Oral delivery of carrier-free dual-drug nanocrystal self-assembled microspheres improved NAD+ bioavailability and attenuated cardiac ischemia/reperfusion injury in mice

Hongfei Nie; Yarong Zhang; Haiyang Yu; Hong Xiao; Tao Li; Qian Yang

doi:10.1080/10717544.2021.1886198

Oral delivery of carrier-free dual-drug nanocrystal self-assembled microspheres improved NAD⁺ bioavailability and attenuated cardiac ischemia/reperfusion injury in mice

Drug Deliv. 2021 Dec;28(1):433-444. doi: 10.1080/10717544.2021.1886198.

Authors

Hongfei Nie^{1

2}, Yarong Zhang^{1

3}, Haiyang Yu³, Hong Xiao^{1

2}, Tao Li^{1

2}, Qian Yang⁴

Affiliations

¹ Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
² Laboratory of Anesthesia and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China.
³ State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
⁴ Laboratory of Plastic Surgery and Burns, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China.

Abstract

Nicotinamide riboside (NR), as a dietary supplement, can be converted to nicotinamide adenine dinucleotide (NAD⁺) in cells to support mitochondrial energy metabolism. However, the efficacy of oral administrated NR is limited due to its quick degradation in circulation and low bioavailability in targeted organs. In this study, we fabricated nanocrystal self-assembled microspheres by Nano Spray Dryer for oral delivery of NR. The structure of NR and resveratrol (RES) nanocrystal self-assembled microspheres (NR/RESms) is confirmed by the morphology, chemical structure, and crystallization. The NR/RESms displayed restricted NR release at the gastric acid-mimic condition (<15% in the first 8 hours), while achieved accelerated NR release in an enteric-mimic environment (>46% within 8 hours). Oral administration of NR/RESms for 8 hours significantly elevated NAD⁺ levels in serum (169.88 nM versus 30.93 nM in the NR group, p < .01; and 66.89 nM in the NR + RES group, p < .05), and enhanced NAD⁺ abundance in multiple organs in mice, exhibiting an improved oral NAD⁺ bioavailability. In addition, without any serious adverse effects on major organs, oral delivery of NR/RESms attenuated myocardial infarction (15.82% versus 19.38% in the I/R + NR group and 20.76% in the I/R + NR + RES group) in a cardiac ischemia/reperfusion (I/R) injury mouse model. Therefore, our data supported that the NR/RESms is a promising candidate as NAD⁺ booster for oral administration.

Keywords: Carrier-free microspheres; NAD + Bioavailability; cardiac I/R injury; nicotinamide riboside; oral administration.

MeSH terms

Administration, Oral
Animals
Biological Availability
Dietary Supplements
Disease Models, Animal
Drug Delivery Systems*
Drug Liberation
Male
Mice
Mice, Inbred C57BL
Microspheres
NAD / blood*
Nanoparticles
Niacinamide / administration & dosage
Niacinamide / analogs & derivatives*
Niacinamide / pharmacology
Pyridinium Compounds / administration & dosage*
Pyridinium Compounds / pharmacology
Reperfusion Injury / drug therapy*
Time Factors

Substances

Pyridinium Compounds
nicotinamide-beta-riboside
NAD
Niacinamide

Grants and funding

This study was supported by grants from the National Nature Science Foundation of China [81970715 and 81770815], the Science and Technology Foundation for Distinguished Young Scholar of Sichuan Province [2020JDJQ0048]; the Key Research and Development Program of Sichuan Province [2019YFS0252]; the Scientific Research Foundation of Sichuan Province for the Returned Overseas Chinese Scholars; the Sichuan Science and Technology Program [2018SZ0386] and the Innovation Spark Project of Sichuan university [2018SCUH0065].