Highlights

·        Nanocrystals containing nicotinamide riboside (NR) and resveratrol boost NAD+ levels in multiple mouse organs.
·        These nanocrystals attenuate heart damage and dysfunction after injury in mice.

Nicotinamide riboside (NR), as a dietary supplement, can be converted to nicotinamide adenine dinucleotide (NAD+) in cells to support metabolism and a myriad of critical cell functions. However, the efficacy of orally administered NR is limited due to its quick degradation in circulation and low bioavailability in targeted organs.

In this study, Nie and colleagues of the West China Hospital of Sichuan University fabricated nanocrystals of NR and resveratrol — an enhancer of NAD+ activity. Their article published in Drug Discovery showed that oral administration of these nanocrystals for just 8 hours significantly elevated NAD+ levels in serum and enhanced NAD+ abundance in multiple organs in mice, exhibiting an improved oral NAD+ bioavailability. Also, when mice underwent procedures that mimic heart injury, these nanocrystals protected the hearts from damage. Nie and colleagues propose, “Our data supported that the [nanocrystals] containing NR and resveratrol] is a promising candidate as NAD+ booster for oral administration.”

Maximizing drug bioavailability

The major challenge for orally administered drugs is to prevent undesired degradation of active ingredients in the environment of our digestive system. Ideal carriers for oral drug delivery should provide sufficient protection and facilitate active ingredients to reach the targets.

Nanocrystals are a novel approach to increase the solubility of drugs and control drug release rates that exhibit great potential for industrialization. Small molecule nanocrystals can be self-formed by drugs without pharmaceutic adjuvant — a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. exhibiting a great potential for industrialization.

NR and resveratrol nanocrystals boost NAD+ levels in multiple mouse organs

In the present study, Nie and colleagues fabricated nanocrystals out of NR and resveratrol. After optimizing the particle shape, size, and chemical parameters, they evaluated the effectiveness of nanocrystals in elevating NAD+ levels in serum and multiple organs after oral delivery. What they found was that the nanocrystal formulation significantly increased NAD+ levels in mouse serum and multiple organs, including the heart, brain, kidney, and liver, after oral administration, suggesting an improved NAD+ bioavailability.

(Nie et al. 2021| Drug Discovery) Nanocrystals with NR and resveratrol increase NAD+ levels in multiple organs. The NAD+ levels in heart, brain, kidney, and liver in untreated mice (vehicle) and 8 hours after mice were treated with nicotinamide riboside (NR), nicotinamide and resveratrol (NR + Res), or nanocrystals fabricated out of NR and resveratrol (NR/RESms). These results show that the nanocrystals were more potent than NR alone or with resveratrol not fabricated into nanocrystals.

NR and resveratrol nanocrystals protect mouse hearts from injury

With no adverse effect on major organs, Nie and colleagues tested whether improving NAD+ abundance with these nanocrystals protects organs against acute stress. To do so, they performed a procedure that put stress on the hearts of mice following short-term treatment with the nanocrystals and then examined heart damage and function.

One day after the procedure, the untreated mice exhibited significantly reduced pumping of the heart as compared to the mice that were not operated on. However, administration of the NR and resveratrol containing nanocrystals improved the heart’s pumping ability even more so than NR or resveratrol alone, suggesting that the operation-induced decline in heart function was ameliorated by enhancing NAD+ availability. In line with this, the procedure damaged roughly one-third of the heart, which was reduced by half with nanocrystals treatment. Taken together, their data suggested that these nanocrystals are a promising NAD+ booster that could mitigate acute heart injuries.

(Nie et al. 2021| Drug Discovery) Oral administration of microspheres containing NR and resveratrol attenuated heart injury. The top of this figure shows a schematic representation of the experimental protocol for heart injury. Nie and colleagues examined mice that underwent operations to put stress on the heart for heart function (bottom left), which is called the ejection fraction. They also examined the amount of heart damage in these mice, which they measured as the percentage of the heart that was damaged (IS/AAR). NR, nicotinamide riboside; NR + RES, nicotinamide riboside and resveratrol; NR/RESms, nanocrystals of nicotinamide riboside and resveratrol. IS, injury size; AAR, area at risk.

Nie and colleagues conclude, “We fabricated a carrier-free dual-drug [nanocrystals containing NR and resveratrol], and demonstrated it as an orally administered NAD+ booster to attenuate cardiac I/R injury in mice.” It will be interesting to see how these nanocrystals work in humans and whether they can aid in the effectiveness of compounds that boost NAD+ or are linked to improved health- or life-span.

(Nie et al. 2021| Drug Discovery) Oral delivery of carrier-free dual-drug nanocrystal self-assembled nanocrystals improved NAD+ bioavailability and attenuated cardiac ischemia/reperfusion injury in mice. The NR/RES-assembled nanocrystals are constructed by the Nano Spray Dryer B90 to improve the oral bioavailability of nicotinamide riboside (NR). The sustained release of NR in an enteric environment endowed the nanocrystals for oral administration with a significant increase of NAD+ levels in circulation and multiple organs, which offered a protective effect on the stressed hearts of mice.