New research in the journal ACS Nano describes a method to improve the efficiency of NMN and metformin in the liver by using a novel nanoparticle delivery method.
Nanotechnology in drug delivery
Nanotechnology is a broad field that utilizes the unique properties of extraordinarily small materials. In medicine, it has been applied in drug delivery to make drugs more targeted, less toxic, and more efficient. The nanomaterial can serve as a carrier for a drug to improve its kinetics, such as increasing its absorption by the intestines or allowing for tightly controlled release of the drug in the bloodstream. However, one difficulty facing nanomedicines is their increased uptake by the liver relative to other tissues. Instead of a more evenly distributed, systemic exposure of the drug, a drug with a nano-carrier may accumulate in the liver.
While this is a major hurdle for applying these technologies to something like cancer, it may be beneficial when targeting metabolic conditions in the liver. Two drugs which do exactly that and are already well known to longevity researchers include metformin and nicotinamide mononucleotide (NMN). Both drugs have the potential to be improved upon by more efficient and targeted delivery, but metformin, in particular, may benefit from this strategy. Gastrointestinal side effects appear in 25% of metformin patients, which is related to high concentrations of this drug inside the intestines. A carrier that improves absorption by the intestines or allows for the same treatment effect at a lower dose could likely resolve this side effect. Additionally, some patients are intolerant to metformin due to a polymorphism in the OCT1 receptor responsible for its uptake into cells. These patients stand to benefit from a delivery of metformin that uses a different uptake mechanism.
Delivering metformin and NMN with Ag2S quantum dots
Researchers at the University of Sydney have developed Ag2S quantum dots (QDs) to serve as a drug delivery vehicle . These QDs are only 7 nanometers in size and have previously been shown to accumulate in the liver, after which they are rapidly cleared from the body. The researchers first successfully conjugated metformin and NMN to these QDs, characterized the conjugated drugs, and optimized the process for loading efficiency. After oral administration in the drinking water, the pharmacokinetics and pharmacodynamics of the drug were investigated. QD-metformin and QD-NMN were absorbed by the small intestine dramatically faster, and accumulated in the liver in greater amounts, than metformin and NMN alone.
The dose response effects were compared with metabolic measures such as a glucose tolerance test. QD-metformin was able to achieve the same effects as metformin alone with 100-fold lower dosing, while QD-NMN dosed at 1000-fold lower concentrations performed similarly to NMN only. The researchers then looked into the uptake mechanisms of QD-metformin, metformin, QD-NMN, and NMN.
Metformin is previously known to be transported into cells via OCT1. It was also previously known that NMN requires dephosphorylation to be brought into hepatocytes. As expected, inhibiting these processes also prevented the uptake of metformin and NMN, respectively. However, QD-metformin and QD-NMN were both still brought into the cells under these conditions, indicating a different pathway. The researchers hypothesized that the QD conjugated drugs were utilizing endocytosis. They experimentally confirmed this by inhibiting endocytosis with sucrose, which prevented QD-metformin and QD-NMN from entering the cells.
Improved metabolic outcomes with QD-delivered NMN
Finally, the researchers investigated the metabolic effects of high-dose NMN relative to low-dose QD-NMN in young (3-month) and old (18- and 24-month) mice. The older mice showed typical signs of metabolic dysregulation relative to young mice. At 3 months old, no differences were seen between the NMN and QD-NMN treatments, despite the much lower dose of QD-NMN. However, at 18 months of age, the mice treated with QD-NMN had improved fed and fasting insulin levels and less insulin resistance compared to untreated controls. Similarly, at 24 months of age, mice treated with QD-NMN had improved glucose tolerance, lower fasting insulin, and less insulin resistance compared to untreated controls. NMN alone did not improve any of these outcomes in either 18- or 24-month-old mice even though the dosing was 100 times higher than QD-NMN.
Finally, the toxicity of QD was investigated for up to 100 days of daily treatment. No liver toxicity was detected via AST or ALT levels. Liver, spleen, kidney, and small intestine histology were normal in both control and mice treated with QD for up to 100 days. Measures of inflammation also remained unchanged. Finally, levels of QD and its byproducts were unchanged between 14 and 100 days, indicating that it is being cleared by the liver effectively and not accumulating over time.
Ag2S QDs dramatically increased the hepatoselectivity of two pharmaceutical agents acting on AMPK and SIRT1 pathways: metformin and NMN. We have demonstrated that these QDs can be utilized as effective nanocarriers that (i) have greater biodistribution and selective uptake in the liver compared to the drug alone; (ii) utilize lower doses of the drug; (iii) have greater physiological effects at multiple time points post-treatment; (iv) bypass drug specific receptor uptake into hepatocytes, mitigating age-related decline in drug responses; (v) enhance the efficacy of treatment by regulating the local microenvironment via controlling the drug uptake in neighboring LSECs; and (vi) demonstrate negligible cellular toxicity, inflammation or tissue damage for at least 100 days of daily intake.
This research represents a substantial improvement on the current body of work for metformin and NMN. An improved efficiency for metformin can mean fewer side effects. While other strategies have improved the efficiency of metformin previously, it has not yet been accomplished for NMN. The side effect profile of potential longevity therapies will be critical to their success. Drugs that are meant to be given over the long term are particularly susceptible to having unintended consequences. Furthermore, a drug being given in a preventative context to otherwise healthy individuals will need minimal side effects for the benefits to outweigh the risks. Nanomedicine strategies such as the QD carrier presented in this study are a promising technique to more efficiently and safely deliver drugs.
However, future work will be needed to determine if QD-NMN is a better treatment than NMN alone. NMN is a precursor to NAD, a coenzyme signaling molecule critical to metabolism. Despite the increased efficiency of QD-NMN, the NAD levels were similar between QD-NMN- and NMN-treated mice because of the differences in dosing. However, improved outcomes were still seen in older mice treated with QD-NMN, suggesting that other variables besides NAD may be at play. It will be interesting to see if follow-up research is able to repeat these results, determine these mechanisms at play, and eventually translate the findings to humans.
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 Hunt, N.J., Lockwood, G.P., Kang, S.W.S, Westwood, L.J., Limantoro, C., … & Cogger, V.C. (2021). Quantum Dot Nanomedicine Formulations Dramatically Improve Pharmacological Properties and Alter Uptake Pathways of Metformin and Nicotinamide Mononucleotide in Aging Mice. ACS Nano, in press. https://doi.org/10.1021/acsnano.0c09278