Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we...Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.展开更多
Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous i...Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.展开更多
Novel insulin-loaded nanoparticles based on hydroxypropyl-β-cyclodextrin modified carboxymethyl chitosan(CMC-HP-β-CD) were prepared to improve the oral bioavailability of insulin. The CMC-HP-β-CD was characterize...Novel insulin-loaded nanoparticles based on hydroxypropyl-β-cyclodextrin modified carboxymethyl chitosan(CMC-HP-β-CD) were prepared to improve the oral bioavailability of insulin. The CMC-HP-β-CD was characterized by FT-IR spectroscopy and 1H-NMR spectra. The insulin-loaded nanoparticles were prepared through crosslinking with calcium ions, and the morphology and size of the prepared nanoparticles were characterized by transmission electron microscopy(TEM) and dynamic light scattering(DLS). Cumulative release in vitro study was performed respectively in simulated gastric medium fluid(SGF, p H=1.2), simulated intestinal fluid(SIF, p H=6.8) and simulated colonic fluid(SCF, p H=7.4). The encapsulation efficiency of insulin was up to 87.14 ± 4.32% through high-performance liquid chromatography(HPLC). Statistics indicated that only 15% of the encapsulated insulin was released from the CMC-HP-β-CD nanoparticles in 36 h in SGF, and about 50% of the insulin could be released from the nanoparticles in SIF, whereas more than 80% was released in SCF. In addition, the solution containing insulin nanoparticles could effectively reduce the blood glucose level of diabetic mice. The cytotoxicity test showed that the samples had no cytotoxicity. CMC-HP-β-CD nanoparticles are promising candidates as potential carriers in oral insulin delivery systems.展开更多
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix(ECM),which is primarily produced by activated hepatic stellate cells(HSCs).However,effective therapies for hepatic fibrosis are cur...Liver fibrosis is characterized by the excessive accumulation of extracellular matrix(ECM),which is primarily produced by activated hepatic stellate cells(HSCs).However,effective therapies for hepatic fibrosis are currently lacking.Artesunate is a promising anti-fibrotic drug candidate,but its clinical application is hindered by limited absorption.Here,we present a novel oral delivery platform that enhances the HSCs uptake of artesunate and induces potent ferroptosis.The platform is vitamin Adecorated nanoparticles encapsulated with artesunate.The multifunctional ligand vitamin A interacts with retinol-binding proteins that are highly expressed on the intestinal epithelium to promote transcytosis,highly expressed on the surface of HSCs but lowly expressed in normal hepatocytes.After oral administration,this oral delivery platform enhances transepithelial transport in the intestine,improves drug accumulation in the liver,and continuously increases HSCs uptake of artesunate.Upon drug release in HSCs,artesunate depletes glutathione peroxidase 4 and glutathione,effectively initiating ferroptosis.In vivo experiments demonstrate that this strategy induces pronounced ferroptosis,efficiently relieving liver fibrosis.This work provides a proof-ofconcept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for liver fibrosis treatment.展开更多
The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in oral delivery.Inspired by the“antiskid tires”with complex chiral patterns,mesoporous silica nanopart...The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in oral delivery.Inspired by the“antiskid tires”with complex chiral patterns,mesoporous silica nanoparticles AT-R@CMSN exhibiting geometrical chiral structure were designed to improve the surface/interface roughness in nanoscale,and employed as the hosting system for insoluble drugs nimesulide(NMS)and ibuprofen(IBU).Once performing the delivery tasks,AT-R@CMSN with rigid skeleton protected the loaded drug and reduced the irritation of drug on gastrointestinal tract(GIT),while their porous structure deprived drug crystal and improved drug release.More importantly,AT-R@CMSN functioned as“antiskid tire”to produce higher friction on intestinal mucosa and substantively influencedmultiple biological processes,including“contact”,“adhesion”,“retention”,“permeation”and“uptake”,compared to the achiral S@MSN,thereby improving the oral adsorption effectiveness of such drug delivery systems.By engineering AT-R@CMSN to overcome the stability,solubility and permeability bottlenecks of drugs,orally administered NMS or IBU loaded AT-R@CMSN could achieve higher relative bioavailability(705.95%and 444.42%,respectively)and stronger anti-inflammation effect.In addition,AT-R@CMSN displayed favorable biocompatibility and biodegradability.Undoubtedly,the present finding helped to understand the oral adsorption process of nanocarriers,and provided novel insights into the rational design of nanocarriers.展开更多
Proteins and peptides(PPs)have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy,but fewer side effects.Owing to the poor stability and limite...Proteins and peptides(PPs)have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy,but fewer side effects.Owing to the poor stability and limited permeability through gastrointestinal(GI)tract and epithelia,the therapeutic PPs are usually administered by parenteral route.Given the big demand for oral administration in clinical use,a variety of researches focused on developing new technologies to overcome GI barriers of PPs,such as enteric coating,enzyme inhibitors,permeation enhancers,nanoparticles,as well as intestinal microdevices.Some new technologies have been developed under clinical trials and even on the market.This review summarizes the history,the physiological barriers and the overcoming approaches,current clinical and preclinical technologies,and future prospects of oral delivery of PPs.展开更多
Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills 〉500 000 people each year. The primary cost of artemisinin is the very expensive...Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills 〉500 000 people each year. The primary cost of artemisinin is the very expensive process used to extract and purify the drug from Artemisia annua. Elimination of this apparently unnecessary step will make this potent antimalarial drug affordable to the global population living in endemic regions. Here we reported the oral delivery of a non-protein drug artemisinin biosynthesized (~0.8 mg/g dry weight) at clinically meaningful levels in tobacco by engineering two metabolic pathways targeted to three different cellular compartments (chloroplast, nucleus, and mitochondria). The doubly transgenic lines showed a three-fold enhancement of isopentenyl pyrophosphate, and targeting AACPR, DBR2, and CYP71AV1 to chloroplasts resulted in higher expression and an efficient photo-oxidation of di- hydroartemisinic acid to artemisinin. Partially purified extracts from the leaves of transgenic tobacco plants inhibited in vitro growth progression of Plasmodium falciparum-infected red blood cells. Oral feeding of whole intact plant cells bioencapsulating the artemisinin reduced the parasitemia levels in challenged mice in comparison with commercial drug. Such novel synergistic approaches should facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants.展开更多
In this study,a polymeric lipid nanoparticle(NP)(simplified as Lipid NP)was reported as a promising oral vaccine delivery system.The Lipid NPs composed of a hydrophobic polymeric poly(D,L-lactide-co-glycolide)(PLGA)co...In this study,a polymeric lipid nanoparticle(NP)(simplified as Lipid NP)was reported as a promising oral vaccine delivery system.The Lipid NPs composed of a hydrophobic polymeric poly(D,L-lactide-co-glycolide)(PLGA)core and a surface coating of lipid monolayer.Membrane emulsification technique was used to obtain uniform-sized Lipid NPs.Ovalbumin(OVA)was used as a model vaccine.Compared with the pure PLGA NPs,the Lipid NPs achieved higher loading capacity(LC)and entrapment efficiency(EE)for the encapsulated OVA.An in vitro oral release profile showed that the OVA-Lipid NPs were with lower initial burst and could protect the loaded OVA from the harsh gastrointestinal(GI)environment for a long time.In addition,a human microfold cell(M-cell)transcytotic assay demonstrated that due to a lipid layer structure on the particle surface,the Lipid NPs showed higher affinity to the M-cells.Since the M-cell in the intestinal epithelium played an important role in particle transportation as well as intimately associated with the underlying immune cells,the OVA-Lipid NPs effectively induced mucosal and humoral immune responses.展开更多
Semiconductor quantum dots(QDs)have shown great promise as fluorescent probes for molecular,cellular and in vivo imaging.However,the fluorescence of traditional polymer-encapsulated QDs is often quenched by proton-ind...Semiconductor quantum dots(QDs)have shown great promise as fluorescent probes for molecular,cellular and in vivo imaging.However,the fluorescence of traditional polymer-encapsulated QDs is often quenched by proton-induced etching in acidic environments.This is a major problem for applications of QDs in the gastrointestinal tract because the gastric(stomach)environment is strongly acidic(pH 12).Here we report the use of proton-resistant surface coatings to stabilize QD fl uorescence under acidic conditions.Using both hyperbranched polyethylenimine(PEI)and its polyethylene glycol derivative(PEG-grafted PEI),we show that the fl uorescence of coreshell CdSe/CdS/ZnS QDs is effectively protected from quenching in simulated gastric fluids.In comparison,amphiphilic lipid or polymer coatings provide no protection under similarly acidic conditions.The proton-resistant QDs are found to cause moderate membrane damage to cultured epithelial cells,but PEGylation(PEG grafting)can be used to reduce cellular toxicity and to improve nanoparticle stability.展开更多
Oral administration of nutrient/drug is the most common and preferred route. However, a number of barriers are encountered after ingestion, limiting efficient oral nutrient/drug absorption. Both lipid-based (e.g., nan...Oral administration of nutrient/drug is the most common and preferred route. However, a number of barriers are encountered after ingestion, limiting efficient oral nutrient/drug absorption. Both lipid-based (e.g., nanoemulsion, solid lipid nanoparticles) and polymer-based (e.g., protein and polysaccharide nanoparticles) nanoscale delivery systems have demonstrated capability to overcome some of these physiological barriers during transportation and metabolism stages. To better deal with those barriers, polymer-lipid complex nanoparticles are being explored and developed to merge the beneficial features and overcome the respective shortcomings of lipid-based and polymer-based nanoparticles. This paper aims to provide an overview of the various preparation strategies and supramolecular interactions of orally administered polymer-lipid complex nanoparticles by reviewing recent studies. Two types of polymer-lipid complex nanoparticles have been developed, i.e., lipid core with polymer shell nanoparticles and polymer core with lipid shell nanoparticles (lipid-polymer hybrid nanoparticles). Besides, both natural and synthetic polymers used for fabrication are discussed and their advantages and disadvantages are highlighted. Further research work is needed to optimize the fabrication and scaling up processes, so that these versatile polymer-lipid complex nanoparticles could have a significant impact on the oral delivery of nutrient/drug.展开更多
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...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.展开更多
In-situ oral delivery of therapeutic antibodies,like monoclonal antibody,for chronic inflammation treatment is the most convenient approach compared with other administration routes.Moreover,the abundant links between...In-situ oral delivery of therapeutic antibodies,like monoclonal antibody,for chronic inflammation treatment is the most convenient approach compared with other administration routes.Moreover,the abundant links between the gut microbiota and colonic inflammation indicate that the synergistic or antagonistic effect of gut microbiota to colonic inflammation.However,the antibody activity would be significantly affected while transferring through the gastrointestinal tract due to hostile conditions.Moreover,these antibodies have short serum half-lives,thus,require to be frequently administered with high doses to be effective,leading to low patient tolerance.Here,we develop a strategy utilizing thin shell hydrogel microcapsule fabricated by microfluidic technique as the oral delivering carrier.By encapsulating antibodies in these microcapsules,antibodies survive in the hostile gastrointestinal environment and rapidly release into the small intestine through oral administration route,achieving the same therapeutic effect as the intravenous injection evaluated by a colonic inflammation disease model.Moreover,the abundance of some intestinal microorganisms as the indication of the improvement of inflammation has remarkably altered after in-situ antibody-laden microcapsules delivery,implying the restoration of micro-ecology of the intestine.These findings prove our microcapsules are exploited as an efficient oral delivery agent for antibodies with programmable function in clinical application.展开更多
Gut microbiome(GM)is closely related to the overall health status for the human being.The dysfunction of microbiome can lead to many diseases such as inflammation,cancer and neurodegenerative disease.Therefore,it'...Gut microbiome(GM)is closely related to the overall health status for the human being.The dysfunction of microbiome can lead to many diseases such as inflammation,cancer and neurodegenerative disease.Therefore,it's of great importance to develop effective strategy to regulate GM.Gut lumen-targeted oral delivery system(GLT-ODS)has been extensively investigated and widely used in food science and engineering in these years,due to the targeted delivery property,controlled release profile,high biocompatibility and enhanced bioavailability of cargos.Herein,we comprehensively summarized the current advances in GLT-ODS for bioactive agent.Specifically,we systematically summarize the GLT-ODS for pre-agents(prebiotics and probiotics)and anti-agents(antibiotics and bacteriophages)according to the type of cargos.Through in-depth discussion of representative researches,we refined the limitations of existing research in carrier material and target selection,and drew a blueprint for the future technological research and development.We believe that GLT-ODS will become a safe,efficient,simple and precise GM management strategy for improvement of health and shine in the development of precision food and pharmaceutical engineering in future.展开更多
Imatinib has been widely used as a selective kinase inhibitor for treating a variety of cancers,and this molecule is very hydrophobic so it is usually modified with mesylate salt in clinic to increase bioavailability....Imatinib has been widely used as a selective kinase inhibitor for treating a variety of cancers,and this molecule is very hydrophobic so it is usually modified with mesylate salt in clinic to increase bioavailability.However,pH-dependent aqueous solubility and relatively high dosage of imatinib mesylate greatly reduce the clinical outcomes.To solve this problem,we developed an intestine enzyme-responsive hydrogel to efficiently encapsulate hydrophobic imatinib with long-term controlled release and enhanced intestinal permeability through oral administration.Methacrylic anhydride-modified carboxymethyl chitosan(MA-CMCS)was synthesized via amidation reaction and then MA-CMCS was crosslinked with photoinitator under UV-irradation to form a three-dimensional hydrophilic polymer network.The intestine enzyme responsiveness was endowed with imatinib-loaded hydrogel through hydrolyzation of glucosidic bond,which could achieve enzyme-triggered long-term drug release of up to 2 days.Furthermore,sodium deoxycholate was embedded into the hydrogel to synchronously open epithelial tight junctions with improved intestinal permeability.In vitro studies revealed similar lethality against colon cancer cell for both imatinib mesylate and imatinib-loaded hydrogels.Moreover,significantly enhanced in vivo tumor inhibition(6-fold higher compared to imatinib mesylate)was achieved after oral administration with imatinib-loaded hydrogels.Overall,this enzyme-responsive hydrogel could achieve long-term synchronous release of kinase inhibitor(imatinib)and tight junction permeation enhancer(sodium deoxycholate)at intestine with enhanced therapeutic efficiency,which could provide an effective approach to improve the bioavailability of hydrophobic anticancer chemodrugs with oral administration.展开更多
Permeation enhancers(PEs),such as N-[8-(2-hydroxybenzoyl)amino]-caprylate(SNAC),have been reported to improve the oral absorption of various macromolecules.However,the bioavailabilities of these formulations are quite...Permeation enhancers(PEs),such as N-[8-(2-hydroxybenzoyl)amino]-caprylate(SNAC),have been reported to improve the oral absorption of various macromolecules.However,the bioavailabilities of these formulations are quite low and variable due to the influences of enzymes,pH and other gastrointestinal barriers.In this study,we revealed that SNAC could interact with insulin to form tight complexes in a specific concentration(insulin≥ 40μg/mL)-,ratio(SNAC/insulin≥ 20:1)-and pH(≥ 6.8)-dependent manner,thus contributing to a significantly high efficacy of oral insulin delivery.Specifically,absorption mechanism studies revealed that the SNAC/insulin complexes were internalized into the cells by passive diffusion and remained intact when transported in the cytosol.Furthermore,the complexes accelerated the exocytosis of insulin to the basolateral side,thereby enhancing its intestinal mucosal permeability.Eudragit;S100-entrapped SNAC/insulin microspheres were then prepared and exhibited an apparent permeability coefficient(P;) that was 6,6-fold higher than that of the insulin solution.In diabetic rats,hypoglycemic activity was sustained for more than 10 h after the microspheres were loaded into entericcoated capsules.Further pharmacokinetic studies revealed an approximately 6.3% oral bioavailability in both the fasted and fed states,indicating a negligible food effect.Collectively,this study provides insight into the interaction between PEs and payloads and presents an SNAC-based oral insulin delivery system that has high oral bioavailability and patient-friendly medication guidance.展开更多
An oral drug delivery system using proteinoid microspheres is discussed with respect to itsunique dependence on pH. It has been found that certain drugs such as insulin and heparin canbe encapsulated in proteinoid sph...An oral drug delivery system using proteinoid microspheres is discussed with respect to itsunique dependence on pH. It has been found that certain drugs such as insulin and heparin canbe encapsulated in proteinoid spheres at stomach pH's (1--3). These spheres also dissemble atintestinal pH's (6--7) releasing the drug for absorption. Using this technique low molecularweight heparin and human growth hormone have been orally delivered successfully to severalanimal species. Future work has been proposed to study the interaction and binding of thespecific drugs with synthesized oligopeptides.展开更多
Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,m...Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,most of the nanocarriers are administered intravenously,which is inconvenient and may cause complications.Herein,we developed an oral lipid-polymer based nanoparticles(FA-LNPs)decorated with folic acid,which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages.Subsequently,naringenin(Nrg),one of the antiinflammation drugs,was designed to be the oral nanomedicine(FA-LNPs/Nrg)for the first time via the encapsulation of FALNPs.FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy.After the atherosclerotic ApoE−/−mice were treated by FALNPs/Nrg via oral administration for three months,the aortic lesion area,plaque area,and necrotic core area of the aortic root were significantly decreased.Meanwhile,the lipid-related blood parameters recovered to normal levels.Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.展开更多
Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads(i.e.,immunogens)against gastric damage.In this study,hollowed nan...Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads(i.e.,immunogens)against gastric damage.In this study,hollowed nanocarriers(NCs:silica nanospheres and gold nanocages)with poly-l-lysine(PLL)coating and mammalian orthoreovirus cell attachment proteinσ1 functionalization(NC-PLL-σ1)were explored as functional oral drug delivery vehicles(ODDVs).The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells(M-cells)mediated transcytosis(viaσ1-α2–3-linked sialic acids adherence)across gastrointestinal epithelia.PLL coating provided protection and slow-release of rhodamine 6 G(R6G),a model payload.The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro.When compared with other experimental groups,the fully functionalized ODDV system(with PLL-σ1)demonstrated two significant advantages:a significantly higher transport efficiency(198%over blank control at 48 h);and protection of payloads which led to both better transport efficiency and extended-release of payloads(61%over uncoated carriers at 48 h).In addition,it was shown that the M cell presence in intestinal organoid monolayers(modulated by Rank L stimulation)was a determining factor on the transport efficiency of the ODDVs:more M-cells(induced by higher Rank L)in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload(R6G).The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.展开更多
Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantag...Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration(oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.展开更多
Self-propelling micro-and nano-motors(MNMs)have been extensively investigated as an emerging oral drug delivery carrier for gastrointestinal(GI)tract diseases.However,the propulsion of current MNMs reported so far is ...Self-propelling micro-and nano-motors(MNMs)have been extensively investigated as an emerging oral drug delivery carrier for gastrointestinal(GI)tract diseases.However,the propulsion of current MNMs reported so far is mostly based on the redox reaction of metals(such as Zn and Mg)with severe propulsion gas generation,remaining non-degradable residue in the GI tract.Here,we develop a bioinspired enzyme-powered biopolymer micromotor mimicking the mucin penetrating behavior of Helicobacter pylori in the stomach.It converts urea to ammonia and the subsequent increase of pH induces local gel-sol transition of the mucin layer facilitating the penetration into the stomach tissue layer.The successful fabrication of micromotors is confirmed by high-resolution transmission electron microscopy,electron energy loss spectroscopy,dynamic light scattering analysis,zeta-potential analysis.In acidic condition,the immobilized urease can efficiently converted urea to ammonia,comparable with that of neutral condition because of the increase of surrounding pH during propulsion.After administration into the stomach,the micromotors show enhanced penetration and prolonged retention in the stomach for 24 h.Furthermore,histological analysis shows that the micromotors are cleared within 3 days without causing any toxicity in the GI tract.The enhanced penetration and retention of the micromotors as an active oral delivery carrier in the stomach would be successfully harnessed for the treatment of various GI tract diseases.展开更多
基金The authors gratefully acknowledge financial support from National Natural Science Foundation of China(81872818)National Key R&D Program of China(2021YFE0115200).
文摘Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.
基金financial support from National Natural Science Foundation of China (81872818)National Key R&D Program of China (2021YFE0115200)
文摘Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.
基金Funded by the National Nature Science Foundation of China(No.51273156)the Open Foundation of Hubei key laboratory of Purification and Application of Plant Anti-cancer Active Ingredients(No.HLPAI2014005)
文摘Novel insulin-loaded nanoparticles based on hydroxypropyl-β-cyclodextrin modified carboxymethyl chitosan(CMC-HP-β-CD) were prepared to improve the oral bioavailability of insulin. The CMC-HP-β-CD was characterized by FT-IR spectroscopy and 1H-NMR spectra. The insulin-loaded nanoparticles were prepared through crosslinking with calcium ions, and the morphology and size of the prepared nanoparticles were characterized by transmission electron microscopy(TEM) and dynamic light scattering(DLS). Cumulative release in vitro study was performed respectively in simulated gastric medium fluid(SGF, p H=1.2), simulated intestinal fluid(SIF, p H=6.8) and simulated colonic fluid(SCF, p H=7.4). The encapsulation efficiency of insulin was up to 87.14 ± 4.32% through high-performance liquid chromatography(HPLC). Statistics indicated that only 15% of the encapsulated insulin was released from the CMC-HP-β-CD nanoparticles in 36 h in SGF, and about 50% of the insulin could be released from the nanoparticles in SIF, whereas more than 80% was released in SCF. In addition, the solution containing insulin nanoparticles could effectively reduce the blood glucose level of diabetic mice. The cytotoxicity test showed that the samples had no cytotoxicity. CMC-HP-β-CD nanoparticles are promising candidates as potential carriers in oral insulin delivery systems.
基金supported by the Fundamental Research Funds for the Central Universities(No.SWU-KQ22024)the NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparation and Excipients(No.PPE2023005)+3 种基金the China Postdoctoral Science Foundation(No.2023M740731)the Chongqing Science and Technology Commission(No.CSTB2022TIAD-KPX0094)National Key Research and Development Program of China(No.2021YFD1800900)National Natural Science Foundation of China(No.82073790).
文摘Liver fibrosis is characterized by the excessive accumulation of extracellular matrix(ECM),which is primarily produced by activated hepatic stellate cells(HSCs).However,effective therapies for hepatic fibrosis are currently lacking.Artesunate is a promising anti-fibrotic drug candidate,but its clinical application is hindered by limited absorption.Here,we present a novel oral delivery platform that enhances the HSCs uptake of artesunate and induces potent ferroptosis.The platform is vitamin Adecorated nanoparticles encapsulated with artesunate.The multifunctional ligand vitamin A interacts with retinol-binding proteins that are highly expressed on the intestinal epithelium to promote transcytosis,highly expressed on the surface of HSCs but lowly expressed in normal hepatocytes.After oral administration,this oral delivery platform enhances transepithelial transport in the intestine,improves drug accumulation in the liver,and continuously increases HSCs uptake of artesunate.Upon drug release in HSCs,artesunate depletes glutathione peroxidase 4 and glutathione,effectively initiating ferroptosis.In vivo experiments demonstrate that this strategy induces pronounced ferroptosis,efficiently relieving liver fibrosis.This work provides a proof-ofconcept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for liver fibrosis treatment.
文摘The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in oral delivery.Inspired by the“antiskid tires”with complex chiral patterns,mesoporous silica nanoparticles AT-R@CMSN exhibiting geometrical chiral structure were designed to improve the surface/interface roughness in nanoscale,and employed as the hosting system for insoluble drugs nimesulide(NMS)and ibuprofen(IBU).Once performing the delivery tasks,AT-R@CMSN with rigid skeleton protected the loaded drug and reduced the irritation of drug on gastrointestinal tract(GIT),while their porous structure deprived drug crystal and improved drug release.More importantly,AT-R@CMSN functioned as“antiskid tire”to produce higher friction on intestinal mucosa and substantively influencedmultiple biological processes,including“contact”,“adhesion”,“retention”,“permeation”and“uptake”,compared to the achiral S@MSN,thereby improving the oral adsorption effectiveness of such drug delivery systems.By engineering AT-R@CMSN to overcome the stability,solubility and permeability bottlenecks of drugs,orally administered NMS or IBU loaded AT-R@CMSN could achieve higher relative bioavailability(705.95%and 444.42%,respectively)and stronger anti-inflammation effect.In addition,AT-R@CMSN displayed favorable biocompatibility and biodegradability.Undoubtedly,the present finding helped to understand the oral adsorption process of nanocarriers,and provided novel insights into the rational design of nanocarriers.
基金financially supported by National Natural Science Foundation of China(No.s 81872815,81872826 and 82073801)Science and Technology Commission of Shanghai Municipality(No.18ZR1404100,China)+1 种基金Shanghai Pujiang Program(No.18PJD001,China)Key Subject of Shanghai Skin Disease Hospital(No.2019ZDXK03,China)
文摘Proteins and peptides(PPs)have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy,but fewer side effects.Owing to the poor stability and limited permeability through gastrointestinal(GI)tract and epithelia,the therapeutic PPs are usually administered by parenteral route.Given the big demand for oral administration in clinical use,a variety of researches focused on developing new technologies to overcome GI barriers of PPs,such as enteric coating,enzyme inhibitors,permeation enhancers,nanoparticles,as well as intestinal microdevices.Some new technologies have been developed under clinical trials and even on the market.This review summarizes the history,the physiological barriers and the overcoming approaches,current clinical and preclinical technologies,and future prospects of oral delivery of PPs.
文摘Artemisinin is highly effective against drug-resistant malarial parasites, which affects nearly half of the global population and kills 〉500 000 people each year. The primary cost of artemisinin is the very expensive process used to extract and purify the drug from Artemisia annua. Elimination of this apparently unnecessary step will make this potent antimalarial drug affordable to the global population living in endemic regions. Here we reported the oral delivery of a non-protein drug artemisinin biosynthesized (~0.8 mg/g dry weight) at clinically meaningful levels in tobacco by engineering two metabolic pathways targeted to three different cellular compartments (chloroplast, nucleus, and mitochondria). The doubly transgenic lines showed a three-fold enhancement of isopentenyl pyrophosphate, and targeting AACPR, DBR2, and CYP71AV1 to chloroplasts resulted in higher expression and an efficient photo-oxidation of di- hydroartemisinic acid to artemisinin. Partially purified extracts from the leaves of transgenic tobacco plants inhibited in vitro growth progression of Plasmodium falciparum-infected red blood cells. Oral feeding of whole intact plant cells bioencapsulating the artemisinin reduced the parasitemia levels in challenged mice in comparison with commercial drug. Such novel synergistic approaches should facilitate low-cost production and delivery of artemisinin and other drugs through metabolic engineering of edible plants.
基金This work was financially supported by the 973 Program(Grant No.2009CB930300)National Natural Science Foundation of China(No.81273449).
文摘In this study,a polymeric lipid nanoparticle(NP)(simplified as Lipid NP)was reported as a promising oral vaccine delivery system.The Lipid NPs composed of a hydrophobic polymeric poly(D,L-lactide-co-glycolide)(PLGA)core and a surface coating of lipid monolayer.Membrane emulsification technique was used to obtain uniform-sized Lipid NPs.Ovalbumin(OVA)was used as a model vaccine.Compared with the pure PLGA NPs,the Lipid NPs achieved higher loading capacity(LC)and entrapment efficiency(EE)for the encapsulated OVA.An in vitro oral release profile showed that the OVA-Lipid NPs were with lower initial burst and could protect the loaded OVA from the harsh gastrointestinal(GI)environment for a long time.In addition,a human microfold cell(M-cell)transcytotic assay demonstrated that due to a lipid layer structure on the particle surface,the Lipid NPs showed higher affinity to the M-cells.Since the M-cell in the intestinal epithelium played an important role in particle transportation as well as intimately associated with the underlying immune cells,the OVA-Lipid NPs effectively induced mucosal and humoral immune responses.
基金by NIH Grants(P20 GM072069,R01 CA108468-01,U01 HL080711,and U54CA119338)the Georgia Cancer Coalition Distinguished Cancer Scholars Program(to S.N.).
文摘Semiconductor quantum dots(QDs)have shown great promise as fluorescent probes for molecular,cellular and in vivo imaging.However,the fluorescence of traditional polymer-encapsulated QDs is often quenched by proton-induced etching in acidic environments.This is a major problem for applications of QDs in the gastrointestinal tract because the gastric(stomach)environment is strongly acidic(pH 12).Here we report the use of proton-resistant surface coatings to stabilize QD fl uorescence under acidic conditions.Using both hyperbranched polyethylenimine(PEI)and its polyethylene glycol derivative(PEG-grafted PEI),we show that the fl uorescence of coreshell CdSe/CdS/ZnS QDs is effectively protected from quenching in simulated gastric fluids.In comparison,amphiphilic lipid or polymer coatings provide no protection under similarly acidic conditions.The proton-resistant QDs are found to cause moderate membrane damage to cultured epithelial cells,but PEGylation(PEG grafting)can be used to reduce cellular toxicity and to improve nanoparticle stability.
基金This work was supported by the National Key R&D Program(No.2017YFA0204503)the National Natural Science Foundation of China(Nos.22071172,91833306,21875158,51633006,and 51733004)+1 种基金Z.F.thanks the funding support from ITC via Hong Kong Branch of National Precious Metals Material Engineering Research Center(NPMM),and the Start-Up Grants(Nos.9610480 and 7200651)Grant from City University of Hong Kong(No.7005512).
文摘Oral administration of nutrient/drug is the most common and preferred route. However, a number of barriers are encountered after ingestion, limiting efficient oral nutrient/drug absorption. Both lipid-based (e.g., nanoemulsion, solid lipid nanoparticles) and polymer-based (e.g., protein and polysaccharide nanoparticles) nanoscale delivery systems have demonstrated capability to overcome some of these physiological barriers during transportation and metabolism stages. To better deal with those barriers, polymer-lipid complex nanoparticles are being explored and developed to merge the beneficial features and overcome the respective shortcomings of lipid-based and polymer-based nanoparticles. This paper aims to provide an overview of the various preparation strategies and supramolecular interactions of orally administered polymer-lipid complex nanoparticles by reviewing recent studies. Two types of polymer-lipid complex nanoparticles have been developed, i.e., lipid core with polymer shell nanoparticles and polymer core with lipid shell nanoparticles (lipid-polymer hybrid nanoparticles). Besides, both natural and synthetic polymers used for fabrication are discussed and their advantages and disadvantages are highlighted. Further research work is needed to optimize the fabrication and scaling up processes, so that these versatile polymer-lipid complex nanoparticles could have a significant impact on the oral delivery of nutrient/drug.
基金Supported by the Natural Science Fund for Colleges and Universities in Jiangsu Province(No.18KJB350009)the Natural Science Fund for Colleges and Universities in Jiangsu Province(No.17KJB350009)the Natural Science Foundation of Jiangsu Province(No.BK20170445).
文摘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.
基金support from the National Key Science and Technology Project of China(grant number 2018YFC2000500,03)National Natural Science Foundation of China 81703430 and 81803449,CAMS Innovation Fund for Medical Sciences(grant number 2019-I2M-5-045)the Natural Science Foundation of Zhejiang Province(LYY20H300003).
文摘In-situ oral delivery of therapeutic antibodies,like monoclonal antibody,for chronic inflammation treatment is the most convenient approach compared with other administration routes.Moreover,the abundant links between the gut microbiota and colonic inflammation indicate that the synergistic or antagonistic effect of gut microbiota to colonic inflammation.However,the antibody activity would be significantly affected while transferring through the gastrointestinal tract due to hostile conditions.Moreover,these antibodies have short serum half-lives,thus,require to be frequently administered with high doses to be effective,leading to low patient tolerance.Here,we develop a strategy utilizing thin shell hydrogel microcapsule fabricated by microfluidic technique as the oral delivering carrier.By encapsulating antibodies in these microcapsules,antibodies survive in the hostile gastrointestinal environment and rapidly release into the small intestine through oral administration route,achieving the same therapeutic effect as the intravenous injection evaluated by a colonic inflammation disease model.Moreover,the abundance of some intestinal microorganisms as the indication of the improvement of inflammation has remarkably altered after in-situ antibody-laden microcapsules delivery,implying the restoration of micro-ecology of the intestine.These findings prove our microcapsules are exploited as an efficient oral delivery agent for antibodies with programmable function in clinical application.
基金This work was financially supported by the Scientific Research Start-up Funds(QD2021020C)at Shenzhen International Graduate School at Tsinghua University,the Research Fund Program of Guangdong Provincial Key Lab of Green Chemical Product Technology(20212779)Shenzhen Science and Technology Innovation Commission(KCXFZ20201221173207022).
文摘Gut microbiome(GM)is closely related to the overall health status for the human being.The dysfunction of microbiome can lead to many diseases such as inflammation,cancer and neurodegenerative disease.Therefore,it's of great importance to develop effective strategy to regulate GM.Gut lumen-targeted oral delivery system(GLT-ODS)has been extensively investigated and widely used in food science and engineering in these years,due to the targeted delivery property,controlled release profile,high biocompatibility and enhanced bioavailability of cargos.Herein,we comprehensively summarized the current advances in GLT-ODS for bioactive agent.Specifically,we systematically summarize the GLT-ODS for pre-agents(prebiotics and probiotics)and anti-agents(antibiotics and bacteriophages)according to the type of cargos.Through in-depth discussion of representative researches,we refined the limitations of existing research in carrier material and target selection,and drew a blueprint for the future technological research and development.We believe that GLT-ODS will become a safe,efficient,simple and precise GM management strategy for improvement of health and shine in the development of precision food and pharmaceutical engineering in future.
基金financially supported by the National Natural Science Foundation of China(Nos.22075212 and 21925505)Natural Science Foundation of Shanghai(No.19ZR1478800)+1 种基金the program for professor of special appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning and Shanghai international scientific collaboration fund(No.21520710100)the recipient of a 5-year National Science Fund for Distinguished Young Scholars。
文摘Imatinib has been widely used as a selective kinase inhibitor for treating a variety of cancers,and this molecule is very hydrophobic so it is usually modified with mesylate salt in clinic to increase bioavailability.However,pH-dependent aqueous solubility and relatively high dosage of imatinib mesylate greatly reduce the clinical outcomes.To solve this problem,we developed an intestine enzyme-responsive hydrogel to efficiently encapsulate hydrophobic imatinib with long-term controlled release and enhanced intestinal permeability through oral administration.Methacrylic anhydride-modified carboxymethyl chitosan(MA-CMCS)was synthesized via amidation reaction and then MA-CMCS was crosslinked with photoinitator under UV-irradation to form a three-dimensional hydrophilic polymer network.The intestine enzyme responsiveness was endowed with imatinib-loaded hydrogel through hydrolyzation of glucosidic bond,which could achieve enzyme-triggered long-term drug release of up to 2 days.Furthermore,sodium deoxycholate was embedded into the hydrogel to synchronously open epithelial tight junctions with improved intestinal permeability.In vitro studies revealed similar lethality against colon cancer cell for both imatinib mesylate and imatinib-loaded hydrogels.Moreover,significantly enhanced in vivo tumor inhibition(6-fold higher compared to imatinib mesylate)was achieved after oral administration with imatinib-loaded hydrogels.Overall,this enzyme-responsive hydrogel could achieve long-term synchronous release of kinase inhibitor(imatinib)and tight junction permeation enhancer(sodium deoxycholate)at intestine with enhanced therapeutic efficiency,which could provide an effective approach to improve the bioavailability of hydrophobic anticancer chemodrugs with oral administration.
基金financial support from the National Natural Science Foundation of China (Nos. 81773651,82025032 and 82073773)NN-CAS foundation+3 种基金National Key R&D Program of China (No. 2020YFE0201700)Chinese Pharmacopoeia Commission (Nos. 2021Y30 and 2021Y25)the Shanghai Science and Technology Committee (No. 18430721600)the Major International Joint Research Project of Chinese Academy of Sciences(No. 153631KYSB20190020。
文摘Permeation enhancers(PEs),such as N-[8-(2-hydroxybenzoyl)amino]-caprylate(SNAC),have been reported to improve the oral absorption of various macromolecules.However,the bioavailabilities of these formulations are quite low and variable due to the influences of enzymes,pH and other gastrointestinal barriers.In this study,we revealed that SNAC could interact with insulin to form tight complexes in a specific concentration(insulin≥ 40μg/mL)-,ratio(SNAC/insulin≥ 20:1)-and pH(≥ 6.8)-dependent manner,thus contributing to a significantly high efficacy of oral insulin delivery.Specifically,absorption mechanism studies revealed that the SNAC/insulin complexes were internalized into the cells by passive diffusion and remained intact when transported in the cytosol.Furthermore,the complexes accelerated the exocytosis of insulin to the basolateral side,thereby enhancing its intestinal mucosal permeability.Eudragit;S100-entrapped SNAC/insulin microspheres were then prepared and exhibited an apparent permeability coefficient(P;) that was 6,6-fold higher than that of the insulin solution.In diabetic rats,hypoglycemic activity was sustained for more than 10 h after the microspheres were loaded into entericcoated capsules.Further pharmacokinetic studies revealed an approximately 6.3% oral bioavailability in both the fasted and fed states,indicating a negligible food effect.Collectively,this study provides insight into the interaction between PEs and payloads and presents an SNAC-based oral insulin delivery system that has high oral bioavailability and patient-friendly medication guidance.
文摘An oral drug delivery system using proteinoid microspheres is discussed with respect to itsunique dependence on pH. It has been found that certain drugs such as insulin and heparin canbe encapsulated in proteinoid spheres at stomach pH's (1--3). These spheres also dissemble atintestinal pH's (6--7) releasing the drug for absorption. Using this technique low molecularweight heparin and human growth hormone have been orally delivered successfully to severalanimal species. Future work has been proposed to study the interaction and binding of thespecific drugs with synthesized oligopeptides.
基金This study was supported by the Youth Fund of National Natural Science Foundation of China(No.82104081)Sichuan Province Science and Technology Support Program(No.2020JDRC0052)+1 种基金the 1.3.5 Project for Disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD18020/ZYJC18006)Science and Technology Project of Xinjiang Production and Construction Corps(No.2022AB020).
文摘Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,most of the nanocarriers are administered intravenously,which is inconvenient and may cause complications.Herein,we developed an oral lipid-polymer based nanoparticles(FA-LNPs)decorated with folic acid,which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages.Subsequently,naringenin(Nrg),one of the antiinflammation drugs,was designed to be the oral nanomedicine(FA-LNPs/Nrg)for the first time via the encapsulation of FALNPs.FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy.After the atherosclerotic ApoE−/−mice were treated by FALNPs/Nrg via oral administration for three months,the aortic lesion area,plaque area,and necrotic core area of the aortic root were significantly decreased.Meanwhile,the lipid-related blood parameters recovered to normal levels.Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.
基金the National Institute of Biomedical Imaging and Bioengineering(NIBIB)Trailblazer Award(1R21EB032991-01)the Shanti V.Sitaraman,MD,PhD Inflammatory Bowel Diseases Young Investigator Award(No.439516)Dr.Yu would like to thank USDA-NIFA(grant no.2016-07802)and USDA-ARS(award no.019636-00001)for partially funding this research.
文摘Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads(i.e.,immunogens)against gastric damage.In this study,hollowed nanocarriers(NCs:silica nanospheres and gold nanocages)with poly-l-lysine(PLL)coating and mammalian orthoreovirus cell attachment proteinσ1 functionalization(NC-PLL-σ1)were explored as functional oral drug delivery vehicles(ODDVs).The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells(M-cells)mediated transcytosis(viaσ1-α2–3-linked sialic acids adherence)across gastrointestinal epithelia.PLL coating provided protection and slow-release of rhodamine 6 G(R6G),a model payload.The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro.When compared with other experimental groups,the fully functionalized ODDV system(with PLL-σ1)demonstrated two significant advantages:a significantly higher transport efficiency(198%over blank control at 48 h);and protection of payloads which led to both better transport efficiency and extended-release of payloads(61%over uncoated carriers at 48 h).In addition,it was shown that the M cell presence in intestinal organoid monolayers(modulated by Rank L stimulation)was a determining factor on the transport efficiency of the ODDVs:more M-cells(induced by higher Rank L)in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload(R6G).The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.
基金financially supported by Basic and Applied Basic Research Project of Guangzhou Science and Technology Plan (202201010743, China)Shanghai Municipal Commission of Science and Technology (19XD1400300 and 21430760800, China)。
文摘Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration(oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.
基金This research was supported by the Basic Science Research Program(2020R1A2C3014070)the Korea Medical Device Development Fund grant(2020M3E5D8105732)+1 种基金Bio&Medical Technology Development Program(2021M3E5E7021473)the Engineering Research Center(ERC)Program(NRF-2017R1A5A1014708)of the National Research Foundation(NRF)funded by the Ministry of Science and ICT,Korea.
文摘Self-propelling micro-and nano-motors(MNMs)have been extensively investigated as an emerging oral drug delivery carrier for gastrointestinal(GI)tract diseases.However,the propulsion of current MNMs reported so far is mostly based on the redox reaction of metals(such as Zn and Mg)with severe propulsion gas generation,remaining non-degradable residue in the GI tract.Here,we develop a bioinspired enzyme-powered biopolymer micromotor mimicking the mucin penetrating behavior of Helicobacter pylori in the stomach.It converts urea to ammonia and the subsequent increase of pH induces local gel-sol transition of the mucin layer facilitating the penetration into the stomach tissue layer.The successful fabrication of micromotors is confirmed by high-resolution transmission electron microscopy,electron energy loss spectroscopy,dynamic light scattering analysis,zeta-potential analysis.In acidic condition,the immobilized urease can efficiently converted urea to ammonia,comparable with that of neutral condition because of the increase of surrounding pH during propulsion.After administration into the stomach,the micromotors show enhanced penetration and prolonged retention in the stomach for 24 h.Furthermore,histological analysis shows that the micromotors are cleared within 3 days without causing any toxicity in the GI tract.The enhanced penetration and retention of the micromotors as an active oral delivery carrier in the stomach would be successfully harnessed for the treatment of various GI tract diseases.