Journal
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
Volume 158, Issue -, Pages 273-283Publisher
ELSEVIER
DOI: 10.1016/j.ejpb.2020.10.018
Keywords
Nanomedicine; Low-density lipoprotein; Docosahexaenoic acid; Locoregional delivery; Toxicity; Nanoparticle safety
Categories
Funding
- Remeditex ventures LCC [OTD109946]
- NCI, National Institutes of Health (NIH) [R01CA215702]
- Society of Interventional Radiology Foundation Dr. Ernest J. Ring Academic Development Grant
- Henan University visiting scholar program [2016051]
- UTSW Cancer Center [5P30 CA 142543-05]
- Cancer Prevention Research Institute of Texas Core Facilities Support Award [RP170003]
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Hepatic-arterial infusion of LDL nanoparticles reconstituted with DHA was found to be safe and well tolerated in a rat model, with no significant adverse effects observed. The nanoparticles were rapidly extracted by the liver and lipidomics analyses showed preferential oxidation to an anti-inflammatory mediator. This treatment may offer potential hepatoprotective benefits.
Hepatic-arterial infusion (HAI) of low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) (LDL-DHA) has been shown in a rat hepatoma model to be a promising treatment for hepatocellular carcinoma. To date, little is known regarding the safety of HAI of LDL-DHA to the liver. Therefore, we aimed to investigate the deposition, metabolism and safety of HAI of LDL-DHA (2, 4 or 8 mg/kg) in the rat. Following HAI, fluorescent labeled LDL nanoparticles displayed a biexponential plasma concentration time curve as the particles were rapidly extracted by the liver. Overall, increasing doses of HAI of LDL-DHA was well tolerated in the rat. Body weight, plasma biochemistry and histology were all unremarkable and molecular markers of inflammation did not increase with treatment. Lipidomics analyses showed that LDL-DHA was preferentially oxidized to the anti-inflammatory mediator, protectin DX. We conclude that HAI of LDL-DHA nanoparticles is not only safe, but provides potential hepatoprotective benefits.
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