We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) (11.1% w/w) and poly(ethyleneglycol) 10,000 daltons (5.6% w/w) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min) analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus^® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration extracted from MN was 4.29 nmol/L, detected after 3 hours skin insertion in human volunteers. Whilst not directly correlated, concentrations extracted from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clinical insertion times and develop mathematical algorithms enabling determination of blood levels directly from MN measurements.

We describe, for the first time, hydrogel-forming microneedle (s) (MN) arrays for minimally-invasive extraction and quantification of lithium in vitro and in vivo. MN arrays, prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) and crosslinked by poly(ethyleneglycol), imbibed interstitial fluid (ISF) upon skin insertion. Such MN were always removed intact. In vitro, mean detected lithium concentrations showed no significant difference following 30min MN application to excised neonatal porcine skin for lithium citrate concentrations of 0.9 and 2mmol/l. However, after 1h application, the mean lithium concentrations extracted were significantly different, being appropriately concentration-dependent. In vivo, rats were orally dosed with lithium citrate equivalent to 15mg/kg and 30mg/kg lithium carbonate, respectively. MN arrays were applied 1h after dosing and removed 1h later. The two groups, having received different doses, showed no significant difference between lithium concentrations in serum or MN. However, the higher dosed rats demonstrated a lithium concentration extracted from MN arrays equivalent to a mean increase of 22.5% compared to rats which received the lower dose. Hydrogel-forming MN clearly have potential as a minimally-invasive tool for lithium monitoring in outpatient settings. We will now focus on correlation between serum and MN lithium concentrations.

The emerging field of microneedle-based minimally invasive patient monitoring and diagnosis is reviewed. Microneedle arrays consist of rows of micron-scale projections attached to a solid support. They have been widely investigated for transdermal drug and vaccine delivery applications since the late 1990s. However, researchers and clinicians have recently realized the great potential of microneedles for extraction of skin interstitial fluid and, less commonly, blood, for enhanced monitoring of patient health. We reviewed the journal and patent literature, and summarized the findings and provided technical insights and critical analysis. We describe the basic concepts in detail and extensively review the work performed to date. It is our view that microneedles will have an important role to play in clinical management of patients and will ultimately improve therapeutic outcomes for people worldwide.

The nano-drug delivery system has gained greater acceptability for poorly soluble drugs. Alogliptin (ALG) is a FDA-approved oral anti-hyperglycemic drug that inhibits dipeptidyl peptidase-4. The present study is designed to prepare polymeric ALG nanoparticles (NPs) for the management of diabetes. ALG-NPs were prepared using the nanoprecipitation method and further optimized by Box–Behnken experimental design (BBD). The formulation was optimized by varying the independent variables Eudragit RSPO (A), Tween 20 (B), and sonication time (C), and the effects on the hydrodynamic diameter (Y1) and entrapment efficiency (Y2) were evaluated. The optimized ALG-NPs were further evaluated for in vitro release, intestinal permeation, and pharmacokinetic and anti-diabetic activity. The prepared ALG-NPs show a hydrodynamic diameter of between 272.34 nm and 482.87 nm, and an entrapment efficiency of between 64.43 and 95.21%. The in vitro release data of ALG-NPs reveals a prolonged release pattern (84.52 ± 4.1%) in 24 h. The permeation study results show a 2.35-fold higher permeation flux than pure ALG. ALG-NPs exhibit a significantly (p < 0.05) higher pharmacokinetic profile than pure ALG. They also significantly (p < 0.05) reduce the blood sugar levels as compared to pure ALG. The findings of the study support the application of ALG-entrapped Eudragit RSPO nanoparticles as an alternative carrier for the improvement of therapeutic activity.

Several studies have linked Cancer stem cells (CSCs) to cancer resistance development to chemotherapy and radiotherapy. ALDH1A1 is a key enzyme that regulates the gene expression of CSCs and creates an immunosuppressive tumor microenvironment. It was reported that quercetin and resveratrol were among the inhibitors of ALDH1A1. In early 2022, it was reported that new 11 flavonostilbenes (rhamnoneuronal D-N) were isolated from Rhamnoneuron balansae as potential antiaging natural products. Rhamnoneuronal H (5) could be envisioned as a natural hybrid of quercetin and resveratrol. It was therefore hypothesized that 5 and its analogous isolates rhamnoneuronal D-G (1-4) and rhamnoneuronal I-N (6-11) would have potential ALDH1A1 inhibitory activity. To this end, all isolates were subjected to molecular docking, MM-GBSA, ADMET, and molecular dynamics simulations studies to assess their potential as new leads for cancer treatment targeting ALDH1A1. In silico findings revealed that natural hybrid 5 has a similar binding affinity, judged by MM-GBSA, to the ALDH1A1 active site when compared to the co-crystalized ligand (-64.71 kcal/mole and -64.12 kcal/mole, respectively). Despite having lesser affinity than that of the co-crystalized ligand, the rest of the flavonostilbenes, except 2-4, displayed better binding affinities (-37.55 kcal/mole to -58.6 kcal/mole) in comparison to either resveratrol (-34.44 kcal/mole) or quercetin (-36.48 kcal/mole). Molecular dynamic simulations showed that the natural hybrids 1, 5-11 are of satisfactory stability up to 100 ns. ADMET outcomes indicate that these hybrids displayed acceptable properties and hence could represent an ideal starting point for the development of potent ALDH1A1 inhibitors for cancer treatment.Communicated by Ramaswamy H. Sarma.