Drug Analogues Research Articles

The Role of Pain Medications in Modulating Peripheral Nerve Injury Recovery.

Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non-steroidal anti-inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma-aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI-related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti-inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage-gated Ca2+ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery.

Effects of two carbonic anhydrase inhibitors on exercise performance in acute hypoxia.

Acute mountain sickness occurs due to rapid altitude ascents and/or insufficient acclimatization. Acetazolamide (AZ) is commonly prescribed for AMS prophylaxis but inhibits exercise performance. Methazolamide (MZ), an analogous drug, has similar prophylactic benefits but does not impair isolated muscle mass exercise performance in normoxia. We sought to compare whole-body exercise performance in acute hypoxia (FIO2 = 0.15) between AZ, MZ and placebo (PLA). Fifteen healthy participants completed 5 testing visits: day 1 maximal exercise test, day 2 a familiarization, and days 3-5 were the experimental visits. Each experimental visit involved a 5-km hypoxic cycling time trial performed after a 2-day dosing protocol of either AZ (250 mg t.i.d.), MZ (100 mg b.i.d.) or PLA (t.i.d.); the order was randomized and double-blinded. Prior to exercise, capillary blood samples were taken, and maximal voluntary contractions of quadriceps were performed. AZ and MZ resulted in a partially compensated metabolic acidosis at rest compared to PLA (capillary H+ 47±3, 43±2, 39±2 nmol for AZ, MZ and PLA respectively, p<0.01). Time to complete 5-km with PLA (562±32 seconds, p<0.01) was significantly faster than AZ and MZ (577±38 vs. 581±37s respectively), with no differences between AZ and MZ (p=0.96). There were no differences in average ventilation (124±27, 127±24, 127±19 l/min) and oxyhemoglobin saturation (87±2, 88±2, 88±3%) between AZ, MZ and PLA respectively (p>0.05). Overall, both AZ and MZ impair whole-body exercise performance in acute normobaric hypoxia.

Copper‐Catalyzed Cross Coupling Reaction of Alkyl Bromides with (DMPU)2Zn(Rf)2 Reagent: A Method for the Synthesis of Perfluoroalkylated Compounds

AbstractA method for the copper‐catalyzed cross‐coupling of alkyl bromides with a range of (DMPU)2Zn(Rf)2 reagents has been developed. This protocol tolerates multiple functional groups and provides broad access to aliphatic perfluoroalkylated compounds. The applicability of this procedure is demonstrated in the late‐stage functionalization of drug analogues.

Deuteration and Tritiation of Pharmaceuticals by Non-Directed Palladium-Catalyzed C-H Activation in Heavy and Super-Heavy Water.

Deuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical and medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction of drugs using non-directed homogeneous Pd-catalysis. Aromatic C-H activation is achieved by a commercially available pyridine ligand. Using the most convenient and cheapest deuterium source, D2O, as the only solvent 39 pharmaceuticals were labelled with clean reaction profiles and high deuterium uptakes. Additionally, we describe the first application of non-directed homogeneous Pd-catalysis for H/T exchange on three different pharmaceuticals by using T2O as isotopic source, demonstrating the applicability to the synthesis of radiotracers.

Deuteration and Tritiation of Pharmaceuticals by Non‐Directed Palladium‐Catalyzed C−H Activation in Heavy and Super‐Heavy Water

AbstractDeuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical and medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction of drugs using non‐directed homogeneous Pd‐catalysis. Aromatic C−H activation is achieved by a commercially available pyridine ligand. Using the most convenient and cheapest deuterium source, D2O, as the only solvent 39 pharmaceuticals were labelled with clean reaction profiles and high deuterium uptakes. Additionally, we describe the first application of non‐directed homogeneous Pd‐catalysis for H/T exchange on three different pharmaceuticals by using T2O as isotopic source, demonstrating the applicability to the synthesis of radiotracers.

Exploring the inhibitory potential of hormone replacement therapy drugs on glutathione transferase P1-1

Aim: Glutathione transferase P1-1 (GST P1-1) plays a crucial role in the human phase II detoxication system and is implicated in drug resistance in certain cancer cells. Analogs of drugs used in Hormone Replacement Therapy (HRT) have been reported to exhibit inhibition of various GSTs. This study aims to investigate the inhibitory potential of several HRT drugs on GST P1-1 for the possible use of counteracting drug resistance and for other therapeutic purposes. Materials and Methods: GST P1-1 was expressed and then purified in a single step using Nickel Sepharose affinity chromatography. Synthetic drugs that are used in HRT were screened for inhibition of GST P1-1 using 1-chloro-2,4-dinitrobenzene as the substrate. The IC50 value of the most potent compound was calculated and binding location and formation of bonds to GST P1-1 were identified through docking analysis. Results: Screening the inhibitory effect of eight synthetic estrogenic drugs reveals that estradiol valerate is the most potent inhibitor, showing 72 ± 4% inhibition of GST P1-1. This effect is followed by estradiol cypionate 53 ± 5%, mestranol 39 ± 4%, and estradiol propionate 35 ± 2%. The most potent compound estradiol valerate has an IC50 value of 30 ± 2 μM. According to docking analysis, it binds to the H-site of the enzyme where the residues Phe9, Arg14, Val36, Trp39, Ile105, Tyr109, Pro203, Asn207, and Gln210 were within 5 Å proximity of the ligand. Estradiol valerate forms Pi-alkyl interactions with Phe9 and Val36, as well as an alkyl interaction with Ile104. Conclusion: Estradiol valerate is a modest inhibitor for hGST P1-1, however it fits in the area of H-site of the enzyme and forms bonds with critical key residues. Understanding its binding site on the enzyme is critical for designing other inhibitors targeting GSTs or possibility for the potential use as a substrate with other GSTs.

Catalytic undirected methylation of unactivated C(sp3)-H bonds suitable for complex molecules.

In pharmaceutical discovery, the "magic methyl" effect describes a substantial improvement in the pharmacological properties of a drug candidate with the incorporation of methyl groups. Therefore, to expedite the synthesis of methylated drug analogs, late-stage, undirected methylations of C(sp3)-H bonds in complex molecules would be valuable. However, current methods for site-selective methylations are limited to activated C(sp3)-H bonds. Here we describe a site-selective, undirected methylation of unactivated C(sp3)-H bonds, enabled by photochemically activated peroxides and a nickel(II) complex whose turnover is enhanced by an ancillary ligand. The methodology displays compatibility with a wide range of functional groups and a high selectivity for tertiary C-H bonds, making it suitable for the late-stage methylation of complex organic compounds that contain multiple alkyl C-H bonds, such as terpene natural products, peptides, and active pharmaceutical ingredients. Overall, this method provides a synthetic tool to explore the "magic methyl" effect in drug discovery.

Role of tenofovir dipivoxil in gut microbiota recovery from HBV-infection induced dysbiosis

BackgroundStudies have found dysbiosis of the gut microbiota in individuals infected with the hepatitis B virus (HBV). Tenofovir dipivoxil (TDF) is one of the preferred oral antiviral drugs used for the treatment of chronic hepatitis B (CHB), but the extent to which TDF is able to affect the gut microbiota and inflammatory factors of a patient remains largely unexplored. In this study, we collected stool samples from HBV patients prior to medication and from CHB patients treated with TDF.ResultsThe gut microbiota and inflammatory factors were assessed in 42 healthy subjects (HC group), 109 HBV-infected subjects, including 48 CHB patients who were not medicated with nucleoside analogue drugs (No-NAs group), and 61 CHB patients who were medicated with TDF (TDF group). 16 S rRNA sequencing revealed that TDF treatment caused significant changes in the gut microbiota of HBV-infected individuals; however, the gut microbiota of HBV-infected individuals did not fully recover to a pre-dysbiosis state. The relative abundance of Bacteroidota gradually decreased from the HC group to the No-NAs and TDF groups. The relative abundance of Fusobacteriota was significantly higher in the No-NAs group than in the HC group. At the genus level, Dialister, Eubacterium_hallii_group, Halomonas, Collinsella, Sphingomonas, Xanthomonadaceae_unclassified, and Rhizobiaceae_unclassified were overrepresented; while the abundance of Bacteroides and Fusobacterium decreased significantly in the No-NAs and TDF groups.ConclusionsThis study showed that TDF treatment significantly improved the regulation of the gut microbiota and aided in dysbiosis recovery. We did not observe significant improvement in serum inflammatory factor concentrations, which may be related to the relatively short duration of TDF administration in this study.

MCMVDRP: a multi-channel multi-view deep learning framework for cancer drug response prediction.

Drug therapy remains the primary approach to treating tumours. Variability among cancer patients, including variations in genomic profiles, often results in divergent therapeutic responses to analogous anti-cancer drug treatments within the same cohort of cancer patients. Hence, predicting the drug response by analysing the genomic profile characteristics of individual patients holds significant research importance. With the notable progress in machine learning and deep learning, many effective methods have emerged for predicting drug responses utilizing features from both drugs and cell lines. However, these methods are inadequate in capturing a sufficient number of features inherent to drugs. Consequently, we propose a representational approach for drugs that incorporates three distinct types of features: the molecular graph, the SMILE strings, and the molecular fingerprints. In this study, a novel deep learning model, named MCMVDRP, is introduced for the prediction of cancer drug responses. In our proposed model, an amalgamation of these extracted features is performed, followed by the utilization of fully connected layers to predict the drug response based on the IC50 values. Experimental results demonstrate that the presented model outperforms current state-of-the-art models in performance.

Silver nanoparticles modified with MoS2 and β-cyclodextrin as SERS substrate for rapid determination of cysteamine hydrochloride in meat products

An efficient Surface-enhanced Raman scattering (SERS) method for the detection of cysteamine hydrochloride (CSH) was developed by synthesizing a composite substrate comprising silver nanoparticles (AgNPs) functionalized with MoS2 and β-cyclodextrin (β-CD). The enhanced Raman signals of CSH by β-CD/MoS2/AgNPs substrate were the contribution of electromagnetic enhancement (EM) as well as chemical enhancement (CM), and the enhancement factor (EF) can reach up to 3.11 × 106 (peak at 633 cm−1). Various instrumental techniques were used to characterize the substrate, such as X-ray diffraction (XRD), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) and ultraviolet visible (UV–vis). The binding of β-CD/MoS2/AgNPs and CSH was confirmed by UV–vis and Fourier transform infrared (FT-IR). The optimal experimental conditions were determined by single factor experiments as well as response surface model. The influences of different metal ions and analogous drugs on the detection of CSH were investigated. Under optimum conditions, a good linear correlation (R = 0.9997) was established for CSH in the range of 10.00–1000.00 nmol/L, and the limit of detection (LOD) was as low as 0.78 nmol/L (S/N = 3). The contents of CSH in meat samples were detected. The recovery was 96.6–103.1 %, and the relative standard deviation (RSD) of the measurement was 0.7–3.9 % (n = 7).

A Metal‐Free Amination of 1,2‐Diaza‐1,3‐dienes Using Hydrazine Hydrate Through N‐N Bond Cleavage

: Herein, we have developed a metal‐free, atom‐economical, intrinsically sustainable approach for synthesizing unprotected 4,5‐diamino pyrazoles from readily available 1,2‐diaza‐1,3‐dienes. This approach utilizes inexpensive hydrazine hydrate as the aminating source. Further, we have explored the reactivity of 4,5‐diamino pyrazole to synthesize fused pyrazolo[3,4‐d]‐1,2,3‐triazole heterocyclic compounds. We have also successfully demonstrated the synthetic utility of this methodology in synthesizing two drug analogs: analgesic difenamizole and anti‐psychotic CDPPB. The role of the phenyl ring of 3‐substituted‐1,2‐diaza‐1,3‐diene was explained with the help of control experimental and density functional theory (DFT) computation studies.

Predicting the Hallucinogenic Potential of Molecules Using Artificial Intelligence.

The development of new drugs addressing serious mental health and other disorders should avoid the psychedelic experience. Analogs of psychedelic drugs can have clinical utility and are termed "psychoplastogens". These represent promising candidates for treating opioid use disorder to reduce drug dependence, with rarely reported serious adverse effects. This drug abuse cessation is linked to the induction of neuritogenesis and increased neuroplasticity, a hallmark of psychedelic molecules, such as lysergic acid diethylamine. Some, but not all psychoplastogens may act through the G-protein coupled receptor (GPCR) 5HT2A whereas others may display very different polypharmacology making prediction of hallucinogenic potential challenging. In the process of developing tools to help design new psychoplastogens, we have used artificial intelligence in the form of machine learning classification models for predicting psychedelic effects using a published in vitro data set from PsychLight (support vector classification (SVC), area under the curve (AUC) 0.74) and in vivo human data derived from books from Shulgin and Shulgin (SVC, AUC, 0.72) with nested five-fold cross validation. We have also explored conformal predictors with ECFP6 and electrostatic descriptors in an effort to optimize them. These models have been used to predict known 5HT2A agonists to assess their potential to act as psychedelics and induce hallucinations for PsychLight (SVC, AUC 0.97) and Shulgin and Shulgin (random forest, AUC 0.71). We have tested these models with head twitch data from the mouse. This predictive capability is desirable to reliably design new psychoplastogens that lack in vivo hallucinogenic potential and help assess existing and future molecules for this potential. These efforts also provide useful insights into understanding the psychedelic structure activity relationship.

Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis.

NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.

Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition.

The direct construction of bioisosteric compounds enriched in Csp3 content represents an attractive and dependable approach to imbuing biologically active molecules with enhanced three-dimensional characteristics, finding wide utility across the synthetic and medicinal chemistry community. Despite recent advancements in the synthesis of (aza)-bicyclo[3.1.1]heptanes (BCHeps and aza-BCHeps), which serve as meta-substituted (aza)-arene bioisosteres, the enantioselective assembly of chiral 3-aza-BCHeps remains a coveted goal yet to be achieved. Here, we disclose an unprecedented copper-catalyzed asymmetric formal [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) and azomethine ylides, furnishing a diverse array of enantioenriched 3-aza-BCHeps with exceptional levels of diastereo- and enantioselectivites (51 examples, all >20:1 dr, mostly 97-99% ee). Both mono- and disubstituted BCBs are well compatible with this protocol, offering an enticing route for the efficient synthesis of challenging tetrasubstituted bicyclic products bearing two quaternary centers. The synthetic significance of this methodology is further demonstrated by the successful preparation of several piperidine drug analogues.

Structural insights into somatostatin receptor 5 bound with cyclic peptides.

Somatostatin receptor5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2. Pasireotide is preferential binding to SSTR5 than octreotide, while octreotide is biased to SSTR2 than SSTR5. The lack of selectivity of both pasireotide and octreotide causes side effects, such as hyperglycemia, gastrointestinal disturbance, and abnormal glucose homeostasis. However, little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5, limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5. Here, we report two cryo-electron microscopy (cryo-EM) structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09 Å and 3.24 Å, respectively. In combination with structural analysis and functional experiments, our results reveal the molecular mechanisms of ligand recognition and receptor activation. We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/DTrp of pasireotide and SSTR5. Moreover, we find that the Q2.63, N6.55, F7.35 and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes.

Establishment of human induced pluripotent stem cell-derived hepatobiliary organoid with bile duct for pharmaceutical research use

In vitro models of the human liver are promising alternatives to animal tests for drug development. Currently, primary human hepatocytes (PHHs) are preferred for pharmacokinetic and cytotoxicity tests. However, they are unable to recapitulate the flow of bile in hepatobiliary clearance owing to the lack of bile ducts, leading to the limitation of bile analysis. To address the issue, a liver organoid culture system that has a functional bile duct network is desired. In this study, we aimed to generate human iPSC-derived hepatobiliary organoids (hHBOs) consisting of hepatocytes and bile ducts. The two-step differentiation process under 2D and semi-3D culture conditions promoted the maturation of hHBOs on culture plates, in which hepatocyte clusters were covered with monolayered biliary tubes. We demonstrated that the hHBOs reproduced the flow of bile containing a fluorescent bile acid analog or medicinal drugs from hepatocytes into bile ducts via bile canaliculi. Furthermore, the hHBOs exhibited pathophysiological responses to troglitazone, such as cholestasis and cytotoxicity. Because the hHBOs can recapitulate the function of bile ducts in hepatobiliary clearance, they are suitable as a liver disease model and would be a novel in vitro platform system for pharmaceutical research use.

Exploring the Antiproliferative Potential of Morpholine‐Functionalized Aurones: Design, Synthesis, SAR, DFT, Hirshfeld Surface, 3D Energy Frameworks and Molecular Docking Analysis

AbstractIn quest of generating a diverse array of potential cytotoxic candidates through molecular hybridization approach, herein we have designed a library of forty‐one morpholine‐functionalized aurones 7(a–ao), each with a distinct substitution pattern. These aurones were obtained by reacting 6‐hydroxyaurones, with 4‐(2‐chloroethyl)morpholine hydrochloride, characterized by various spectroscopic techniques including single crystal XRD (7b) and in‐vitro screened for their antiproliferative potential against human gastric adenocarcinoma (AGS) cells. Most of the synthesized compounds have exhibited excellent cytotoxic results. Twenty analogs were found to have cytotoxic potential better than the reference drug Leucovorin and analog 7j emerged as the most potent with IC50=5.98 μM nearly one fifth to the standard drug Leucovorin (IC50=30.8 μM). This library, consisting of twenty three novel and eighteen reported morpholine‐functionalized aurones, bearing diverse substitution pattern, further helped in making a concrete structure‐activity relationship for antiproliferative potential. Additionally, in‐silico molecular docking, Hirshfeld surface analysis and two dimensional fingerprint plots were also studied to understand the molecular interactions and various structural aspects. Further computational investigations of these compounds were conducted using the DFT/B3LYP method, for the determination of HOMO and LUMO energy values as well as the calculation of chemical softness, hardness, electronegativity and electrophilic index etc.

Sugar ring alignment and dynamics underline cytarabine and gemcitabine inhibition on Pol η catalyzed DNA synthesis

Nucleoside analogue drugs are pervasively used as antiviral and chemotherapy agents. Cytarabine and gemcitabine are anti-cancer nucleoside analogue drugs that contain C2´ modifications on the sugar ring. Despite carrying all the required functional groups for DNA synthesis, these two compounds inhibit DNA extension once incorporated into DNA. It remains unclear how the C2´ modifications on cytarabine and gemcitabine affect the polymerase active site during substrate binding and DNA extension. Using steady-state kinetics, static and time-resolved X-ray crystallography with DNA polymerase η (Pol η) as a model system, we showed that the sugar ring C2´ chemical groups on cytarabine and gemcitabine snugly fit within the Pol η active site without occluding the steric gate. During DNA extension, Pol η can extend past gemcitabine but with much lower efficiency past cytarabine. Pol η crystal structures show that the -OH modification in the β direction on cytarabine locks the sugar ring in an unfavorable C2´-endo geometry for product formation. On the other hand, the addition of fluorine atoms on gemcitabine alters the proper conformational transition of the sugar ring for DNA synthesis. Our study illustrates mechanistic insights into chemotherapeutic drug inhibition and resistance and provides guidance for future optimization of nucleoside analogue drugs.

Differentiation of regioisomeric N-substituted meta-chlorophenylpiperazine derivatives

A series ofN,N-disubstituted piperazines were synthesized containing the structural elements of meta-chlorophenylpiperazine (mCPP) in combination with methoxybenzyl-, and dimethoxybenzyl substituents to yield nineN,N-disubstituted piperazine compounds. These nine potential designer-like drug analogs were prepared based on common designer trends and regioisomeric differentiation was based on gas chromatography-mass spectrometry (GC–MS) and gas chromatography-vapor phase infrared (GC–vpIR) studies.The compounds in this study have not been reported as drugs of abuse at this time. However, commercial availability of precursor chemicals including mCPP suggests the possibility of further designer exploration. Capillary GC separation showed the regioisomers to elute according to the position of aromatic ring substitution and/or the degree of substituent crowding on the aromatic ring. Numerous electron ionization (EI) mass spectral fragment ions occur via processes initiated by one of the two nitrogen atoms of the piperazine ring. The major EI-MS fragment ions observed in all nine spectra occur at m/z 195 from the loss of the substituted benzyl radical and the cation atm/z56 (C3H6N)+from the piperazine ring. Unique radical cations at m/z 136 and m/z 152 are characteristic of the 2,3- and 3,5-dimethoxybenzyl isomers, respectively. The vapor phase infrared spectra for all nine compounds show a strong absorption band in the 1591–1593 cm−1region indicative of the chloroaniline moiety. Numerous bands in the 1600–650 cm−1region provide data for the differentiation of the methoxy and dimethoxybenzyl ring substitution patterns. Thus, a combination of EI-MS and vapor phase IR allow for the differentiation and specific identification of each regioisomer in this study.

Monitoring the Degradation of Metal‐Organic Framework Drug Nanocarriers by In‐Situ NMR Spectroscopy

AbstractAn accurate characterization methodology is indispensable to design nanoparticle‐based drug delivery system (DDS) adapted to specific diseases and therapies. However, characterization techniques employed to investigate drug release and nanoparticle degradation require separating the nanoparticles from their suspension media, which can lead to artefacts. Therefore, there is a clear need to implement novel versatile in‐situ methods. Here, we report the use of in‐situ NMR spectroscopy to monitor drug delivery processes from MOF nanocarriers, both in solution and in the solid state simultaneously. In‐situ 1H NMR investigation of nanoMIL‐100(Al) suspension in phosphate medium enabled recording the trimesate ligand loss in the solid phase and the ligand release in the liquid phase as a function of time. Simultaneously, 27Al NMR enabled assessing the progressive replacement of carboxylate ligands by phosphates leading to the formation of new aluminum species. Using the same strategy, we also compared the degradation of nanoMIL‐100(Al) loaded with two drug analogs, highlighting an effect of metal‐ligand complexing strength. Furthermore, our in‐situ technique is applicable to studying the reaction of paramagnetic nanoMIL‐100(Fe) in the liquid phase. This work offers an alternative to ex‐situ techniques for understanding the degradation mechanism of MOF nanocarriers and could be an asset for other nanoscale DDSs.