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

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.

Highly Biocompatible Apigenin-Loaded Silk Fibroin Nanospheres: Preparation, Characterization, and Anti-Breast-Cancer Activity

“…Compared with free AGN, SF-AGN effectively prolonged the half-life and increased the relative bioavailability by 1.47 times, while the C max , AUC 0-t , and MRT t were all raised to different degrees. The improved bioavailability may be attributed to the direct uptake of SF through the cell membrane by the lymphatic system, which facilitates drug absorption [ 31 ].…”

NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities

“… 104 Mice treated with the alternative precursor NR (100 mg/kg BW) also exhibited improved cardiac function and smaller infarcts. 105 The NAD + intermediate NMN consistently normalized alterations in the mitochondrial membrane potential and ROS levels associated with ischemic myocardial injury in aged rats. 106 NMN not only protected against ischemic injury, but also had beneficial effects against coronary reperfusion injuries.…”

The emerging potential of crystalline drug‐polymer combination for medical applications

“…Moreover, crystalline formulations provide a continuous and elongated release 11–19 owing to their compact structure, 19 where the releasing profile can be modified by monitoring the crystals' size and shape. During the past few years, several works on crystalline carrier‐free DDS included surface coatings 14–18 and either single 11,19 /multi‐component 9,12 crystals for different clinical conditions.…”

“…The crystalline formulation can improve the physicochemical properties of the drugs such as stability, dissolution rate, solubility, and so forth, solving this issue. 10 Moreover, crystalline formulations provide a continuous and elongated release [11][12][13][14][15][16][17][18][19] owing to their compact structure, 19 where the releasing profile can be modified by monitoring the crystals' size and shape. During the past few years, several works on crystalline carrier-free DDS included surface coatings [14][15][16][17][18] and either single 11,19 /multi-component 9,12 crystals for different clinical conditions.…”

“…In another example, single-component drug crystals of GW2580, a selective colony stimulating factor-1 receptor inhibitor, with the size range of tens-to-hundreds of micrometers were reported to prevent longterm implant fibrosis, when implemented intraperitoneally or subcutaneously in rodents and non-human primates for 1.3 years and 6 months, respectively. 19 Expanding the use of crystalline drugs for oral 11,12,20 and intravenous (IV) administration 21,22 was also done by down scaling them to the nanometric range. This enabled to improve the drugs solubility, leading to the enhancement of the bioavailability of poorly soluble drugs.…”