The purpose of this study was to develop an extended-release(ER) matrix tablet that shows robust dissolution properties able to account for the variability of pH and mechanical stress in the GI tract using a combinati...The purpose of this study was to develop an extended-release(ER) matrix tablet that shows robust dissolution properties able to account for the variability of pH and mechanical stress in the GI tract using a combination of enteric polymer and hydrophilic polymer. Hypromellose acetate succinate(HPMCAS) and hydroxypropylcellulose(HPC) were selected as ER polymers for the ER matrix tablet(HPMCAS/HPC ER matrix tablet). Oxycodone hydrochloride was employed as a model drug. Dissolution properties of the HPMCAS/HPC ER matrix tablets were evaluated and were not affected by the pH of the test medium or paddle rotating speed.In a USP apparatus 3(bio-relevant dissolution method), dissolution profiles of the HPMCAS/HPC ER matrix tablets containing oxycodone hydrochloride were similar to that of the reference product(OxyC ontin). Moreover, in vivo performance after oral administration of the HPMCAS/HPC ER matrix tablets to humans was simulated by GastroP lus based on dissolution profiles from the USP apparatus 3. The plasma concentration-time profile simulated was similar to that of the reference product. These results suggest that the combination of HPMCAS and HPC shows a robust dissolution profile against pH and paddle rotating speed and indicates the appropriate extended-release profile in humans.展开更多
The coastal zone of Bangladesh is very heterogeneous in nature and has marvelous potential to create opportunities of national importance and contribute to GDP. Among the potentials—intensification of agriculture, aq...The coastal zone of Bangladesh is very heterogeneous in nature and has marvelous potential to create opportunities of national importance and contribute to GDP. Among the potentials—intensification of agriculture, aqua-culture and marine fishery, ship building industry, eco-tourism, deep sea port etc. are most significant. Unfortunately, the coastal zone of the country is disaster prone area. Poor communication, lack of education and health care facilities, prolonged absence of safe drinking water and inadequate cyclone shelters contribute and multiply the dimension of vulnerability. Furthermore, increasing population pressure increases the competition for limited resources. As a consequence, in order to unlock these potentials, existing and new interventions are required to serve in an integrated and inclusive way;calling for a distinct and integrated coastal development strategy. This study aims to investigate the issues of the western floodplain of the Ganges and propose some identical strategies and subsequent adaptation pathways to delineate the development roadmaps to decision makers and researches. Analyses have been conducted through GIS and RS technology, Dynamic Pathway Generator, Excel analysis and field investigation.展开更多
Vehicle delay is an important measure to evaluate the signal timings of signalized intersections.When optimization the signal control parameters, delays of vehicles from all approach directions of an intersection shou...Vehicle delay is an important measure to evaluate the signal timings of signalized intersections.When optimization the signal control parameters, delays of vehicles from all approach directions of an intersection should be considered. Based on the analysis of the vehicle delay on an approach of intersection, directed against the typical condition of a congested intersection-over-saturated condition, the paper has analyzed and inferred the intersection delay dynamic formulation, and has established the relation between intersection delay,the signal timings, vehicle arrival rate and the queue lengths, and that provides useful information for understanding vehicle delay of signalized intersection and for establishing performance index function of signal timing optimization.展开更多
Solid formulations represent the most widely used dosage forms,and their structural attributes significantly impact the efficacy of drugs.Consequently,delving into the study of solid formulation structures is of param...Solid formulations represent the most widely used dosage forms,and their structural attributes significantly impact the efficacy of drugs.Consequently,delving into the study of solid formulation structures is of paramount importance.This paper employs bibliometrics to summarize references on solid formulations and physical structure over the past 5 years,providing a visual representation through CiteSpace.Additionally,we explore influential factors affecting the structure of solid formulations at three distinct levels:raw material,intermediate,and final product.It delves into the discussion of various characterization techniques employed to analyze the physical structure of solid formulations.The techniques include scanning electron microscopy,transmission electron microscopy,X-ray diffraction,nuclear magnetic resonance,LF-nuclear magnetic resonance,thermal analysis,and terahertz.Emphasis is placed on the significance of investigating formulation structures,serving as a found ational step for future research and development in this field.This comprehensive approach aims to contribute to the understanding and advancement of solid formulations for enhanced drug effectiveness.展开更多
OBJECTIVE:To investigate the mechanism of Dan Ze mixture(丹泽合剂,DZM)in the treatment of lipotoxic cardiomyopathy.METHODS:Ultra-performance liquid chromatography tandem mass spectrometry was employed to characterize ...OBJECTIVE:To investigate the mechanism of Dan Ze mixture(丹泽合剂,DZM)in the treatment of lipotoxic cardiomyopathy.METHODS:Ultra-performance liquid chromatography tandem mass spectrometry was employed to characterize the serum migration constituents of DZM.A lipotoxic cardiomyopathy rat model was established through high-fat diet and intervened by different doses of DZM.The cardiac function was assessed using echocardiography,and hematoxylin and eosin,oil red O,and Masson staining were conducted to evaluate morphological changes,lipid accumulation,and fibrosis in myocardial tissue.Serum myocardial enzyme activity,lipid levels,and lipid content of myocardial tissue were measured,while fluorescent staining and colorimetry were used to assess oxidation levels in myocardial tissue.Mitochondrial membrane potential was detected by 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanineiodide(JC-1).Transmission electron microscopy was employed to observe ultrastructure and mitochondrial structure changes in myocardial tissue.Fluorescence double staining and colocalization were utilized to observe the binding of autophagosomes and mitochondria,while immunohistochemical staining was used to detect the expression of mitophagy-related proteins.Terminal deoxynucleoitidyl transferase mediated nick end labeling staining was employed for the identification of apoptosis in myocardial tissue,while quantitative real-time reverse transcriptase polymerase chain reaction(q RT-PCR)and Western blot were utilized for the detection of apoptosis,B-cell lymphoma-2 adenovirus E1B 19 k Da-interacting protein 3(BNIP3)/mitophagy signaling pathway-related genes and proteins.In palmitic acid-induced Rat H9C2 cardiomyocytes(H9c2)cells,various cellular parameters including cell viability,lactate dehydrogenase release,apoptosis rate,oxidative stress level,mitochondrial structure and function,and mitophagy level were assessed after the treatment of DZM drug-containing serum for a duration of 24 h.The cellular expressions of BNIP3/mitophagy signaling pathway relevant genes and proteins were further evaluated using q RT-PCR and Western blot techniques.RESULTS:A total of 295 prototypes(e.g.,phenolic acids,quinones,terpenoids)were identified in serum of rats after oral administration of DZM.In vivo,DZM therapy has been shown to effectively enhance cardiac function,mitigate high-fat diet-induced myocardial structural damage and lipid accumulation.Furthermore,DZM has demonstrated the ability to reduce lipid levels,attenuate cell apoptosis,combat oxidative stress,enhance mitochondrial structure and function,and activate the BNIP3/mitophagy signaling pathway.Furthermore,the silencing of BNIP3 has been shown to exacerbate palmitic acid-induced damages in H9c2 cells,while inhibiting the BNIP3/mitophagy signaling pathway can mitigate the inhibitory effects of DZM on palmitic acidinduced apoptosis,lipid deposition and oxidative stress.CONCLUSION:This study presents preliminary evidence for the therapeutic efficacy of DZM on lipotoxic cardiomyopathy through the activating BNIP3/mitophagy signaling pathway.展开更多
The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING...The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING agonists is impeded by several challenges,including limited biostability,poor pharmacokinetics,and inefficient cytosolic delivery.Herein,we meticulously designed a doublelayer polyethylenimine(PEI)modified nanoscale covalent organic polymer(CPGP)for efficient delivery of 23cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),a natural STING agonist.The double-layer PEI structured CPGP enhanced both the loading capacity and stability of cGAMP.Furthermore,CPGP improved the intracellular delivery efficiency and amplified the activation of STING pathway for the secretion of type-I interferon and pro-inflammatory cytokines.In contrast,single-layered nanoparticles failed to permit stable loading and intracellular delivery of cGAMP for immune response.The nano-STING agonist also mitigated the immunosuppressive tumor microenvironment(TME)by reducing regulatory T cells and polarizing M2 macrophages to the M1 phenotype,thereby creating an immune-supportive TME to enhance adaptive immune responses.The combination of CPGP and immune checkpoint blockers showed synergistic effect,further enhancing the inhibition effect on tumor growth.This double-layer PEI modified CPGP may offer a generalizable platform for other natural dinucleotide STING agonists to overcome the cascade delivery barriers,augmenting immune activation for tumor immunotherapy.展开更多
Alzheimer’s dementia(AD)and type 2 diabetes(T2D)are interrelated global public health problems,and the current epidemics of both AD and T2D are insulin resistance diseases.Thus,AD and T2D may share common risk factor...Alzheimer’s dementia(AD)and type 2 diabetes(T2D)are interrelated global public health problems,and the current epidemics of both AD and T2D are insulin resistance diseases.Thus,AD and T2D may share common risk factors such as an unhealthy diet,lifestyle,and obesity.Meat products is an important part of the diet of consumers worldwide.This systematic review and meta-analysis aims to assess and estimate the effect of meat products consumption on AD and T2D in humans.Web of Science,MEDLINE,PubMed,Cochrane Library,and Embase were searched from January 2012 to April 2024.29 articles reported 32 cohort studies with 1785769 subjects,with 3546 AD cases and 91092 T2D cases that met the inclusion criteria and were included in our analysis.Consumption of various meat products increased the risk of T2D(hazard ratios(HR)=1.19,95%confidence intervals(CI):1.13−1.26,P=0.000;I2=88.5%),consumption of smoked,grilled/roasted and fried meat products was more likely to induce T2D(HR=1.24,95%CI:1.18−1.30,P=0.000;I2=76.1%),but was borderline significant for the risk of AD(HR=1.11,95%CI:0.98−1.25,P=0.094;I2=58.8%),with consumption of mainly livestock and poultry products increasing the risk(HR=1.21,95%CI:1.03−1.42,P=0.017;I2=66.8%).The association between meat products consumption and AD risk was influenced by meat type and sample size,while the risk of T2D was influenced by meat type,follow-up and sex.A daily intake of 27,123 and 170 g of livestock products increased the risk of T2D by 10%,51%and 70%respectively,whereas the risk of T2D was reduced when the intake of various meat products was less than 23 g/day.展开更多
Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the...Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the past decades and tumor progression or recurrence is inevitable in many patients.RNAibased therapy presents a novel disease-related gene targeting therapy,including otherwise undruggable genes,and generates therapeutic options.However,the therapeutic effect of siRNA is hindered by multiple biological barriers,primarily the blood-brain barrier(BBB).A glycoprotein-derived peptide-mediated delivery system is the preferred option to resolve this phenomenon.RDP,a polypeptide composed of 15 amino acids derived from rabies virus glycoprotein(RVG),possesses an N-type acetylcholine receptor(nAChR)-binding efficiency similar to that of RVG29.Given its lower cost and small particle size when used as a ligand,RDP should be extensively evaluated.First,we verified the brain-targeting efficacyy of RDP at the cellular and animal levels and further explored the possibility of using the RDP-oligoarginine peptide(designated RDP-5R)as a bio-safe vehicle to deliver therapeutic siRNA into glioma cells in vitro and in vivo.The polypeptide carrier possesses a diblock design composed of oligoarginine for binding siRNA through electrostatic interactions and RDP for cascade BBB-and glioma cell-targeting.The results indicated that RDP-R5/siRNA nanoparticles exhibited stable and suitable physicochemical properties for in vivo application,desirable glioma-targeting effects,and therapeutic efficiency.As a novel and efficient polypeptide carrier,RDP-based polypeptides hold great promise as a noninvasive,safe,and efficient treatment for various brain diseases.展开更多
Most anti-tumor agents suffer from systemic non-specific distribution and low aggregation in tumors,which not only decreases the therapeutic efficacy,but also causes systemic toxic side effects in the treatments of tu...Most anti-tumor agents suffer from systemic non-specific distribution and low aggregation in tumors,which not only decreases the therapeutic efficacy,but also causes systemic toxic side effects in the treatments of tumors.In recent years,the rapid development of nanotechnology has brought new ideas for the application of anti-tumor drugs.Nanomedicines,such as liposomes and micelles,can improve drug targeting and prolong systemic circulation time to promote anti-tumor efficacy and reduce toxic side effects.However,conventional micelles bear the risk of instability and premature drug leaking in the blood circulation.We designed a reduction-responsive core-cross-linked micelle PTX@Fmoc-LA-PEG efficiently encapsulating Paclitaxel(PTX)viaπ-πstacking and hydrophobic interactions of Fmoc and PTX.Moreover,the micelle was further locked based on the cross-linking properties of the disulfide bonds formed by lipoic acid(LA).As expected,the core-cross-linked micelles PTX@Fmoc-LA-PEG remained stable in normal physiological environments,while restoring the normal drug release rate of micelles under the highly reducing environment due to LA unlocking.The blank micelles(Fmoc-LA-PEG)exhibited excellent biocompatibility,while the drug-loaded micelles(PTX@Fmoc-LA-PEG)displayed a remarkable anti-tumor effect in vitro and in vivo experiments.These results suggested that core-cross-linked micelles PTX@FmocLA-PEG have great potential to improve the targeting and stability of anti-tumor drugs.展开更多
Microneedles(MNs)have attracted increasing attention as a transdermal delivery system(TDDS)[1].However,traditional volatile Chinese medicines cannot be dissolved in conventional soluble MN materials,such as hyaluronic...Microneedles(MNs)have attracted increasing attention as a transdermal delivery system(TDDS)[1].However,traditional volatile Chinese medicines cannot be dissolved in conventional soluble MN materials,such as hyaluronic acid and chitosan,making it difficult for many traditional Chinese medicine ingredients to be applied to MN.Elemene(ELE)was successfully isolated from Curcuma longa,and has numerous antitumor and curative effects[2].展开更多
Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized s...Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract.These formulations offer multiple advantages such as reduction in food effect and inter-individual variability,ease of preparation,and the possibility of manufacturing using common excipients available in the market.Despite these advantages,very few products are available in the present market,perhaps due to limited knowledge in the in vitro tests(for prediction of in vivo fate)and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration.The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations,their pharmacokinetic aspects and in vitro in vivo correlation(IVIVC)perspectives.Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion,bioavailability enhancement mechanisms,impact of excipients on efflux transporters,and lymphatic transport are discussed with examples.In addition,various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation,in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.展开更多
The current paper has elaborated the efficient utilization of liquid biodiesel waste in combination with dillapiole and citronella essential oil as active ingredients.Sawdust,cellulose and hydrophobic silica were used...The current paper has elaborated the efficient utilization of liquid biodiesel waste in combination with dillapiole and citronella essential oil as active ingredients.Sawdust,cellulose and hydrophobic silica were used as inert ingredients,which make the tablet to float over the water surface.ATR-FTIR analysis of tablet confirmed the compatibility with citronella oil,dillapiole,liquid biodiesel waste in tablet composition after compression.Physico-chemical analysis studies show that tablet parameters are in standard limits.SEM analysis shows some porous structures in tablet composition which confirms the floating nature of the tablets.The specific ratio(2:2:1)of citronella oil,dillapiole and liquid biodiesel waste showed maximum mortality,i.e.95%after 24 h.After application,the tablet is nontoxic towards the aquatic organisms and water quality remains unaf-fected.The better performance of the tablets has been evaluated in terms of characterization studies,viz.ATR-FTIR and SEM studies and bioefficacy trials which confirmed the presence of active ingredients responsible for insecticidal activity.展开更多
Ulcerative colitis(UC)is a common progressive inflammatory disease whose incidence has increased rapidly in recent years,and can develop into colorectal cancer in severe cases.There are currently no adequate or effect...Ulcerative colitis(UC)is a common progressive inflammatory disease whose incidence has increased rapidly in recent years,and can develop into colorectal cancer in severe cases.There are currently no adequate or effective treatments for UC due to the fact that some patients have found suboptimal results after repeated administration,while others have experienced adverse effects.With the rapid development of nanotechnology,developing innovative colon-targeting platforms is essential to improving efficacy,reducing side effects,and improving patient compliance.In this review,we summarize the pathophysiological characteristics of UC and the most recent status of numerous nanodrug delivery systems based on different targeting mechanisms in treating UC.Oral,intravenous,and rectal drug delivery nanoparticles targeting the colon are discussed,which can provide ideas for the design of colon-targeting nanoparticles for the treatment of colon diseases,especially for the treatment of UC.Last but not least,we provide a glimpse into the future of colon-targeted delivery systems,as well as future advancements in the field.展开更多
As one of the most promising adoptive T-cell therapies,chimeric antigen receptor T-cell(CAR-T)therapy has acquired Food and Drug Administration(FDA)approval for a variety of products and has been used successfully in ...As one of the most promising adoptive T-cell therapies,chimeric antigen receptor T-cell(CAR-T)therapy has acquired Food and Drug Administration(FDA)approval for a variety of products and has been used successfully in the treatment of malignant hematological tumors.CAR-T therapy,on the other hand,faces a number of obstacles in the field of solid tumor therapy that limit its widespread clinical implementation.Significant advances in nanoparticle research in cancer therapy and immunotherapy have been made in recent years,providing novel strategies to address the challenges encountered by CAR-T therapy in the treatment of solid tumors.This review commences with a comprehensive explanation of the basic framework of CAR-T therapy as well as the challenges it faces in the treatment of solid tumors.Subsequently,we encapsulate a summary of the developmental research combining nanoparticles with CAR-T cells for the treatment of solid tumors,which includes gene transfection,cell activation and expansion,targeted infiltration,immune escape inhibition,and combination with other therapies.Coupled with the overview of the research progress,a discussion has been initiated on the challenges and perspectives of CAR-T based on nanoparticles.展开更多
This study reports the isolation of four newβ-carboline alkaloids(1−4)and six previously identified alkaloids(5−10)from the roots of Peganum harmala L.Among these compounds,1 and 2 were characterized as rareβ-carbol...This study reports the isolation of four newβ-carboline alkaloids(1−4)and six previously identified alkaloids(5−10)from the roots of Peganum harmala L.Among these compounds,1 and 2 were characterized as rareβ-carboline-quinazoline dimers exhibiting axial chirality.Compound 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring,and compound 4 was a novel annomontineβ-carboline.The structures of these compounds were elucidated by spectroscopic data and quantum mechanical calculations.The biosynthetic pathways of 1−3 were proposed.Additionally,the cytotoxicity of some isolates against four cancer cell lines(HL-60,A549,MDA-MB-231,and DU145)was evaluated.Notably,compound 4 exhibited significant cytotoxicity against HL-60,A549,and DU145 cells with IC_(50) values of 12.39,12.80,and 30.65μmol·L^(−1),respectively.Furthermore,compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC_(50) value of 17.32μmol·L^(−1).展开更多
Natural endogenous materials(NEMs),such as cell and cell derivatives,polysaccharide,protein and peptide,and nucleic acid-derived vectors,often exhibit biocompatibility,biodegradability and natural homing ability,which...Natural endogenous materials(NEMs),such as cell and cell derivatives,polysaccharide,protein and peptide,and nucleic acid-derived vectors,often exhibit biocompatibility,biodegradability and natural homing ability,which can minimize adverse reactions in vivo and have the potential to improve drug delivery efficacy.Currently,a variety of drug delivery systems(DDSs)based on NEMs have been constructed for macromolecules to address the challenges posed by their inherent large size,intricate structure,low permeability,and susceptibility to harsh environments.The aim of this article is to provide a comprehensive overview of various delivery strategies that predominantly utilize NEMs as carriers for macromolecular delivery.By thoroughly discussing the pros and cons of NEM-based DDSs,we hope to provide valuable insights into future innovations in pharmaceutical science,with a focus on improving therapeutic outcomes through advanced drug formulations.展开更多
Ulcerative colitis(UC)is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon and disrupted intestinal function.Ramulus mori(Sangzhi)alkaloids(SZ-A),derived from twigs of mulberry...Ulcerative colitis(UC)is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon and disrupted intestinal function.Ramulus mori(Sangzhi)alkaloids(SZ-A),derived from twigs of mulberry,were approved by the National Medical Products Administration in 2020 for treating type 2 diabetes mellitus.Accumulated evidence has confirmed that SZ-A also alleviates non-alcoholic fatty liver disease and ameliorates inflammation,indicating its potential to address inflammation in UC.However,the treatment of UC faces challenges due to low drug delivery efficiency and short retention time.To overcome these challenges,an injectable and adherent in-situ thermo-sensitive hydrogel containing SZ-A was developed for rectal drug delivery,utilizing the thermo-sensitive polymers Poloxamer 407and 188.The thermo-sensitive hydrogel system was designed with a moderate gelation temperature of 32±0.5℃,a short gelation time of 64 s,a p H range of 7-10,high moisturizing capability exceeding 90%,and moderate mechanical strength of 4-5 s.In a rat model with UC,the in situ thermo-sensitive hydrogel significantly extended the retention time at the colonic site and enabled sustained release after rectal administration.Symptoms of UC were markedly reduced following rectal administration of SZ-A thermosensitive hydrogel.Furthermore,the release of inflammatory factors,such as interleukin-1β(IL-1β),IL-6,IL-18,tumor necrosis factor-α(TNF-α),and transforming growth factor-β1(TGF-β1),significantly decreased in the SZ-A thermo-sensitive hydrogel group.The integrity of the colonic mucosal barrier was significantly enhanced following the application of SZ-A thermo-sensitive hydrogel.In conclusion,rectal administration of SZ-A in situ thermo-sensitive hydrogel effectively alleviated UC symptoms,inhibited the secretion of inflammatory factors,and promoted the repair of the colonic mucosal barrier.This approach holds promise as a potential treatment for UC.展开更多
Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)wi...Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied clinically.In this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for chemo-immunotherapy.In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages.Furthermore,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition.The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.展开更多
Objective: Bergenia ciliata(Haw.) Sternb. is used in the Indian traditional system of medicine to treat various ailments including rheumatism and to heal wounds. The objective of the present study was to perform a pre...Objective: Bergenia ciliata(Haw.) Sternb. is used in the Indian traditional system of medicine to treat various ailments including rheumatism and to heal wounds. The objective of the present study was to perform a preclinical characterization of the B. ciliata-based botanical extract IIIM-160.Methods: ⅢM-160 was chemically standardized and analyzed for heavy metal content, aflatoxins,pesticides and microbial load. The in vitro and in vivo efficacies were determined in suitable models of inflammation, arthritis and nociception. An acute oral toxicity study was performed in Swiss albino mice.A suitable oral formulation was developed and characterized.Results: Bergenin was found to be the major component(9.1% w/w) of ⅢM-160. The botanical lead displayed inhibition of lipopolysaccharide-induced production of proinflammatory cytokines in THP-1 cells, with selectivity toward interleukin-6(IL-6) and had an excellent safety-window. It showed anti-inflammatory, anti-arthritic and antinociceptive activity in animal models and was not toxic at oral doses up to 2 g/kg in Swiss-albino mice. The gastroretentive, sustained-release capsule formulation showed sustained-release of the bergenin over the period of 24 h, resulting in improved plasma-exposure of bergenin in Sprague–Dawley rats.Conclusion: The dual-activity of IL-6 inhibition and antinociception marks the suitability of ⅢM-160 for treating rheumatoid arthritis. This study will serve as the benchmark for further research on this botanical formulation.展开更多
Pharmaceutical scientists throughout the world are trying to explore thin films as a novel drug delivery tool. Thin films have been identified as an alternative approach to conventional dosage forms. The thin films ar...Pharmaceutical scientists throughout the world are trying to explore thin films as a novel drug delivery tool. Thin films have been identified as an alternative approach to conventional dosage forms. The thin films are considered to be convenient to swallow, selfadministrable, and fast dissolving dosage form, all of which make it as a versatile platform for drug delivery. This delivery system has been used for both systemic and local action via several routes such as oral, buccal, sublingual, ocular, and transdermal routes. The design of efficient thin films requires a comprehensive knowledge of the pharmacological and pharmaceutical properties of drugs and polymers along with an appropriate selection of manufacturing processes. Therefore, the aim of this review is to provide an overview of the critical factors affecting the formulation of thin films, including the physico-chemical properties of polymers and drugs, anatomical and physiological constraints, as well as the characterization methods and quality specifications to circumvent the difficulties associated with formulation design. It also highlights the recent trends and perspectives to develop thin film products by various companies.展开更多
文摘The purpose of this study was to develop an extended-release(ER) matrix tablet that shows robust dissolution properties able to account for the variability of pH and mechanical stress in the GI tract using a combination of enteric polymer and hydrophilic polymer. Hypromellose acetate succinate(HPMCAS) and hydroxypropylcellulose(HPC) were selected as ER polymers for the ER matrix tablet(HPMCAS/HPC ER matrix tablet). Oxycodone hydrochloride was employed as a model drug. Dissolution properties of the HPMCAS/HPC ER matrix tablets were evaluated and were not affected by the pH of the test medium or paddle rotating speed.In a USP apparatus 3(bio-relevant dissolution method), dissolution profiles of the HPMCAS/HPC ER matrix tablets containing oxycodone hydrochloride were similar to that of the reference product(OxyC ontin). Moreover, in vivo performance after oral administration of the HPMCAS/HPC ER matrix tablets to humans was simulated by GastroP lus based on dissolution profiles from the USP apparatus 3. The plasma concentration-time profile simulated was similar to that of the reference product. These results suggest that the combination of HPMCAS and HPC shows a robust dissolution profile against pH and paddle rotating speed and indicates the appropriate extended-release profile in humans.
文摘The coastal zone of Bangladesh is very heterogeneous in nature and has marvelous potential to create opportunities of national importance and contribute to GDP. Among the potentials—intensification of agriculture, aqua-culture and marine fishery, ship building industry, eco-tourism, deep sea port etc. are most significant. Unfortunately, the coastal zone of the country is disaster prone area. Poor communication, lack of education and health care facilities, prolonged absence of safe drinking water and inadequate cyclone shelters contribute and multiply the dimension of vulnerability. Furthermore, increasing population pressure increases the competition for limited resources. As a consequence, in order to unlock these potentials, existing and new interventions are required to serve in an integrated and inclusive way;calling for a distinct and integrated coastal development strategy. This study aims to investigate the issues of the western floodplain of the Ganges and propose some identical strategies and subsequent adaptation pathways to delineate the development roadmaps to decision makers and researches. Analyses have been conducted through GIS and RS technology, Dynamic Pathway Generator, Excel analysis and field investigation.
基金Sponsored by the Mulfidiscipline Scientific Research Foundation of Harbin Institute of Technology( Grant No. HIT. MD. 2002.28)
文摘Vehicle delay is an important measure to evaluate the signal timings of signalized intersections.When optimization the signal control parameters, delays of vehicles from all approach directions of an intersection should be considered. Based on the analysis of the vehicle delay on an approach of intersection, directed against the typical condition of a congested intersection-over-saturated condition, the paper has analyzed and inferred the intersection delay dynamic formulation, and has established the relation between intersection delay,the signal timings, vehicle arrival rate and the queue lengths, and that provides useful information for understanding vehicle delay of signalized intersection and for establishing performance index function of signal timing optimization.
基金The National Natural Science Foundation of China(Grant No.82003953,82360777)the National Natural Science Foundation of Jiangxi Province(Grant No.20232ACB216015)+2 种基金2020–2022 Young Talents Support Project of Chinese Society of Chinese Medicine(Grant No.2020-QNRC2-07)Jiangxi University of Chinese Medicine Science and Technology Innovation Team Development Program(Grant No.CXTD-22004)the Doctoral Research start-up Fund Project of Jiangxi University of Chinese Medicine(Grant No.2021BSZR015 and 2022BSZR003)。
文摘Solid formulations represent the most widely used dosage forms,and their structural attributes significantly impact the efficacy of drugs.Consequently,delving into the study of solid formulation structures is of paramount importance.This paper employs bibliometrics to summarize references on solid formulations and physical structure over the past 5 years,providing a visual representation through CiteSpace.Additionally,we explore influential factors affecting the structure of solid formulations at three distinct levels:raw material,intermediate,and final product.It delves into the discussion of various characterization techniques employed to analyze the physical structure of solid formulations.The techniques include scanning electron microscopy,transmission electron microscopy,X-ray diffraction,nuclear magnetic resonance,LF-nuclear magnetic resonance,thermal analysis,and terahertz.Emphasis is placed on the significance of investigating formulation structures,serving as a found ational step for future research and development in this field.This comprehensive approach aims to contribute to the understanding and advancement of solid formulations for enhanced drug effectiveness.
基金Scientific Research Project of Hebei Province Administration of Traditional Chinese Medicine:to Explore the Protective Effect and Mechanism of Zexie Decoction on Lipotoxic Cardiomyopathy based on the p-mitogen-activated protein kinases/Peroxisome proliferator-activated receptorγcoactivator 1-alpha(p MAPK/PGC-1α)Signaling Pathway(No.2022096)Medical Science Research Project of Hebei Province:the Effect of 23-acetyl Alismol-B on Mitochondrial Function in Palmitic Acid-induced H9c2 Cells Was Investigated based on the Ca2+-Cyclic Adenosine Monophosphate(c AMP)-Response Element Binding Protein/c AMP Response Element(CREB/CRE)-PGC-1αSignaling Pathway(No.20221490)+1 种基金Hebei province natural science fund project:Study on the Mechanism of Danshen Zexie Decoction in Activating Nuclear Factor Erythroid 2-related Factor 2 Signaling Pathway to Trigger 0mi/Htr A2,Restoring Autophagic Flux and Enhancing Metabolism-Related Fatty Liver Disease(No.H2023423064)Hebei graduate student innovation ability funding training project:to Investigate the Protective Effects and Underlying Mechanisms of Zexie Decoction on Lipotoxic Cardiomyopathy,with A Focus on the PGC-1a Signaling Pathway(No.CXZZBS2022096)。
文摘OBJECTIVE:To investigate the mechanism of Dan Ze mixture(丹泽合剂,DZM)in the treatment of lipotoxic cardiomyopathy.METHODS:Ultra-performance liquid chromatography tandem mass spectrometry was employed to characterize the serum migration constituents of DZM.A lipotoxic cardiomyopathy rat model was established through high-fat diet and intervened by different doses of DZM.The cardiac function was assessed using echocardiography,and hematoxylin and eosin,oil red O,and Masson staining were conducted to evaluate morphological changes,lipid accumulation,and fibrosis in myocardial tissue.Serum myocardial enzyme activity,lipid levels,and lipid content of myocardial tissue were measured,while fluorescent staining and colorimetry were used to assess oxidation levels in myocardial tissue.Mitochondrial membrane potential was detected by 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanineiodide(JC-1).Transmission electron microscopy was employed to observe ultrastructure and mitochondrial structure changes in myocardial tissue.Fluorescence double staining and colocalization were utilized to observe the binding of autophagosomes and mitochondria,while immunohistochemical staining was used to detect the expression of mitophagy-related proteins.Terminal deoxynucleoitidyl transferase mediated nick end labeling staining was employed for the identification of apoptosis in myocardial tissue,while quantitative real-time reverse transcriptase polymerase chain reaction(q RT-PCR)and Western blot were utilized for the detection of apoptosis,B-cell lymphoma-2 adenovirus E1B 19 k Da-interacting protein 3(BNIP3)/mitophagy signaling pathway-related genes and proteins.In palmitic acid-induced Rat H9C2 cardiomyocytes(H9c2)cells,various cellular parameters including cell viability,lactate dehydrogenase release,apoptosis rate,oxidative stress level,mitochondrial structure and function,and mitophagy level were assessed after the treatment of DZM drug-containing serum for a duration of 24 h.The cellular expressions of BNIP3/mitophagy signaling pathway relevant genes and proteins were further evaluated using q RT-PCR and Western blot techniques.RESULTS:A total of 295 prototypes(e.g.,phenolic acids,quinones,terpenoids)were identified in serum of rats after oral administration of DZM.In vivo,DZM therapy has been shown to effectively enhance cardiac function,mitigate high-fat diet-induced myocardial structural damage and lipid accumulation.Furthermore,DZM has demonstrated the ability to reduce lipid levels,attenuate cell apoptosis,combat oxidative stress,enhance mitochondrial structure and function,and activate the BNIP3/mitophagy signaling pathway.Furthermore,the silencing of BNIP3 has been shown to exacerbate palmitic acid-induced damages in H9c2 cells,while inhibiting the BNIP3/mitophagy signaling pathway can mitigate the inhibitory effects of DZM on palmitic acidinduced apoptosis,lipid deposition and oxidative stress.CONCLUSION:This study presents preliminary evidence for the therapeutic efficacy of DZM on lipotoxic cardiomyopathy through the activating BNIP3/mitophagy signaling pathway.
基金supported by the Beijing Natural Science Foundation(No.Z230021)the National Natural Science Foundation of China(No.52202356)+1 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2021-RC350-001)the CAMS Innovation Fund for Medical Sciences(No.2022-I2M-1-013).
文摘The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING agonists is impeded by several challenges,including limited biostability,poor pharmacokinetics,and inefficient cytosolic delivery.Herein,we meticulously designed a doublelayer polyethylenimine(PEI)modified nanoscale covalent organic polymer(CPGP)for efficient delivery of 23cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),a natural STING agonist.The double-layer PEI structured CPGP enhanced both the loading capacity and stability of cGAMP.Furthermore,CPGP improved the intracellular delivery efficiency and amplified the activation of STING pathway for the secretion of type-I interferon and pro-inflammatory cytokines.In contrast,single-layered nanoparticles failed to permit stable loading and intracellular delivery of cGAMP for immune response.The nano-STING agonist also mitigated the immunosuppressive tumor microenvironment(TME)by reducing regulatory T cells and polarizing M2 macrophages to the M1 phenotype,thereby creating an immune-supportive TME to enhance adaptive immune responses.The combination of CPGP and immune checkpoint blockers showed synergistic effect,further enhancing the inhibition effect on tumor growth.This double-layer PEI modified CPGP may offer a generalizable platform for other natural dinucleotide STING agonists to overcome the cascade delivery barriers,augmenting immune activation for tumor immunotherapy.
基金supported by the Agricultural Science and Technology Innovation Program,Institute of Food Science and Technology,Chinese Academy of Agricultural Sciences under Grant CAAS-ASTIP-2023-IFSTGuangdong Provincial Key R&D Programme(2023B0202080003).
文摘Alzheimer’s dementia(AD)and type 2 diabetes(T2D)are interrelated global public health problems,and the current epidemics of both AD and T2D are insulin resistance diseases.Thus,AD and T2D may share common risk factors such as an unhealthy diet,lifestyle,and obesity.Meat products is an important part of the diet of consumers worldwide.This systematic review and meta-analysis aims to assess and estimate the effect of meat products consumption on AD and T2D in humans.Web of Science,MEDLINE,PubMed,Cochrane Library,and Embase were searched from January 2012 to April 2024.29 articles reported 32 cohort studies with 1785769 subjects,with 3546 AD cases and 91092 T2D cases that met the inclusion criteria and were included in our analysis.Consumption of various meat products increased the risk of T2D(hazard ratios(HR)=1.19,95%confidence intervals(CI):1.13−1.26,P=0.000;I2=88.5%),consumption of smoked,grilled/roasted and fried meat products was more likely to induce T2D(HR=1.24,95%CI:1.18−1.30,P=0.000;I2=76.1%),but was borderline significant for the risk of AD(HR=1.11,95%CI:0.98−1.25,P=0.094;I2=58.8%),with consumption of mainly livestock and poultry products increasing the risk(HR=1.21,95%CI:1.03−1.42,P=0.017;I2=66.8%).The association between meat products consumption and AD risk was influenced by meat type and sample size,while the risk of T2D was influenced by meat type,follow-up and sex.A daily intake of 27,123 and 170 g of livestock products increased the risk of T2D by 10%,51%and 70%respectively,whereas the risk of T2D was reduced when the intake of various meat products was less than 23 g/day.
基金supported by CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-026,China).
文摘Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the past decades and tumor progression or recurrence is inevitable in many patients.RNAibased therapy presents a novel disease-related gene targeting therapy,including otherwise undruggable genes,and generates therapeutic options.However,the therapeutic effect of siRNA is hindered by multiple biological barriers,primarily the blood-brain barrier(BBB).A glycoprotein-derived peptide-mediated delivery system is the preferred option to resolve this phenomenon.RDP,a polypeptide composed of 15 amino acids derived from rabies virus glycoprotein(RVG),possesses an N-type acetylcholine receptor(nAChR)-binding efficiency similar to that of RVG29.Given its lower cost and small particle size when used as a ligand,RDP should be extensively evaluated.First,we verified the brain-targeting efficacyy of RDP at the cellular and animal levels and further explored the possibility of using the RDP-oligoarginine peptide(designated RDP-5R)as a bio-safe vehicle to deliver therapeutic siRNA into glioma cells in vitro and in vivo.The polypeptide carrier possesses a diblock design composed of oligoarginine for binding siRNA through electrostatic interactions and RDP for cascade BBB-and glioma cell-targeting.The results indicated that RDP-R5/siRNA nanoparticles exhibited stable and suitable physicochemical properties for in vivo application,desirable glioma-targeting effects,and therapeutic efficiency.As a novel and efficient polypeptide carrier,RDP-based polypeptides hold great promise as a noninvasive,safe,and efficient treatment for various brain diseases.
基金supported by CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-026)the Postdoctoral Fellowship Program of CPSF(No.GZC20230313)。
文摘Most anti-tumor agents suffer from systemic non-specific distribution and low aggregation in tumors,which not only decreases the therapeutic efficacy,but also causes systemic toxic side effects in the treatments of tumors.In recent years,the rapid development of nanotechnology has brought new ideas for the application of anti-tumor drugs.Nanomedicines,such as liposomes and micelles,can improve drug targeting and prolong systemic circulation time to promote anti-tumor efficacy and reduce toxic side effects.However,conventional micelles bear the risk of instability and premature drug leaking in the blood circulation.We designed a reduction-responsive core-cross-linked micelle PTX@Fmoc-LA-PEG efficiently encapsulating Paclitaxel(PTX)viaπ-πstacking and hydrophobic interactions of Fmoc and PTX.Moreover,the micelle was further locked based on the cross-linking properties of the disulfide bonds formed by lipoic acid(LA).As expected,the core-cross-linked micelles PTX@Fmoc-LA-PEG remained stable in normal physiological environments,while restoring the normal drug release rate of micelles under the highly reducing environment due to LA unlocking.The blank micelles(Fmoc-LA-PEG)exhibited excellent biocompatibility,while the drug-loaded micelles(PTX@Fmoc-LA-PEG)displayed a remarkable anti-tumor effect in vitro and in vivo experiments.These results suggested that core-cross-linked micelles PTX@FmocLA-PEG have great potential to improve the targeting and stability of anti-tumor drugs.
基金supported by Shandong Provincial Natural Science Foundation Innovation and Development Joint Project,China(Grant No.:ZR2021LZY039)Zhejiang Provincial Traditional Chinese Medicine Science and Technology Plan,China(Grant No.:2021ZB184)。
文摘Microneedles(MNs)have attracted increasing attention as a transdermal delivery system(TDDS)[1].However,traditional volatile Chinese medicines cannot be dissolved in conventional soluble MN materials,such as hyaluronic acid and chitosan,making it difficult for many traditional Chinese medicine ingredients to be applied to MN.Elemene(ELE)was successfully isolated from Curcuma longa,and has numerous antitumor and curative effects[2].
文摘Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract.These formulations offer multiple advantages such as reduction in food effect and inter-individual variability,ease of preparation,and the possibility of manufacturing using common excipients available in the market.Despite these advantages,very few products are available in the present market,perhaps due to limited knowledge in the in vitro tests(for prediction of in vivo fate)and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration.The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations,their pharmacokinetic aspects and in vitro in vivo correlation(IVIVC)perspectives.Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion,bioavailability enhancement mechanisms,impact of excipients on efflux transporters,and lymphatic transport are discussed with examples.In addition,various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation,in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.
基金support from the University Grants Commission,India,Grant number:F.15*42/SAII/2012.
文摘The current paper has elaborated the efficient utilization of liquid biodiesel waste in combination with dillapiole and citronella essential oil as active ingredients.Sawdust,cellulose and hydrophobic silica were used as inert ingredients,which make the tablet to float over the water surface.ATR-FTIR analysis of tablet confirmed the compatibility with citronella oil,dillapiole,liquid biodiesel waste in tablet composition after compression.Physico-chemical analysis studies show that tablet parameters are in standard limits.SEM analysis shows some porous structures in tablet composition which confirms the floating nature of the tablets.The specific ratio(2:2:1)of citronella oil,dillapiole and liquid biodiesel waste showed maximum mortality,i.e.95%after 24 h.After application,the tablet is nontoxic towards the aquatic organisms and water quality remains unaf-fected.The better performance of the tablets has been evaluated in terms of characterization studies,viz.ATR-FTIR and SEM studies and bioefficacy trials which confirmed the presence of active ingredients responsible for insecticidal activity.
基金financially supported by Beijing Nova Program(Nos.Z211100002121127 and 20220484219)Beijing Natural Science Foundation(No.L212059)+1 种基金Fundamental Research Funds for the Central Universities(No.3332021101)CAMS Innovation Fund for Medical Sciences(CIFMS,Nos.2021-I2M-1-026 and 2021-I2M-1-028).
文摘Ulcerative colitis(UC)is a common progressive inflammatory disease whose incidence has increased rapidly in recent years,and can develop into colorectal cancer in severe cases.There are currently no adequate or effective treatments for UC due to the fact that some patients have found suboptimal results after repeated administration,while others have experienced adverse effects.With the rapid development of nanotechnology,developing innovative colon-targeting platforms is essential to improving efficacy,reducing side effects,and improving patient compliance.In this review,we summarize the pathophysiological characteristics of UC and the most recent status of numerous nanodrug delivery systems based on different targeting mechanisms in treating UC.Oral,intravenous,and rectal drug delivery nanoparticles targeting the colon are discussed,which can provide ideas for the design of colon-targeting nanoparticles for the treatment of colon diseases,especially for the treatment of UC.Last but not least,we provide a glimpse into the future of colon-targeted delivery systems,as well as future advancements in the field.
基金supported by Innovation Fund for Medical Sciences(CIFMS)(No.2021-I2M-1-026,China)National Natural Science Foundation of China(Nos.82104106,82073778)。
文摘As one of the most promising adoptive T-cell therapies,chimeric antigen receptor T-cell(CAR-T)therapy has acquired Food and Drug Administration(FDA)approval for a variety of products and has been used successfully in the treatment of malignant hematological tumors.CAR-T therapy,on the other hand,faces a number of obstacles in the field of solid tumor therapy that limit its widespread clinical implementation.Significant advances in nanoparticle research in cancer therapy and immunotherapy have been made in recent years,providing novel strategies to address the challenges encountered by CAR-T therapy in the treatment of solid tumors.This review commences with a comprehensive explanation of the basic framework of CAR-T therapy as well as the challenges it faces in the treatment of solid tumors.Subsequently,we encapsulate a summary of the developmental research combining nanoparticles with CAR-T cells for the treatment of solid tumors,which includes gene transfection,cell activation and expansion,targeted infiltration,immune escape inhibition,and combination with other therapies.Coupled with the overview of the research progress,a discussion has been initiated on the challenges and perspectives of CAR-T based on nanoparticles.
基金supported by the National Natural Science Foundation of China(No.81773604)the National Science and Technology Major Project of the Ministry of Science and Technology of China(No.2018ZX09735005)+1 种基金the Doctoral Scientific Research Fund Project of Nanyang Institute of Technology(No.510197)the Interdisciplinary Sciences Project,Nanyang Institute of Technology(No.520097).
文摘This study reports the isolation of four newβ-carboline alkaloids(1−4)and six previously identified alkaloids(5−10)from the roots of Peganum harmala L.Among these compounds,1 and 2 were characterized as rareβ-carboline-quinazoline dimers exhibiting axial chirality.Compound 3 possessed a unique 6/5/6/7 tetracyclic ring system with an azepine ring,and compound 4 was a novel annomontineβ-carboline.The structures of these compounds were elucidated by spectroscopic data and quantum mechanical calculations.The biosynthetic pathways of 1−3 were proposed.Additionally,the cytotoxicity of some isolates against four cancer cell lines(HL-60,A549,MDA-MB-231,and DU145)was evaluated.Notably,compound 4 exhibited significant cytotoxicity against HL-60,A549,and DU145 cells with IC_(50) values of 12.39,12.80,and 30.65μmol·L^(−1),respectively.Furthermore,compound 2 demonstrated selective cytotoxicity against HL-60 cells with an IC_(50) value of 17.32μmol·L^(−1).
基金supported by the National Natural Science Foundation of China(No.82273884)。
文摘Natural endogenous materials(NEMs),such as cell and cell derivatives,polysaccharide,protein and peptide,and nucleic acid-derived vectors,often exhibit biocompatibility,biodegradability and natural homing ability,which can minimize adverse reactions in vivo and have the potential to improve drug delivery efficacy.Currently,a variety of drug delivery systems(DDSs)based on NEMs have been constructed for macromolecules to address the challenges posed by their inherent large size,intricate structure,low permeability,and susceptibility to harsh environments.The aim of this article is to provide a comprehensive overview of various delivery strategies that predominantly utilize NEMs as carriers for macromolecular delivery.By thoroughly discussing the pros and cons of NEM-based DDSs,we hope to provide valuable insights into future innovations in pharmaceutical science,with a focus on improving therapeutic outcomes through advanced drug formulations.
基金financially supported by the National Natural Science Foundation(No.82304393,China)Beijing Nova Program(Nos.Z211100002121127 and 20220484219,China)+1 种基金Beijing Natural Science Foundation(No.L212059,China)CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-028,China)。
文摘Ulcerative colitis(UC)is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon and disrupted intestinal function.Ramulus mori(Sangzhi)alkaloids(SZ-A),derived from twigs of mulberry,were approved by the National Medical Products Administration in 2020 for treating type 2 diabetes mellitus.Accumulated evidence has confirmed that SZ-A also alleviates non-alcoholic fatty liver disease and ameliorates inflammation,indicating its potential to address inflammation in UC.However,the treatment of UC faces challenges due to low drug delivery efficiency and short retention time.To overcome these challenges,an injectable and adherent in-situ thermo-sensitive hydrogel containing SZ-A was developed for rectal drug delivery,utilizing the thermo-sensitive polymers Poloxamer 407and 188.The thermo-sensitive hydrogel system was designed with a moderate gelation temperature of 32±0.5℃,a short gelation time of 64 s,a p H range of 7-10,high moisturizing capability exceeding 90%,and moderate mechanical strength of 4-5 s.In a rat model with UC,the in situ thermo-sensitive hydrogel significantly extended the retention time at the colonic site and enabled sustained release after rectal administration.Symptoms of UC were markedly reduced following rectal administration of SZ-A thermosensitive hydrogel.Furthermore,the release of inflammatory factors,such as interleukin-1β(IL-1β),IL-6,IL-18,tumor necrosis factor-α(TNF-α),and transforming growth factor-β1(TGF-β1),significantly decreased in the SZ-A thermo-sensitive hydrogel group.The integrity of the colonic mucosal barrier was significantly enhanced following the application of SZ-A thermo-sensitive hydrogel.In conclusion,rectal administration of SZ-A in situ thermo-sensitive hydrogel effectively alleviated UC symptoms,inhibited the secretion of inflammatory factors,and promoted the repair of the colonic mucosal barrier.This approach holds promise as a potential treatment for UC.
基金financial support from the Basic Research Cooperation Project of Beijing,Tianjin,Hebei from the Natural Science Foundation of Beijing(No.J200018),Tianjin(No.20JCZXJC00070),and Hebei(No.H2020206649)Beijing Natural Science Foundation(No.7214281)the projects of National Natural Science Foundation of China(No.81973259)。
文摘Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied clinically.In this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for chemo-immunotherapy.In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages.Furthermore,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition.The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.
基金financially supported by CSIR 12th Five Year Plan project BSC-0205CSIR-Phytopharmaceutical Mission Project HCP010+1 种基金CSIR-YSA (Young Scientist Award,P90807) Research Grantthe fellowship from Department of Biotechnology,India (GAP-2158).IIIM publication number: ⅢM/2222/2018
文摘Objective: Bergenia ciliata(Haw.) Sternb. is used in the Indian traditional system of medicine to treat various ailments including rheumatism and to heal wounds. The objective of the present study was to perform a preclinical characterization of the B. ciliata-based botanical extract IIIM-160.Methods: ⅢM-160 was chemically standardized and analyzed for heavy metal content, aflatoxins,pesticides and microbial load. The in vitro and in vivo efficacies were determined in suitable models of inflammation, arthritis and nociception. An acute oral toxicity study was performed in Swiss albino mice.A suitable oral formulation was developed and characterized.Results: Bergenin was found to be the major component(9.1% w/w) of ⅢM-160. The botanical lead displayed inhibition of lipopolysaccharide-induced production of proinflammatory cytokines in THP-1 cells, with selectivity toward interleukin-6(IL-6) and had an excellent safety-window. It showed anti-inflammatory, anti-arthritic and antinociceptive activity in animal models and was not toxic at oral doses up to 2 g/kg in Swiss-albino mice. The gastroretentive, sustained-release capsule formulation showed sustained-release of the bergenin over the period of 24 h, resulting in improved plasma-exposure of bergenin in Sprague–Dawley rats.Conclusion: The dual-activity of IL-6 inhibition and antinociception marks the suitability of ⅢM-160 for treating rheumatoid arthritis. This study will serve as the benchmark for further research on this botanical formulation.
文摘Pharmaceutical scientists throughout the world are trying to explore thin films as a novel drug delivery tool. Thin films have been identified as an alternative approach to conventional dosage forms. The thin films are considered to be convenient to swallow, selfadministrable, and fast dissolving dosage form, all of which make it as a versatile platform for drug delivery. This delivery system has been used for both systemic and local action via several routes such as oral, buccal, sublingual, ocular, and transdermal routes. The design of efficient thin films requires a comprehensive knowledge of the pharmacological and pharmaceutical properties of drugs and polymers along with an appropriate selection of manufacturing processes. Therefore, the aim of this review is to provide an overview of the critical factors affecting the formulation of thin films, including the physico-chemical properties of polymers and drugs, anatomical and physiological constraints, as well as the characterization methods and quality specifications to circumvent the difficulties associated with formulation design. It also highlights the recent trends and perspectives to develop thin film products by various companies.
