Indomethacin Research Articles

Small molecules modified mesoporous silica nanoparticles orally deliver indomethacin with synergistic effect

Molecularly functional drug delivery systems possessed huge potentials to realize novel drug administration. To explore small molecules modified drug delivery, a series of small molecules modified mesoporous silica nanoparticles (L-Mal-MSNs, D-Mal-MSNs) were established by grafting small molecules. Poorly water-soluble indomethacin (IMC) was chosen to load into these small molecules modified carriers as well as corresponding control carrier, and further to study characteristics and delivery effects of drug loaded carriers. The results indicated that all these small molecules modified carriers formed hydrogen bonds with drugs and can successfully convert drug crystal phase to amorphous state so as to enhance drug dissolution compared to raw drug. In vivo rat intestinal perfusion demonstrated that IMC loaded L-Mal-MSNs performed the fastest drug absorption while analgesic and anti-inflammatory effects of IMC loaded D-Mal-MSNs turned out to be the best, giving hints that D-malic acid exhibited best synergic functions for IMC. The herein small molecules modified delivery system is an effective solution strategy for the current application of analgesia and anti-inflammatory drugs with outstanding significance.

Indomethacin-omeprazole as therapeutic hybrids? Salt and co-amorphous systems enhancing physicochemical and pharmacological properties

Multidrug therapeutic hybrids constitute a promising proposal to overcome problems associated with traditional formulations containing physical mixtures of drugs, potentially improving pharmacological and pharmaceutical performance. Indomethacin (IND) is a non-selective non-steroidal anti-inflammatory drug (NSAIDs) that acts by inhibiting normal processes of homeostasis, causing a series of side effects, such as gastrointestinal symptoms. Proton pump inhibitors, such as omeprazole (OME), have been used to treat such gastrointestinal tract symptoms. In this work, two new multidrug therapeutic hybrids were prepared (an IND:OME salt and an IND:OME co-amorphous system) by ball mill grinding crystalline IND and OME under different conditions, i.e., liquid assisted grinding (LAG) with ethanol and dry grinding, respectively. The crystalline salt returned to a neutral state co-amorphous system when submitted to ball mill grinding in the absence of solvent (dry grinding), but the reverse process (LAG of the IND:OME co-amorphous system) showed partial decomposition of OME. The IND:OME co-amorphous system showed a higher physical stability than the neat IND and OME amorphous materials (with an amorphous stability longer than 100 days, compared to 4 and 16 h for the neat amorphous drugs, respectively, when stored at dry conditions at room temperature). Furthermore, OME presented a higher chemical stability in solution when dissolved from a salt form than from the pure crystalline form. The dissolution studies showed a dissolution enhancement for IND in both salt (1.8-fold after 8 h of dissolution) and co-amorphous (2.5-fold after 8 h of dissolution) forms. Anti-inflammatory activity using a mice paw oedema model showed an increase of the pharmacological response to IND at a lower dose (∼5mg/kg) for both IND:OME salt (2.8-fold) and IND:OME co-amorphous system (3.2-fold) after 6 h, when compared to the positive control group (IND, administered at 10 mg/kg). Additionally, the anti-inflammatory activity of both salt and co-amorphous form was faster than for the crystalline IND. Finally, an indomethacin-induced gastric ulceration assay in mice resulted in a higher mucosal protection at the same dose (40 mg/kg) for both IND:OME salt and IND:OME co-amorphous system when compared with crystalline OME.

Rational design of ionic covalent organic frameworks for PPCPs elimination: Insights into ibuprofen adsorption performance and mechanism

Over the last few years, non-steroidal drugs (including ibuprofen (IBP)) have been used extensively due to the impacts of COVID-19, with the resulting environmental contamination attracting the attention of researchers. For this study, an ionic covalent organic framework (iCOF), synthesized from 1,2,4,5-tetrakis (4-formylphenyl) benzene (TFPB) and 1,3-diaminoguanidine hydrochloride (DgCl) under hydrothermal conditions, was employed for the effective elimination of non-steroidal anti-inflammatory drugs (NSAIDs) from aqueous media. COFs are relatively ordered spherical structures with excellent adsorption capacities for NSAIDs (IBP, diclofenac (DCF), and indomethacin (IDM)) with a removal rate of more than 99%. The adsorption kinetics and isotherm experiments of the COFs were investigated with IBP as a target contaminant, which revealed that its adsorption attained equilibrium within 120 min. Further, increased temperatures promoted the adsorption of IBP, where its maximum adsorption at 45 °C was calculated by the Langmuir isotherm model up to 434.78 mg·g-1. In addition, different pH, ionic influences, and repeated cycling experiments also confirmed the practical applicability of the COFs. Finally, it was demonstrated that the adsorption kinetics of IBP by TFPB-DgCl-COF could be explained by electrostatic and π-π interactions.

Use of solid thermolytic salts to facilitate microwave-induced in situ amorphization

Moisture was frequently used as dielectric heating source in classical microwave-able systems to facilitate microwave-induced in situ amorphization, however such systems may face the potential of drug hydrolysis. In this study, solid thermolytic salts were proposed to function as moisture substitutes and their feasibility and impacts on microwave-induced in situ amorphization were investigated. It was found that NH4HCO3 was a promising solid alkaline salt to facilitate both microwave-induced in situ amorphization and in situ salt formation of acidic indomethacin (IND). Moreover, it could improve the chemical stability of the drug and the dissolution performance of compacts relative to classical moisture-based compacts upon microwaving. Further mechanistic study suggested that the in situ amorphization occurred prior to the in situ salt formation, especially in formulations with low drug loadings and high solid salt mass ratios. For compacts with low polymer ratios, in situ salt formation took place subsequently, where the previously amorphized IND within compacts could interact with the NH3 gas produced in situ by the decomposition of NH4HCO3 and form the ammonium IND salt. Microwaving time showed great impacts on the decomposition of NH4HCO3 and the in situ generation of water and NH3, which indirectly affected the amorphization and salt formation of IND. In comparison to the moisture-based systems, the NH4HCO3-based system showed a number of advantages, including the reduced potential of IND hydrolysis due to the absence of absorbed moisture, a wider category of applicable polymeric carriers other than hygroscopic polymers, and an increase in drug loading up to 50% (w/w).

Wound microenvironment-responsive dually cross-linked nanofibrillar peptide hydrogels for efficient hemostatic control and multi-faceted wound management

The wound microenvironment-responsive hydrogel, featuring a dually cross-linked architecture, offers distinct advantages in the realm of drug delivery due to its exceptional mechanical properties and responsiveness to stimuli. In this investigation, a versatile dually cross-linked hydrogel was synthesized. The initial framework was established through non-covalent interactions employing a self-assembling peptide indomethacin-Gly-Phe-Phe-Tyr-Gly-Arg-Gly-Asp (abbreviated as IDM-1), while the second framework underwent chemical cross-linking of chitosan (CS) mediated by genipin. This dually-network arrangement significantly bolstered the structure, proving effective for hemostatic control. In addition, hydrogels can be triggered for degradation by proteases highly expressed in the wound microenvironment, releasing drugs like indomethacin (IDM) and CS. This characteristic introduced efficient multi-faceted wound management in vitro and in vivo, such as anti-inflammatory and antibacterial activities, ultimately augmenting the wound healing process. Thus, the development of a dually cross-linked hydrogel that enables smart drug release triggered by specific wound microenvironment presents considerable potential within the realm of wound management.

Reactive oxygen species induced by indomethacin enhance accumulation of heme carrier protein 1 and hematoporphyrin accumulation in vitro and in vivo in a brain tumor model.

Photodynamic therapy (PDT) is useful for various cancers such as high-grade glioma and cancers of other organs. However, the mechanism of tumor-specific accumulation of porphyrin is not clear. The authors previously reported that heme carrier protein 1 (HCP1) contributes to the transport of porphyrins; specifically, we showed that the production of cancer-specific reactive oxygen species from mitochondria (mitROS) leads in turn to enhanced HCP1 expression. Indomethacin (IND), a non-steroidal anti-inflammatory drug, increases ROS production by affecting mitochondrial electron transfer system. In the present work, the authors investigated the effect of pretreatment with IND on cancer-specific porphyrin accumulation, using both a glioma cell line and a rat brain tumor model. This work demonstrated that exposure of a rat glioma cell to IND results in increased generation of cancer-specific mitROS and accumulation of HCP1 expression and porphyrin concentration. Additionally, systemic dosing of a brain tumor animal model with IND resulted in elevated cellular accumulation of porphyrin in tumor cell. This is an effect not seen with normal brain tissue. Thus, the administration of IND increases intracellular porphyrin concentrations in tumor cell without exerting harmful effects on normal brain tissue, and increased porphyrin concentration in tumor cell may lead to improved PDT effect.

Using a systematic and quantitative approach to generate new insights into drug loading of PLGA nanoparticles using nanoprecipitation.

The synthesis of drug-loaded PLGA nanoparticles through nanoprecipitation in solvent/antisolvent mixtures is well reported but lacks clarity in explaining drug loading mechanisms and the prediction of efficiency of drug entrapment. Various methods using physical parameters such as log P and solid-state drug-polymer solubility aim to predict the intensity of drug-polymer interactions but lack precision. In particular, the zero-enthalpy method for drug/polymer solubility may be intrinsically inaccurate, as we demonstrate. Conventional measurement of loading capacity (LC), expressed in weight ratios, can be misleading for comparing different drugs and we stress the importance of using molar units. This research aims to provide new insights and critically evaluate the established methodologies for drug loading of PLGA nanoparticles. The study employs four model drugs with varying solubilities in solvent/antisolvent mixtures, log P values, and solid-state solubility in PLGA: ketoprofen (KPN), indomethacin (IND), sorafenib (SFN), and clofazimine (CFZ). This study highlights that drug loading efficiency is primarily influenced by the drug's solubilities within the solvent system. We emphasise that both kinetic and thermodynamic factors play a role in the behaviour of the system by considering the changes in drug solubility during mixing. The study introduces a pseudo-constant K* to characterise drug-polymer interactions, with CFZ and SFN showing the highest K* values. Interestingly, while IND and KPN have lower K* values, they achieve higher loading capacities due to their greater solubilities, indicating the key role of solubility in determining LC.

Indomethacin and bromfenac may be effective in the prevention of posterior capsule opacification

Posterior capsule opacification (PCO) is the most common long‐term postoperative complication of cataract surgery, leading to secondary vision loss. Optimized intraocular lens (IOL) structure and appropriate pharmacological intervention can provide physical barriers and biological inhibition, respectively, to block the migration, proliferation, and epithelial‐mesenchymal transition (EMT) of lens epithelial cells (LECs) for PCO prophylaxis. We demonstrated that non‐steroidal anti‐inflammatory drugs (NSAIDs) are effective in preventing posterior capsule opacification. Indomethacin (INDOM) not only suppresses cell migration and down‐regulates the expression of cyclooxygenase‐2 (COX‐2) and EMT markers, including alpha‐smooth muscle actin (α‐SMA) and cyclin D1, but also promotes autophagy activation in LECs. Autophagy was also verified as a potential therapeutic target for down‐regulating EMT in LECs. Bromfenac effectively inhibits cell migration, overexpression of EMT markers such as fibronectin (FN), matrix metalloproteinase 2 (MMP2), α‐smooth muscle actin (α‐SMA), and transcription factor Snail, and extracellular signal‐regulated kinase (ERK)/glycogen synthase kinase‐3β (GSK‐3β) signalling induced by transforming growth factor‐β2 (TGF‐β2) in vitro. Based on ultrasonic spray technology, we developed a drug‐eluting intraocular lens (IOL) using poly (lactic‐co‐glycolic acid) (PLGA) with sustained release ability of indomethacin/bromfenac for PCO prevention. The novel IOL, serving as a drug delivery platform, can carry an adjustable dose of drugs with sustained release ability for more than 28 days. In the rabbit PCO model, the novel IOL showed excellent anti‐inflammatory and anti‐PCO effects. In summary, indomethacin and bromfenac are effective pharmacological interventions for PCO prophylaxis, and the novel IOL we developed prevented PCO in vivo, providing a promising approach for PCO prophylaxis in clinical applications.

Quantification of crystallinity during indomethacin crystalline transformation from α- to γ-polymorphic forms and of the thermodynamic contribution to dissolution in aqueous buffer and solutions of solubilizer.

The thermodynamic properties and dissolution of indomethacin (INM) were analyzed as models for poorly water-soluble drugs. Physical mixtures of the most stable γ-form and metastable α-form of INM at various proportions were prepared, and their individual signal intensities proportional to their mole fractions were observed using X-ray powder diffraction and Fourier transform infrared spectrometry at standard temperature. The endothermic signals of the α-form, with a melting point of 426 K, and that of the γ-form, with a melting point of 433 K, were obtained by differential scanning calorimetry (DSC). Furthermore, an exothermic DSC peak of the α/γ-phase transition at approximately 428 K was obtained. As we computed the melting entropy of the α-form and that of its transformation, the frequency of the transition was quantitatively determined, which indicated the maximum of the α/γ-phase transition at an α-form proportion of 68%. Subsequently, the thermodynamic contributions of the α- and γ-forms were analyzed using a Van't Hoff plot for solubility in aqueous solutions at pH 6.8. The dissolution enthalpies for α- and γ-forms were 28.2 and 31.2 kJ mol-1, respectively, which are in agreement with the quantitative contribution predicted by the product of the temperature and melting entropy. The contribution of melting entropy was conserved in different dissolution processes with aqueous solvents containing lidocaine, diltiazem, l-carnosine, and aspartame as solubilizers; their γ-form Setschenow coefficients were -39.6, +82.9, -17.3, and +23.2, whereas those of the α-form were -39.7, +80.4, -16.7, and +22.7, respectively. We conclude that the dissolution ability of the solid state and solubilizers indicate their additivity independently.

PERFORMANCE OF THE JOUYBAN-ACREEAND YALKOWSKY-ROSEMAN MODELSFOR ESTIMATING THE SOLUBILITY OFINDOMETHACIN IN ETHANOL + WATERMIXTURES

Indomethacin (IMC) is an anti-inflammatory drug whose physiochemical properties in aqueous solutions have not been studied thoroughly. For this reason, in this work the validity of the Jouyban-Acree and Yalkowsky-Roseman models is evaluated to predict the solubility of this compound in ethanol + water cosolvent mixtures. The solubility estimation is studied as a function of temperature and cosolvent composition. Both models require only the experimental solubility values in the pure solvents at all the temperatures evaluated. The solubility calculated values by using both models deviate notoriously from experimental values in several cases.

Co-delivery of indomethacin and uricase as a new strategy for inflammatory diseases associated with high uric acid.

Uric acid is the final metabolite in humans. High level of uric acid chronically induces urate deposition, aggravates kidney damage, and concomitantly causes an increase in inflammatory factors. Alleviating acute inflammation and decreasing uric acid levels are the key points in the treatment of inflammatory diseases associated with high uric acid. However, a drug delivery system that combines anti-inflammatory and uric acid reduction functions at the same time remains a challenge to be settled. Here, we designed a nanocrystal-based co-delivery platform, IND Nplex, characterized by loading of indomethacin (IND) and uricase. Compared with free IND or uricase, IND Nplex possessed a better anti-inflammatory effect by restraining the release of inflammation-related factors in vitro. In addition, pharmacokinetic and biodistribution studies revealed that IND Nplex significantly prolonged the retention time in vivo and was more concentrated in the kidney. In acute gouty arthritis model rats, IND Nplex markedly relieved ankle joint swelling and mitigated synovial inflammation. In acute kidney injury model rats, IND Nplex indicated better biocompatibility and significant amelioration of renal fibrosis. Moreover, IND Nplex showed the effect of anti-inflammatory and improved renal function via determination of inflammatory factors and biochemical markers in the serum and kidney. In conclusion, these results indicate that IND Nplex exerts anti-inflammatory activity and uric acid-lowering effect and could become a promising candidate for the treatment of uric acid-related diseases.

Synergistic gastroprotective and antioxidative effects of natural olive oil and usnic acid isolated from Usnea longissima, a lichen species in Anatolia (Türkiye), in the indomethacin ulcer model created in rats

Usnea longissima, a medically important lichen growing up in forests in Anatolia (Turkey). In this study, the gastroprotective effect of usnic acid (UA) was investigated using an indomethacin (IND)-induced gastric ulcer model in rats. While 25, 50, 100 and 200 mg/kg UA doses were dissolved in 2 ml of olive oil (OO) and administered to rats, only OO was given to one group. In addition, lansoprazole (LAN) and ranitidine (RAN) and IND were dissolved in water and administered to rat groups. IND administration caused very high levels of damage to rat stomachs. On the other hand, when four doses of UA, OO, RAN and LAN were administered, it was determined that hyperemias in the stomach of rats was significantly reduced. After macroscopic analysis of gastric tissues, the activities of superoxide dismutase (SOD), catalase (CAT), myeloperoxidase (MPO) and nitric oxide synthase (iNOS and cNOS) enzymes as well as glutathione (GSH) and lipid peroxidation (LPO) levels were determined in these tissues. After IND application, it was detected increases in MPO, CAT and iNOS activities in gastric tissues and decreases in SOD, cNOS and GSH amounts. Four doses of UA, OO, RAN and LAN applications reversed the trend, bringing them closer to healthy levels.

Hypoxia-Responsive Golgi-Targeted Prodrug Assembled with Anthracycline for Improved Antitumor and Antimetastasis Efficacy.

Tumor metastasis is an intricate multistep process regulated via various proteins and enzymes modified and secreted by swollen Golgi apparatus in tumor cells. Thus, Golgi complex is considered as an important target for the remedy of metastasis. Currently, Golgi targeting technologies are mostly employed in Golgi-specific fluorescent probes for diagnosis, but their applications in therapy are rarely reported. Herein, we proposed a prodrug (INR) that can target and destroy the Golgi apparatus, which consisted of indomethacin (IMC) as the Golgi targeting moiety and retinoic acid (RA), a Golgi disrupting agent. The linker between IMC and RA was designed as a hypoxia-responsive nitroaromatic structure, which ensured the release of the prototype drugs in the hypoxic tumor microenvironment. Furthermore, INR could be assembled with pirarubicin (THP), an anthracycline, to form a carrier-free nanoparticle (NP) by emulsion-solvent evaporation method. A small amount of mPEG2000-DSPE was added to shield the positive charges and improve the stability of the nanoparticle to obtain PEG-modified nanoparticle (PNP). It was proved that INR released the prototype drugs in tumor cells and hypoxia promoted the release. The Golgi destructive effect of RA in INR was amplified owing to the Golgi targeting ability of IMC, and IMC also inhibited the protumor COX-2/PGE2 signaling. Finally, PNP exhibited excellent curative efficacy on 4T1 primary tumor and its pulmonary and hepatic metastasis. The small molecular therapeutic prodrug targeting Golgi apparatus could be adapted to multifarious drug delivery systems and disease models, which expanded the application of Golgi targeting tactics in disease treatment.

Comprehensive evaluation of polymer types and ratios in Spray-Dried Dispersions: Compaction, Dissolution, and physical stability

Amorphous solid dispersion (ASD) is a well-established strategy for enhancing the solubility and bioavailability of poorly soluble drugs. A significant portion of ASD products are in tablet form. However, the influence of common polymers and drug loading on the manufacturability of ASD tablets remains underexplored. This study focuses on investigating spray-dried ASDs from a tableting perspective by evaluating their physiochemical and mechanical properties. Itraconazole (ITZ) and indomethacin (IND), at the drug loadings ranging from 10% to 50%, were prepared with two polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP), serving as representative systems. Our findings revealed that increasing the drug loading resulted in a decreased surface area in ITZ-HPMCAS, IND-HPMCAS, and IND-PVP ASDs. However, this trend was not observed in ITZ-PVP dispersions, possibly due to the morphological disparities. Compaction results demonstrated that tabletability improved with decreasing drug loadings, except for ITZ-PVP dispersions. A partial least square analysis underscored particle surface area as the key factor influencing the tensile strength of ASD tablets. Additionally, our study disclosed that ITZ-PVP ASDs exhibited the worst release profiles and stability performance. The comprehensive journey from characterizing ASD particles to analyzing their compaction behavior and investigating drug release and physical stability offered profound insights into the attributes crucial for the downstream processing of amorphous pharmaceuticals.

Recovery from indomethacin-induced gastrointestinal bleeding by treatment with teprenone

BackgroundGastrointestinal injuries caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is a serious side effect in patients with rheumatoid arthritis (RA). However, effective therapeutic strategies have yet to be established. In this study, we investigated the therapeutic effects of teprenone (TEP), a gastric mucosal protective drug, on NSAID-induced gastrointestinal injuries in rats with RA (AA rats).MethodsGastrointestinal injury was induced by oral administration of indomethacin (IMC), a typical NSAID. TEP was orally administered after IMC-induced gastrointestinal bleeding, and the stomach, jejunum, and ileum were excised.ResultsOn day 14 of IMC administration, lesion areas in the stomach, jejunum, and ileum were significantly larger in AA rats than in normal rats. When TEP was orally administered to AA rats, the lesion areas in the stomach, jejunum, and ileum significantly decreased compared with those in control rats (IMC-induced AA rats). Therefore, we measured NOS2 mRNA and NO levels, which were significantly decreased in rats with IMC-induced AA after treatment with TEP.ConclusionsThese results suggest that the oral administration of TEP may be useful for the treatment of NSAID-induced gastrointestinal injuries in patients with RA.

Nanoparticles exhibiting virus-mimic surface topology for enhanced oral delivery

The oral delivery of nano-drug delivery systems (Nano-DDS) remains a challenge. Taking inspirations from viruses, here we construct core–shell mesoporous silica nanoparticles (NPs, ~80 nm) with virus-like nanospikes (VSN) to simulate viral morphology, and further modified VSN with L-alanine (CVSN) to enable chiral recognition for functional bionics. By comparing with the solid silica NPs, mesoporous silica NPs and VSN, we demonstrate the delivery advantages of CVSN on overcoming intestinal sequential barriers in both animals and human via multiple biological processes. Subsequently, we encapsulate indomethacin (IMC) into the nanopores of NPs to mimic gene package, wherein the payloads are isolated from bio-environments and exist in an amorphous form to increase their stability and solubility, while the chiral nanospikes multi-sited anchor and chiral recognize on the intestinal mucosa to enhance the penetrability and ultimately improve the oral adsorption of IMC. Encouragingly, we also prove the versatility of CVSN as oral Nano-DDS.

The inherent AIE feature revealed the drug molecular state in cyclodextrin metal–organic framework for enhanced stability and absorption

The amorphous form of a drug can greatly improve the solubility and rates of dissolution for enhancing oral bioavailability. However, amorphous drugs tend to crystallize thus negating their solubility advantages. Here, we use a nanoconfinement strategy to prevent the crystallization of amorphous solids by loading the poorly soluble drug indomethacin (IMC) into a porous γ-cyclodextrin-based metal–organic framework (CD-MOF). The inherent aggregation-induced emission (AIE) property of IMC was successfully applied as a sensitive fluorescence imaging tool to visualize its molecular state in the solid form. A distinct high-energy, non-aggregated molecular state of IMC in CD-MOF was revealed by the AIE turn-off phenomenon together with other solid-state characterization methods. The IMC@CD-MOF exhibited excellent physical stability even when stored at high temperature or humidity. The high supersaturated drug solutions were immediately generated and maintained during the dissolution of IMC@CD-MOF, resulting in a great enhancement of in vivo bioavailability. The inherent AIE feature of drugs can facilitate the understanding of the structure–property relationship in complex delivery systems, which is essential for the design and optimization of drug carriers with desired stability and biopharmaceutical performance.

Nifuroxazide attenuates indomethacin-induced renal injury by upregulating Nrf2/HO-1 and cytoglobin and suppressing NADPH-oxidase, NF-κB, and JAK-1/STAT3 signals.

Indomethacin (INDO) is an NSAID with remarkable efficacy and widespread utilization for alleviating pain. Nevertheless, renal function impairment is an adverse reaction linked to INDO usage. Nifuroxazide (NFX), an oral nitrofuran antibiotic, is frequently employed as an intestinal anti-infective agent. Our study aimed to investigate the renoprotective effects of NFX against INDO-induced nephrotoxicity and explore the protection mechanisms. Four groups of rats were allocated to (I) the normal control, (II) the NFX-treated (50mg/kg), (III) INDO control (20mg/kg), and (IV) NFX + INDO. NFX attenuates renal impairment in INDO-induced renal injury, proved by decreasing serum levels of urea, creatinine, uric acid, and NGAL while the albumin was elevated. NFX mitigates renal oxidative stress by decreasing MDA levels and restoring the antioxidants' GSH and SOD levels mediated by upregulating Nrf2, HO-1, and cytoglobin pathways. NFX mitigated renal inflammation and effectively decreased MPO, IL-1β, and TNF-α levels in the rat's kidney mediated by significant downregulation of NADPH-oxidase and NF-κB expression and suppression of JAK-1 and STAT3 phosphorylation. NFX mitigates renal apoptosis by decreasing the expression of cleaved caspase-3 expression. In conclusion, NFX treatment prevents INDO nephrotoxicity by regulating Nrf2/HO-1, cytoglobin, NADPH-oxidase, NF-κB, and JAK-1/STAT3 signals.

Tumor‐Activated Prodrug with Synergistic Anti‐Stemness Chemical and Photodynamic Therapies

AbstractPhotodynamic therapy (PDT) has received extensive attention as a promising cancer treatment approach. Still, challenges to in vivo photodynamic therapy have existed for decades. First, the “always on” nature of conventional photosensitizers will cause damage to normal tissues thereby limiting the treatment efficiency of PDT. Second, the hypoxic TME protects cancer stem cells (CSCs) deeply harbored in the center of tumors from PDT administration, thus contributing to the recrudescence and metastasis of tumors. Herein, a ROS‐triggered self‐immolative therapeutic prodrug (Mu‐PS) is reported, comprising of an activatable photosensitizer, an indomethacin (IMC) part, and a ROS‐responsive trigger, for the anti‐stemness chemical and photodynamic therapy of tumors. Intriguingly, Mu‐PS can target the tumor and selectively release the photosensitizer and IMC upon the activation of TME‐related ROS, generating massive phototoxic 1O2 to kill most non‐CSCs tumor cells under the action of PDT and block the growth of CSCs by IMC, hence, it multiplies the therapeutic index. Noteworthy, the anti‐stemness mechanism of IMC in tumors is confirmed and elucidated for the first time. Overall, this study introduces a self‐immolatative prodrug for combined CSCs‐involved chemical therapy and activatable PDT for tumors and provides a design paradigm of prodrug for the precise prognosis and treatment of tumors.

Evaluation of hyaluronic acid-polymacrolactone hydrogels with 3D printing capacity

The implementation of personalized patches, tailored to individual genetic profiles and containing specific amounts of bioactive substances, has the potential to produce a transformative impact within the medical sector. There are several methods of designing scaffolds in the context of personalized medicine, with three-dimensional (3D) printing emerging as a pivotal technique. This innovative approach can be used to construct a wide variety of pharmaceutical dosage forms, characterized by variations in shape, release profile, and drug combinations, allowing precise dose individualization and the incorporation of multiple therapeutic agents. To expand the potential and applicability of personalized medicine, particularly with regards to indomethacin (IND), a drug necessitating individualized dosing, this study proposes the development of new transdermal delivery systems for IND based on hyaluronic acid and a polylactone synthesized within our research group, namely poly(ethylene brasilate-co-squaric acid) (PEBSA). The obtained systems were characterized in terms of their swelling capacity, rheological behavior, and morphological characteristics that highlighted the formation of stable three-dimensional networks. To impart specific shape and geometry to the structures, multi-component systems based on PEBSA, HA, and methacrylate gelatin were obtained. The scaffolds were loaded with IND and subsequently 3D printed. The release capacity of IND and its dependence on the relative ratios of the components comprising the scaffold composition were highlighted. The cytocompatibility studies revealed the successful development of biocompatible and noncytotoxic systems.