 的生物分布。体外PNP 水凝胶中 AuNP-miRNA 的释放在 5 天内呈线性模式，高达 20%。HEK293 中的 AuNP-miR-214 转染导致荧光素酶报告基因活性降低 33%。在 CAVD 模型中，AuNP-miR-214 被追踪到人主动脉瓣间质细胞的细胞质中。最后，皮下注射 11 天后，AuNP-miR-67 主要通过肝脏和肾脏清除，荧光水平再次与对照动物相当。因此，PNP-AuNP-miRNA 药物递送平台可在体外提供功能性 miRNA 的线性释放，并具有体内应用的潜力。

更新日期：2021-11-24

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