OCTN2- and ATB0,+-targeted nanoemulsions for improving ocular drug delivery.

Traditional eye drops are administered via topical instillation. However, frequent dosing is needed due to their relatively rapid precorneal removal and low ocular bioavailability. To address these issues, stearoyl L-carnitine-modified nanoemulsions (SC-NEs) were fabricated. The physicochemical properties of SC-NEs in terms of size, morphology, zeta potential, encapsulation efficiency, and in vitro drug release behavior were characterized. The cellular uptake and mechanisms of SC-NEs were comprehensively studied in human corneal epithelial cells and the stearoyl L-carnitine ratio in SC-NEs was optimized. The optimized SC-NEs could target the novel organic cation/carnitine transporter 2 (OCTN2) and amino acid transporter B (0 +) (ATB0,+) on the corneal epithelium, which led to superior corneal permeation, ocular surface retention ability, ocular bioavailability. Furthermore, SC-NEs showed excellent in vivo anti-inflammatory efficacy in a rabbit model of endotoxin-induced uveitis. The ocular safety test indicated that the SC-NEs were biocompatible. In general, the current study demonstrated that OCTN2 and ATB0,+-targeted nanoemulsions were promising ophthalmologic drug delivery systems that can improve ocular drug bioavailability and boost the therapeutic effects of drugs for eye diseases.

Preventive and therapeutic effects of rifaximin on hepatic encephalopathy with differential application dosages and strategies: a network meta-analysis.

BACKGROUND: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that affects the prognosis of patients with liver disease and is considered an independent risk factor for hospitalization and death. Rifaximin has been approved for HE treatment. This review will analyze the effect of rifaximin on different stages of HE with differential application dosages and strategies by traditional and network meta-analyses. METHODS: We performed a systematic search of PubMed, EmBase, and Cochrane Library databases up to February 26, 2023, to identify randomized controlled trials (RCTs) about rifaximin for the prevention and treatment of HE. The outcomes included incidence of HE and HE progression, HE reversal, mortality, and adverse effects. RESULTS: A total of 21 studies were included. In the primary prevention of HE, rifaximin significantly reduced the incidence of HE (OR: 0.66; 95% CI: 0.45, 0.96; p = 0.032). In secondary prevention, rifaximin significantly reduced the risk of recurrence in patients who were in remission (OR: 0.38; 95% CI: 0.28, 0.52; p < 0.001). In the treatment of minimal HE, rifaximin significantly reduced the breakthrough of MHE to OHE (OR: 0.17; 95% CI: 0.04,0.63; p = 0.008). Rifaximin also significantly improved the clinical symptoms of MHE and OHE patients (OR: 3.76; 95% CI: 2.69, 5.25; p < 0.001). However, rifaximin did not reduce mortality at any stage in HE patients (OR: 0.79; 95% CI: 0.58, 1.08; p = 0.133). Additionally, rifaximin did not increase the risk of adverse effects (OR: 0.96; 95% CI: 0.74, 1.24; p = 0.749). In the network meta-analysis, the 400 mg T.I.D. intervention had a relative advantage for HE risks in primary and secondary prevention. In the treatment of MHE, 600 mg b.i.d. was superior in preventing the breakthrough from MHE to OHE. CONCLUSION: Rifaximin prevented HE risks and progression and improved clinical symptoms in patients with MHE but did not reduce mortality. For primary and secondary prevention, 400 mg t.i.d. could be considered. 600 mg b.i.d. could be considered in patients with MHE.

Nanocarriers containing platinum compounds for combination chemotherapy.

Platinum compounds-based drugs are used widely in the clinic for the treatment of many types of cancer. However, serious undesirable side effects and intrinsic or acquired resistance limit their successful clinic use. Nanocarrier-based combination chemotherapy is considered to be an effective strategy to resolve these challenges. This review introduces the recent advance in nanocarriers containing platinum compounds for combination cancer chemotherapy, including liposomes, polymer nanoparticles, polymer micelles, mesoporous silica nanoparticles, carbon nanohors, polymer-caged nanobins, carbon nanotube, nanostructured lipid carriers, solid lipid nanoparticles, and multilayered fiber mats in detail.

Polypseudorotaxane hydrogel based on Tween 80 and α-cyclodextrin for sustained delivery of low molecular weight heparin.

Low molecular weight heparin (LMWH), an anionic polysaccharide, has been widely used as a clinical anticoagulant. However, repeated subcutaneous injection is sometimes required due to its short half-life. To reduce the dosing frequency, the injectable polypseudorotaxane hydrogel was fabricated by inclusion complexation formation between Tween 80 and α-Cyclodextrin (αCD) for sustained release of LMWH. The physicochemical properties of such hydrogel were characterized by SEM, XRD, DSC, and FTIR. This hydrogel showed shear-thinning and thixotropic behavior and was easily injected through standard syringe needles. The gelation time, mechanical strength, shear viscosity, in vitro drug release rate, in vitro hydrogel dissolution rate, and in vivo hydrogel retention could be tuned by αCD concentration in the hydrogel. In vivo safety evaluation indicated that the polypseudorotaxane hydrogel was biocompatible. Most importantly, this polypseudorotaxane hydrogel could sustain release of LMWH after subcutaneous injection.

Strategies for sustained release of heparin: A review.

Heparin, a sulfate-containing linear polysaccharide, has proven preclinical and clinical efficacy for a variety of disorders. Heparin, including unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and ultra-low-molecular-weight heparin (ULMWH), is administered systematically, in the form of a solution in the clinic. However, it is eliminated quickly, due to its short half-life, especially in the case of UFH and LMWH. Frequent administration is required to ensure its therapeutic efficacy, leading to poor patient compliance. Moreover, heparin is used to coat blood-contacting medical devices to avoid thrombosis through physical interaction. However, the short-term durability of heparin on the surface of the stent limits its further application. Various advanced sustained-release strategies have been used to prolong its half-life in vivo as preparation technologies have improved. Herein, we briefly introduce the pharmacological activity and mechanisms of action of heparin. In addition, the strategies for sustained release of heparin are comprehensively summarized.

γ-Cyclodextrin-based polypseudorotaxane hydrogels for ophthalmic delivery of flurbiprofen to treat anterior uveitis.

Anterior uveitis is a sight-threatening inflammation inside the eyes. Conventional eye drops for anti-inflammatory therapy need to be administered frequently owing to the rapid elimination and corneal barrier. To address these issues, polypseudorotaxane hydrogels were developed by mixing Soluplus micelles (99.4 nm) and cyclodextrins solution. The optimized hydrogels exhibited shear-thinning and sustained release properties. The hydrogels exhibited higher transcorneal permeability coefficient (Papp, 1.84 folds) than that of drug solutions. Moreover, animal study indicated that the hydrogels significantly increased the precorneal retention (AUC, 21.2 folds) and intraocular bioavailability of flurbiprofen (AUCAqueous humor, 17.8 folds) in comparison with drug solutions. Importantly, the hydrogels obviously boosted anti-inflammatory efficacy in rabbit model of endotoxin-induced uveitis at a reduced administration frequency. Additionally, the safety of hydrogels was confirmed by cytotoxicity and ocular irritation studies. In all, the present study demonstrates a friendly non-invasive strategy based on γ-CD-based polypseudorotaxane hydrogels for ocular drug delivery.

Enhanced topical corticosteroids delivery to the eye: A trade-off in strategy choice.

Topical corticosteroids are the primary treatment of ocular inflammation caused by surgery, injury, or other conditions. Drug pre-corneal residence time, drug water solubility, and drug corneal permeability coefficient are the major factors that determine the ocular drug bioavailability after topical administration. Although growing research successfully enhanced local delivery of corticosteroids utilizing various strategies, rational and dynamic approaches to strategy selection are still lacking. Within this review, an overview of the various strategies as well as their performance in retention, solubility, and permeability coefficient of corticosteroids are provided. On this basis, the tradeoff of strategy selection is discussed, which may shed light on the rational choice and application of ophthalmic delivery enhancement strategies.

Hydrogels-based ophthalmic drug delivery systems for treatment of ocular diseases.

An increasing number of people worldwide are affected by eye diseases, eventually leading to visual impairment or complete blindness. Conventional treatment involves the use of eye drops. However, these formulations often confer low ocular bioavailability and frequent dosing is required. Therefore, there is an urgent need to develop more effective drug delivery systems to tackle the current limitations. Hydrogels are multifunctional ophthalmic drug delivery systems capable of extending drug residence time and sustaining release of drugs. In this review, common ocular diseases and corresponding therapeutic drugs are briefly introduced. In addition, various types of hydrogels reported for ophthalmic drug delivery, including in-situ gelling hydrogels, contact lenses, low molecular weight supramolecular hydrogels, cyclodextrin/poly (ethylene glycol)-based supramolecular hydrogels and hydrogel-forming microneedles, are summarized. Besides, marketed hydrogel-based opthalmic formulations and clinical trials are also highlighted. Finally, critical considerations regarding clinical translation of biologics-loaded hydrogels are discussed.

Dithiocarbazate-Copper Complexes for Bioimaging and Treatment of Pancreatic Cancer.

Anticancer agents that present nonapoptotic cell death pathways are required for treating apoptosis-resistant pancreatic cancer. Here, we synthesized three fluorescent dithiocarbazate-copper complexes, {[CuII(L)(Cl)] 1, [CuII2(L)2(NO3)2] 2, and [CuII2CuI(L)2(Br)3] 3}, to assess their antipancreatic cancer activities. Complexes 1-3 showed significantly greater cytotoxicity toward several pancreatic cancer cell lines with better IC50 than those of the HL ligand and cisplatin. Confocal fluorescence imaging showed that complex 3 was primarily localized in the mitochondria. Primarily, compound 3 also can be applied to in vivo imaging. Further studies revealed that complex 3 kills pancreatic cancer cells by triggering multiple mechanisms, including ferroptosis. Complex 3 is the first copper complex to evoke cellular events consistent with ferroptosis in cancer cells. Finally, it significantly retarded the ASPC-1 cells' growth in a mouse xenograft model.

Current advances in the nano-delivery of celastrol for treating inflammation-associated diseases.

Inflammation is ubiquitous in the body, and uncontrolled inflammation often contributes to various diseases. Celastrol, a compound isolated from a Chinese medicinal herb, holds great potential in treating multiple inflammation-associated diseases. However, its further clinical use is limited by its poor solubility, bioavailability, and high organ toxicity. With the advancement of nanotechnology, the nano-delivery of celastrol can effectively improve its oral bioavailability, maximize its efficacy and minimize its side effects. Here, we summarize the roles of celastrol in the treatment of various inflammation-associated diseases, with a special emphasis on its role in modulating immune cell signaling or non-immune cell signaling within the inflammatory microenvironment, and we highlight the latest advances in nano-delivery strategies for celastrol to treat diseases associated with inflammation.

Metabolic Profiling of a Porcine Combat Trauma-Injury Model Using NMR and Multi-Mode LC-MS Metabolomics-A Preliminary Study.

Profiles of combat injuries worldwide have shown that penetrating trauma is one of the most common injuries sustained during battle. This is usually accompanied by severe bleeding or hemorrhage. If the soldier does not bleed to death, he may eventually succumb to complications arising from trauma hemorrhagic shock (THS). THS occurs when there is a deficiency of oxygen reaching the organs due to excessive blood loss. It can trigger massive metabolic derangements and an overwhelming inflammatory response, which can subsequently lead to the failure of organs and possibly death. A better understanding of the acute metabolic changes occurring after THS can help in the development of interventional strategies, as well as lead to the identification of potential biomarkers for rapid diagnosis of hemorrhagic shock and organ failure. In this preliminary study, a metabolomic approach using the complementary platforms of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography coupled with mass spectrometry (LC-MS) was used to determine the metabolic changes occurring in a porcine model of combat trauma injury comprising of penetrating trauma to a limb with hemorrhagic shock. Several metabolites associated with the acute-phase reaction, inflammation, energy depletion, oxidative stress, and possible renal dysfunction were identified to be significantly changed after a thirty-minute shock period.

Advanced delivery strategies facilitating oral absorption of heparins.

Heparins show great anticoagulant effect with few side effects, and are administered by subcutaneous or intravenous route in clinics. To improve patient compliance, oral administration is an alternative route. Nonetheless, oral administration of heparins still faces enormous challenges due to the multiple obstacles. This review briefly analyzes a series of barriers ranging from poorly physicochemical properties of heparins, to harsh biological barriers including gastrointestinal degradation and pre-systemic metabolism. Moreover, several approaches have been developed to overcome these obstacles, such as improving stability of heparins in the gastrointestinal tract, enhancing the intestinal epithelia permeability and facilitating lymphatic delivery of heparins. Overall, this review aims to provide insights concerning advanced delivery strategies facilitating oral absorption of heparins.

Development of Lipid-Polymer Hybrid Nanoparticles for Improving Oral Absorption of Enoxaparin.

Enoxaparin, an anticoagulant that helps prevent the formation of blood clots, is administered parenterally. Here, we report the development and evaluation of lipid-polymer hybrid nanoparticles (LPHNs) for the oral delivery of enoxaparin. The polymer poloxamer 407 (P407) was incorporated into lipid nanoparticles to form gel cores and ensure high encapsulation efficiency and the controlled release of enoxaparin. In vitro results indicated that 30% of P407 incorporation offered higher encapsulation efficiency and sustained the release of enoxaparin. Laser confocal scanning microscopy (LCSM) images showed that LPHNs could not only significantly improve the accumulation of enoxaparin in intestinal villi but also facilitate enoxaparin transport into the underlayer of intestinal epithelial cells. In vivo pharmacokinetic study results indicated that the oral bioavailability of enoxaparin was markedly increased about 6.8-fold by LPHNs. In addition, its therapeutic efficacy against pulmonary thromboembolism was improved 2.99-fold by LPHNs. Moreover, LPHNs exhibited excellent biocompatibility in the intestine. Overall, the LPHN is a promising delivery carrier to boost the oral absorption of enoxaparin.

VE-Albumin Core-Shell Nanoparticles for Paclitaxel Delivery to Treat MDR Breast Cancer.

Multi-drug resistance (MDR) presents a serious problem in cancer chemotherapy. In this study, Vitamin E (VE)-Albumin core-shell nanoparticles were developed for paclitaxel (PTX) delivery to improve the chemotherapy efficacy in an MDR breast cancer model. The PTX-loaded VE-Albumin core-shell nanoparticles (PTX-VE NPs) had small particle sizes (about 100 nm), high drug entrapment efficiency (95.7%) and loading capacity (12.5%), and showed sustained release profiles, in vitro. Docking studies indicated that the hydrophobic interaction and hydrogen bonds play a significant role in the formation of the PTX-VE NPs. The results of confocal laser scanning microscopy analysis demonstrated that the cell uptake of PTX was significantly increased by the PTX-VE NPs, compared with the NPs without VE (PTX NPs). The PTX-VE NPs also exhibited stronger cytotoxicity, compared with PTX NPs with an increased accumulation of PTX in the MCF-7/ADR cells. Importantly, the PTX-VE NPs showed a higher anti-cancer efficacy in MCF-7/ADR tumor xenograft model than the PTX NPs and the PTX solutions. Overall, the VE-Albumin core-shell nanoparticles could be a promising nanocarrier for PTX delivery to improve the chemotherapeutic efficacy of MDR cancer.

Polyester-Solid Lipid Mixed Nanoparticles with Improved Stability in Gastro-Intestinal Tract Facilitated Oral Delivery of Larotaxel.

The objective of this study was to investigate the role of core stability of nanoparticles on their performances in oral drug delivery. Solid lipids (Geleol Mono and Diglycerides Nf) were incorporated into nanoparticles composed of mPEG-b-PCL by the dialysis method. The prepared solid lipid loaded nanoparticles were found to be spherical nanoparticles with a core state and size distribution dependent on the amount of solid lipid incorporated. The critical aggregation concentrations of lipid-loaded nanoparticles were determined using pyrene fluorescence. Then, the stability of block copolymer in nanoparticles with different solid lipid contents was studied in simulated gastric fluid and simulated intestinal fluid. Solid lipids were found to stabilize nanoparticle cores by improving not only the thermodynamic stability (lowered CAC) of the nanoparticle but also the chemical stability of the block copolymer in the gastrointestinal environment. The stability of the loaded drug (larotaxel, LTX) in nanoparticles with different solid lipid contents was challenged by intestinal homogenate and rat liver microsome, and solid lipid loaded nanoparticles showed superior drug-protecting capability. Solid lipid incorporation exhibited limited influence on the cytotoxicity and cellular uptake but improved the transcytosis of nanoparticles in Caco-2 monolayers. The results of pharmacokinetic study indicated that core stabilization was helpful in promoting oral larotaxel absorption as the absolute bioavailability of LTX delivered by solid lipid loaded nanoparticles was found to be 13.17%, compared with that by the lipid-free nanoparticles (6.264%) and LTX solution (2.435%). Additionally, the results of biodistribution study indicated relatively higher particle integrity of solid lipid loaded nanoparticles, shown by slower liver and spleen accumulation rate, compared with its lipid-free counterpart. Overall, incorporation of solid lipids made the nanoparticles more suitable for oral drug delivery.

Biodegradable Polymersomes as Nanocarriers for Doxorubicin Hydrochloride: Enhanced Cytotoxicity in MCF-7/ADR Cells and Prolonged Blood Circulation.

PURPOSE: DOX is one of the most potent anticancer drugs. But its short half-life and the occurrence of multi-drug resistance (MDR) markedly limit its clinical application. To solve these problems, we develop DOX loaded polymersomes (DOX polymersomes). METHODS: An methoxy poly(ethylene glycol)-b-poly(epsilon-caprolactone) (mPEG-b-PCL) copolymer was synthesized and used to prepare DOX polymersomes. The pharmaceutical properties of DOX polymersomes were characterized. The in vitro release profile of DOX from polymersomes was investigated. The in vitro cytotoxicity and cell uptake studies were performed on MCF-7 and MCF-7/ADR cells. The in vivo pharmacokinetic profiles were investigated on Sprague-Dawley rats. RESULTS: DOX polymersomes had a nano-scale particle size of about 60 nm with a hydrophobic membrane about 10 nm in thickness. Release of DOX from the polymersomes took place in a sustained manner. Cell experiments showed DOX polymersomes enhanced the cytotoxicity and the intracellular accumulation of DOX in MCF-7/ADR cells, compared with free DOX. In vivo pharmacokinetic study showed the DOX polymersomes increased the bioavailability and prolonged the circulation time in rats. CONCLUSIONS: The entrapment of DOX in biodegradable polymersomes could enhance cytotoxicity in MCF-7/ADR cells and improve its in vivo pharmacokinetic profile.

Decreased Core Crystallinity Facilitated Drug Loading in Polymeric Micelles without Affecting Their Biological Performances.

Cargo-loading capacity of polymeric micelles could be improved by reducing the core crystallinity and the improvement in the amount of loaded cargo was cargo-polymer affinity dependent. The effect of medium chain triglyceride (MCT) in inhibiting PCL crystallization was confirmed by DSC and polarized microscope. When incorporating MCT into polymeric micelles, the maximum drug loading of disulfiram (DSF), cabazitaxel (CTX), and TM-2 (a taxane derivative) increased from 2.61 ± 0.100%, 13.5 ± 0.316%, and 20.9 ± 1.57% to 8.34 ± 0.197%, 21.7 ± 0.951%, and 28.0 ± 1.47%, respectively. Moreover, the prepared oil-containing micelles (OCMs) showed well-controlled particle size, good stability, and decreased drug release rate. MCT incorporation showed little influence on the performances of micelles in cell studies or pharmacokinetics. These results indicated that MCT incorporation could be a core construction module applied in the delivery of hydrophobic drugs.

Cysteine-Functionalized Nanostructured Lipid Carriers for Oral Delivery of Docetaxel: A Permeability and Pharmacokinetic Study.

Here we report the development and evaluation of cysteine-modified nanostructured lipid carriers (NLCs) for oral delivery of docetaxel (DTX). The NLCs ensure high encapsulation efficiency of docetaxel, while the cysteine bound the NLCs with PEG2000-monostearate (PEG2000-MSA) as a linker, and allowed a specific interaction with mucin of the intestinal mucus layer and facilitated the intestinal transport of docetaxel. The cysteine-modified NLCs (cNLCs) had a small particle size (<100 nm) and a negative zeta potential (-13.72 ± 0.07 mV), which was lower than that of the unmodified NLCs (uNLCs) (-6.39 ± 0.07 mV). This correlates well with the location of the cysteine group on the surface of the NLCs obtained by X-ray photoelectron spectroscopy (XPS). The cNLCs significantly improved the mucoadhesion properties compared with uNLCs. The intestinal absorption of cNLCs in total intestinal segments was greatly improved in comparison with uNLCs and docetaxel solution (DTX-Sol), and the in vivo imaging system captured pictures also showed not only increased intestinal absorption but also improved accumulation in blood. The cNLCs could be absorbed into the enterocytes via both endocytosis and passive transport. The results of the in vivo pharmacokinetic study indicated that the AUC0-t of cNLCs (1533.00 ng/mL·h) was markedly increased 12.3-fold, and 1.64-fold compared with docetaxel solution and uNLCs, respectively. Overall, the cysteine modification makes nanostructured lipid carriers more suitable as nanocarriers for oral delivery of docetaxel.

Liprosomes loading paclitaxel for brain-targeting delivery by intravenous administration: in vitro characterization and in vivo evaluation.

In this study, a lipid-protein nanocomplex (liprosome) was evaluated for its potential use for brain-targeting drug delivery. Liprosome was fabricated with the desolvation-ultrasonication method and characterized in terms of particle size, size distribution, zeta potential, morphology, crystal state of the drug, and in vitro release. The in vivo distribution of paclitaxel loading lipid-protein nanocomplex (PTX-liprosome) and Taxol were compared after i.v. administration in mice. The prepared PTX-liprosome has a high entrapment efficiency (>90%), small particle size (approximately 110 nm), and narrow distribution (P.I.<0.2). Transmission electron microscopy (TEM) indicated that liprosome had a spherical multilayer structure. X-ray photoelectron spectroscopy (XPS) showed that the conjugate of PTX and BSA was in the interior of the PTX-liprosome. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) demonstrated that the drug existed in a molecular or amorphous state. Fourier transform infrared spectroscopy (FTIR) suggested that the hydrophobic interactions, electrostatic interactions and hydrogen bonds among of the PTX, lipid and protein play an important role during the formation of the PTX-liprosome. The hemolysis test showed a good safety profile for the intravenous administration of liprosome. The result of the in vivo distribution suggested that liprosome increased the drug uptake by the brain tissue and decreased drug accumulation in non-target organs. Therefore, liprosome is a potential drug delivery system for transporting PTX to the brain.

Novel hydrophobin-coated docetaxel nanoparticles for intravenous delivery: in vitro characteristics and in vivo performance.

Novel hydrophobin (H star Protein® B, HPB)-coated docetaxel (DTX) nanoparticles were designed for intravenous delivery. DTX-HPB nanoparticles (DTX-HPB-NPs) were prepared using a nanoprecipitation-ultrasonication technique. The physicochemical properties in terms of particle size, size distribution, zeta potential, morphology, crystalline state of the drug, in vitro release and plasma stability were evaluated. To investigate the drug-hydrophobin interaction, FTIR analysis was carried out. The pharmacokinetics of DTX-HPB-NPs and Taxotere were compared after i.v. administration to rats. The optimized formulations have a high drug loading (>25%) and nanoparticle yield (>93%), small particle size with a narrow distribution, and exhibit delayed release. X-ray diffraction (XRD) demonstrated that the drug is present in a crystalline state. FTIR analysis suggested that the interaction of DTX and HPB involved hydrogen bonding. In vitro hemolysis study confirmed the safety of these nanoparticles. In plasma, DTX-HPB nanoparticles exhibited a significantly enhanced Cmax (1300.618±405.045 ng/mL vs 453.174±164.437 ng/mL, p<0.05), and AUC0-t (409.602±70.267 vs 314.924±57.426 µg/Lh, p<0.05), and a significantly reduced volume of distribution (36.635±15.189 vs 95.199±40.972 L/kg, p<0.05) compared with the Taxotere. These results demonstrated that hydrophobin has the potential to be used as a novel biocompatible biomaterial for drug delivery.