ABSTRACT
Attributing to their broad pharmacological effects encompassing anti-inflammation, antitoxin, and immunosuppression, glucocorticoids (GCs) are extensively utilized in the clinic for the treatment of diverse diseases such as lupus erythematosus, nephritis, arthritis, ulcerative colitis, asthma, keratitis, macular edema, and leukemia. However, long-term use often causes undesirable side effects, including metabolic disorders-induced Cushing's syndrome (buffalo back, full moon face, hyperglycemia, etc.), osteoporosis, aggravated infection, psychosis, glaucoma, and cataract. These notorious side effects seriously compromise patients' quality of life, especially in patients with chronic diseases. Therefore, glucocorticoid-based advanced drug delivery systems for reducing adverse effects have received extensive attention. Among them, prodrugs have the advantages of low investment, low risk, and high success rate, making them a promising strategy. In this review, we propose the strategies for the design and summarize current research progress of glucocorticoid-based prodrugs in recent decades, including polymer-based prodrugs, dendrimer-based prodrugs, antibody-drug conjugates, peptide-drug conjugates, carbohydrate-based prodrugs, aliphatic acid-based prodrugs and so on. Besides, we also raise issues that need to be focused on during the development of glucocorticoid-based prodrugs. This review is expected to be helpful for the research and development of novel GCs and prodrugs.
ABSTRACT
The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Liposomes/therapeutic use , Ditiocarb/therapeutic use , Disulfiram , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Zinc , Copper/therapeutic use , Tumor Microenvironment , Aromatic-L-Amino-Acid Decarboxylases/therapeutic useABSTRACT
Excessive reactive oxygen species (ROS) and stressed inflammatory response are major characteristics of ulcerative colitis, which cause disease progression and aggravation. Herein, a novel mesoporous cerium oxide nanozymes (MCN) was designed and then loaded with Myeloid differentiation factor-88 (MyD88) inhibitor for synergistic treatment of colitis by scavenging ROS and regulating inflammation. This innovative MCN with average particle size of 200.7 nm, specific surface area of 119.78 m2/g and mesopores of 4.47 nm not only exhibited excellent SOD-like and CAT-like activities to scavenge ROS but also could act as a carrier to load MyD88 inhibitor, TJ-M2010-5, (abbreviated as TJ-5) into their mesopores, achieving the effect of 'two birds with one stone'. Besides, the modification of dextran sulfate sodium (TJ-5/MCN/DSS) increased the internalization of nanozymes into activated macrophages and enhanced in vitro anti-inflammatory ability. To enhance colon targeting, we coated TJ-5/MCN/DSS with the enteric material Eudragit S100, preventing premature release or absorption of the drug in the gastrointestinal tract after oral administration. The results demonstrated that TJ-5/MCN/DSS/Eudragit not only achieved delayed drug release and improved colon targeting but also exhibited optimal therapeutic efficacy in colitis mice. Mechanistically, the MCN-mediated ROS scavenging and TJ-5-mediated MyD88 blockade synergistically inhibited the NF-κB signaling pathway, thereby reducing the inflammatory response. Importantly, TJ-5/MCN/DSS/Eudragit did not induce systemic toxicity. In conclusion, our work not only presents a novel carrier capable of scavenging ROS but also provides proof of concept for the synergistic treatment of colitis using this carrier in combination with MyD88 inhibitors. This study proposes a safe and efficient strategy for targeting ROS-associated inflammation.
Subject(s)
Colitis, Ulcerative , Animals , Mice , Colitis, Ulcerative/drug therapy , Colon , Dextran Sulfate/pharmacology , Dextran Sulfate/therapeutic use , Disease Models, Animal , Inflammation , Myeloid Differentiation Factor 88/metabolism , Myeloid Differentiation Factor 88/pharmacology , NF-kappa B/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Chemodynamic therapy (CDT) is an emerging oncological treatment that eliminates tumor cells by generating lethal hydroxyl radicals (ËOH) through Fenton or Fenton-like reactions within tumors. However, the effectiveness of CDT is limited by the overexpression of glutathione (GSH) and low reaction efficiency in the tumor microenvironment (TME). To address these challenges and enhance tumor treatment, we developed a novel pH-activatable metal ion-drug coordinated nanoparticle (Cu-AXB NPs) system, incorporating a CDT agent (Cu2+) and a chemotherapeutic agent (axitinib, AXB). The obtained Cu-AXB NPs exhibited exceptional characteristics, including ultrahigh drug loading capacity (87.55%) and an average size of 180 nm. These nanoparticles also demonstrated excellent plasma stability and pH-responsive drug release, enabling prolonged circulation in the bloodstream and targeted therapy at weakly acidic tumor sites. Upon release, AXB acted as a chemotherapeutic agent, effectively eliminating tumor cells, while Cu2+ ions were reduced to Cu+ by GSH, further generating toxic ËOH with hydrogen peroxide (H2O2) for CDT through a Fenton-like reaction. Additionally, the Cu-AXB NPs efficiently disrupted the copper metabolic balance and increased the intracellular Cu content, further amplifying the therapeutic impact of CDT. In vitro studies assessing cytotoxicity and apoptosis confirmed the superior tumor cell-killing efficacy of the Cu-AXB NPs. This enhanced efficacy can be attributed to the synergistic effect of CDT and chemotherapy. Moreover, the Cu-AXB NPs exhibited excellent tumor targeting capabilities, resulting in significant tumor inhibition (77.53% inhibition) while maintaining favorable biocompatibility in tumor-bearing mice. In conclusion, this study presents a promising and safe strategy for cancer therapy by combining CDT with chemotherapy, offering a potential breakthrough in the field of oncology.
Subject(s)
Multifunctional Nanoparticles , Nanoparticles , Neoplasms , Animals , Mice , Copper , Axitinib , Hydrogen Peroxide , Glutathione , Tumor Microenvironment , Hydrogen-Ion Concentration , Cell Line, Tumor , Neoplasms/drug therapyABSTRACT
Chemodynamic therapy (CDT), a novel therapeutic approach based on Fenton (Fenton-like) reaction, has been widely employed for tumor therapy. This approach utilizes Fe, Cu, or other metal ions (Mn, Zn, Co, or Mo) to react with the excess hydrogen peroxide (H2O2) in tumor microenvironments (TME), and form highly cytotoxic hydroxyl radical (ËOH) to kill cancer cells. Recently, nanoscale metal-organic frameworks (nMOFs) have attracted considerable attention as promising CDT agents with the rapid development of cancer CDT. This review focuses on summarizing the latest advances (2020-2022) on the design of nMOFs as nanomedicine for CDT or combination therapy of CDT and other therapies. The future development and challenges of CDT are also proposed based on recent progress. Our group hopes that this review will enlighten the research and development of nMOFs for CDT.
Subject(s)
Antineoplastic Agents , Metal-Organic Frameworks , Neoplasms , Humans , Metal-Organic Frameworks/pharmacology , Metal-Organic Frameworks/therapeutic use , Cell Line, Tumor , Hydrogen Peroxide/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Metals , Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
As a potent glucocorticoid drug (GCs), Dexamethasone (Dex) is widely used clinically for the treatment of inflammatory diseases. However, such side effects as Cushing's syndrome and osteoporosis caused severe distress to patients. Herein, a sialic acid (SA)-modified dexamethasone conjugate (Dex-SA) was synthesized successfully to reduce side effects by targeting inflammatory diseases. The solubility of Dex-SA in water reached 58 times that of Dex, which meets the need for intravenous administration. The excellent stability of Dex-SA in plasma also laid a foundation for targeting disease sites. According to cellular uptake and biodistribution experiments, Dex-SA was more readily to be taken up by inflammatory cells and accumulated in diseased kidneys compared to Dex, which is attributed to the interaction of SA with E-selectin receptors overexpressed on the surface of inflammatory vascular endothelial cells. Besides, the pharmacodynamics studies of acute kidney injury showed that Dex-SA and Dex could produce comparable therapeutic effects. More importantly, Dex-SA was found to significantly reduce Dex-related side effects, as measured by blood glucose, red blood cells and immune cells, etc. At last, molecular docking results were obtained to confirm that Dex-SA could enter the cells by binding specifically with the E-selectin receptor, for combination with glucocorticoid receptors in the cytoplasm to exert pharmacological effects. Our study is expected to contribute a new strategy to the safe and effective targeting treatment of inflammatory diseases.
Subject(s)
Glucocorticoids , N-Acetylneuraminic Acid , Dexamethasone , E-Selectin/metabolism , Endothelial Cells/metabolism , Glucocorticoids/pharmacology , Humans , Inflammation/chemically induced , Molecular Docking Simulation , N-Acetylneuraminic Acid/chemistry , Tissue DistributionABSTRACT
Cisplatin is a widely used anticancer drug for various solid tumors. However, the serious adverse effects caused by systemic distribution limit its wide use. In this study, we intend to use biocompatible materials polyethyleneimine (PEI) and poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-PEG) to construct nanoparticles to enhance the efficacy of cisplatin and reduce its side effects. The micelle-like nanoparticles were fabricated by a simple two-step method, with a core consisting of PEI and cisplatin and a PLG-g-mPEG coating layer. The obtained nanoparticles have a small particle size (41.79 nm) and high drug loading (16.43%). The coated nanoparticles (NP-II) strengthened the structure of PEI and cisplatin complex (NP-I) and slowed the drug release for less than 20% at pH 7.4 PBS in 24 h. Therefore, it could effectively inhibit the binding of free drug and plasma proteins to achieve the long circulation, and the bioavailability could be increased to about 600% and 285% of cisplatin solution and NP-I respectively. Besides, the cellular uptake of NP-II was enhanced in the acidic tumor microenvironment due to the detachment of coating layer and the increase of positive zeta potential of nanoparticles, which was benefit to reduce the side effect of cisplatin to normal cells. In vivo pharmacodynamic experiments also showed that NP-II improved the efficacy and reduced side effects compared to the cisplatin solution. In conclusion, the two-step fabricating micelle-like nanoparticles with the improved therapeutic efficiency and reduced side effects show great potential for cancer chemotherapy.
Subject(s)
Antineoplastic Agents , Nanoparticles , Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Cisplatin , Drug Carriers/therapeutic use , Humans , Micelles , Neoplasms/drug therapy , Particle Size , Polyethylene Glycols/therapeutic use , Polyglutamic Acid , Tumor MicroenvironmentABSTRACT
PURPOSE: The objective of the present study was to prepare stable and high bioavailability ocular atropine loaded films (ATR-films) as potential ocular drug delivery systems for the treatment of myopia. METHODS: ATR-films were prepared by the solvent casting method and the physical properties of films were evaluated including thickness, water content, light transparency, disintegration time, and mechanical properties. FT-IR, DSC, XRD, TGA, AFM, and Raman spectroscopy were performed to characterize the film. The stability test was conducted under different conditions, such as high humidity, high temperature, and strong light. The pharmacokinetic study and irritation assessment were conducted in rabbits. The efficacy of ATR-films was evaluated by refraction and ocular biometry in myopia guinea pigs. RESULT: After optimizing the formulation, the resulting ATR-film was flexible and transparent with lower water content (8.43% ± 1.25). As expected, the ATR-film was stable and hydrolysate was not detected, while the content of hydrolysate in ATR eye drops can reach up to 8.1867% (limit: < 0.2%) in the stability study. The safety assessment both in vitro and in vivo confirmed that the ATR-film was biocompatible. Moreover, the bioavailability (conjunctiva 3.21-fold, cornea 2.87-fold, retina 1.35-fold, sclera 2.05-fold) was greatly improved compared with the ATR eye drops in vivo pharmacokinetic study. The pharmacodynamic study results showed that the ATR-film can slow the progress of form-deprivation myopia (~ 100 ± 0.81D), indicating that it has a certain therapeutic effect on form-deprivation myopia. CONCLUSION: The ATR-film with good stability and high bioavailability will have great potential for the treatment of myopia.
Subject(s)
Atropine/administration & dosage , Drug Delivery Systems/methods , Muscarinic Antagonists/administration & dosage , Myopia/drug therapy , Administration, Ophthalmic , Animals , Atropine/pharmacokinetics , Biological Availability , Disease Models, Animal , Drug Evaluation, Preclinical , Guinea Pigs , Humans , Male , Muscarinic Antagonists/pharmacokinetics , Myopia/diagnosis , Rabbits , Spectroscopy, Fourier Transform InfraredABSTRACT
Resistance to platinum agents is a crucial challenge in the treatment of cancer using platinum drugs. To overcome the resistance of cells, the survivin protein is supposed to be decreased, since it has previously been found to be overexpressed in drug-resistant cancer cells in anti-apoptosis pathways, while the intracellular effective platinum accumulation should be increased. In the present work, a protamine/hyaluronic acid nanocarrier was used to load survivin siRNA with Pt(IV) loaded outside the coated polyglutamic acid (PGA) by chemical conjugation. The siRNA was released from the co-loaded nanoparticle prior to Pt(IV), in this way, the expression of survivin protein was effectively reduced, which, in turn, could avoid the anti-apoptosis of drug resistant cells. Here, Pt(IV) displayed a sustained release effect and gradually reduced to the toxic Pt(II) species, which reduced drug efflux and enhance apoptosis of the cancer cells. In vitro studies demonstrated that co-loaded nanoparticles resulted in similar cell killing performance in A549/DDP cells (cisplatin resistant) compared with non-siRNA loaded nanoparticles in A549 cells (cisplatin sensitive). NP-siRNA/Pt(IV) exhibited a greatly improved therapeutic effect (TIR, 82.46%) in a nude mice A549/DDP tumor model, with no serious adverse effects observed. Thus, co-loading of Pt(IV) and survivin siRNA nanoparticles could reverse cisplatin resistance and therefore has promising prospects for efficient cancer chemotherapy.
Subject(s)
Antineoplastic Agents , Lung Neoplasms , Nanoparticles , Prodrugs , Animals , Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mice , Mice, Nude , Organoplatinum Compounds/pharmacology , Prodrugs/pharmacology , RNA, Small Interfering/pharmacology , Survivin/geneticsABSTRACT
Motor vehicle emissions are increasingly becoming one of the important factors affecting the urban air quality in China. It is necessary and useful to policy makers to demonstrate the situation given the relevant pollutants reduction measures are taken. This paper predicted the reduction potentials of conventional pollutants (PM10, NOx, CO, HC) under different control strategies and policies in the Beijing-Tianjin-Hebei (BTH) region during 2011-2020. There are the baseline and 5 control scenarios designed, which presented the different current and future possible vehicular emissions control measures. Future population of different kinds of vehicles were predicted based on the Gompertz model, and vehicle kilometers travelled estimated as well. After that, the emissions reduction under the different scenarios during 2011-2020 could be estimated using emission factors and activity level data. The results showed that, the vehicle population in the BTH region would continue to grow up, especially in Tianjin and Hebei. Comparing the different scenarios, emission standards updating scenario would achieve a substantial reduction and keep rising up for all the pollutants, and the scenario of eliminating high-emission vehicles can reduce emissions more effectively in short-term than in long-term, especially in Beijing. Due to the constraints of existing economical and technical level, the reduction effect of promoting new energy vehicles would not be significant, especially given the consideration of their lifetime impact. The reduction effect of population regulation scenario in Beijing cannot be ignorable and would keep going up for PM10, CO and HC, excluding NOx. Under the integrated scenario considering all the control measures it would achieve the maximum reduction potential of emissions, which means to reduce emissions of PM10, NOx, CO, HC, by 56%, 59%, 48%, 52%, respectively, compared to BAU scenario for the whole BTH region in 2020.