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
The objective of this study is to utilize the pH sensitivity of modified silica nanoparticles (SNIL) by imidazole-based ionic liquid for oral delivery of insulin. In the first time, the imidazole was covalently attach...The objective of this study is to utilize the pH sensitivity of modified silica nanoparticles (SNIL) by imidazole-based ionic liquid for oral delivery of insulin. In the first time, the imidazole was covalently attached to the 3-trimethoxysily-lpropyl chloride with replacement of all the chlorine atoms. Then, a silica nanoparticle was modified by N-(3-trimeth-oxysilylpropyl) imidazole. The nanocapsule (NCIL) was achieved after the etching of the modified silica nanoparticle template with hydrofluoric acid. The nanoparticles connected through an ionic liquid-like network were characterized by FTIR and SEM. Insulin was entrapped in these carriers and the in vitro release profiles were established separately in both enzyme-free simulated gastric and intestinal fluids (SGF, pH 1) and (SIF, pH 7.4), respectively. When these drug-loaded nanoparticles was placed in physiological buffer solution (pH 7.4), a partial negative surface charge on the modified silica nanoparticle was generated due to the deprotonation of silanol groups, and the strong electrostatic repulsion triggered a sustained release of the loaded molecules.展开更多
Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical trea...Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.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
Oral administration is the most acceptable route of drug delivery at this stage due to its convenience,safety,and non-invasiveness.However,drugs given orally are exposed to a complex gastrointestinal environment,causi...Oral administration is the most acceptable route of drug delivery at this stage due to its convenience,safety,and non-invasiveness.However,drugs given orally are exposed to a complex gastrointestinal environment,causing a tremendous challenge for their successful absorption into the circulation.Over the past decades,researchers have developed various novel pharmaceutical technologies to improve oral absorption,among which the vesicular drug delivery system(like liposomes,niosomes and transfersomes)has received extensive attention.Encouragingly,there have been several investigations confirming the improved effect of vesicular drug delivery systems on oral drug absorption.Nevertheless,the clinical translation of oral vesicular drug delivery systems has been less impressive than implied by the positive results,and few vesicular formulations for oral use have been marketed yet.Against this background,this article provides an overview of the current applications and challenges associated with the vesicular delivery systems available for oral drug delivery,specifically liposomes,niosomes,transfersomes,chitosomes and bilosomes.The composition,formation mechanism,drug delivery advantages and application cases of these carriers in oral drug delivery are summarized.The possible mechanisms by which vesicular carriers enhance oral drug absorption are analyzed in terms of the in vivo process of oral drugs.Further,the challenges that oral vesicular carriers now face,such as safety,undefined in vivo fate,and scale-up production,are summarized,while possible strategies to deal with them are indicated.By reviewing the aforementioned,it can facilitate a more comprehensive knowledge of vesicular systems that can be used for oral drug delivery,providing a theoretical basis and reference for the design of oral formulations.展开更多
Circular RNAs(circRNAs)are ideal biomarkers of oral squamous cell carcinoma(OSCC)because of their highly stable closed-loop structure,and they can act as microRNA(miRNA)sponges to regulate OSCC progression.By analyzin...Circular RNAs(circRNAs)are ideal biomarkers of oral squamous cell carcinoma(OSCC)because of their highly stable closed-loop structure,and they can act as microRNA(miRNA)sponges to regulate OSCC progression.By analyzing clinical samples,we identified circCPNE1,a dysregulated circRNA in OSCC,and its expression level was negatively correlated with the clinical stage of OSCC patients.Gain-of-function assays revealed the tumor-suppressive effect of circCPNE1,which was then identified as a miR-330-3p sponge.MiR-330-3p was recognized as a tumor promoter in multiple studies,consistent with our finding that it could promote the proliferation,migration,and invasion of OSCC cells.These results indicated that selective inhibition of miR-330-3p could be an effective strategy to inhibit OSCC progression.Therefore,we designed cationic polylysine-cisplatin prodrugs to deliver antagomiR-330-3p(a miRNA inhibitory analog)via electrostatic interactions to form PP@miR nanoparticles(NPs).Paratumoral administration results revealed that PP@miR NPs effectively inhibited subcutaneous tumor progression and achieved partial tumor elimination(2/5),which confirmed the critical role of miR-330-3p in OSCC development.These findings provide a new perspective for the development of OSCC treatments.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
Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes,oral delivery of l...Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes,oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract,difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.展开更多
Oral drug delivery,which requires surviving the harsh environment in the gastrointestinal(Gl)tract and penetrating the intestinal epithelium,has not bee n achieved using simple formulatio n nan oparticles(NPs).Medici ...Oral drug delivery,which requires surviving the harsh environment in the gastrointestinal(Gl)tract and penetrating the intestinal epithelium,has not bee n achieved using simple formulatio n nan oparticles(NPs).Medici nal natural products(MNPs)have bee n widely used in traditi onal medicine for disease management through oral consumption.However,most pharmacologically active compounds within MNPs do not have the properties suitable for oral applicatio ns.We hypothesize that some MNPs contain n atural nano materials that can convert those compounds into oral formulations by forming NPs.After screening 66 MNPs,we identified five classes of small molecules that form NPs,many of which are capable of efficient drug encapsulation and Gl penetration.We show that one of them,dehydrotrametenolic acid(DTA),is capable of mediating oral delivery for effective disease treatment.We determined that DTA NPs assemble through hydrogen bonding and penetra怕the Gl tract via apical sodium-depe ndent bile acid tran sporter.Our study reveals a no vel class of single comp orient,small molecule-assembled NPs for oral drug delivery,and suggests a n ovel approach to modernizi ng MNPs through nano material discovery.展开更多
The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel(PTX).Both in vitro and ex ...The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel(PTX).Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact,except in fedstate simulated intestinal fluid and fasted-state pig intestinal fluid,thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)micelles showing higher stability than other micelles.All groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other micelles.The transport of the micelles across Caco-2/Raji(1.6%-3.5%),Caco-2(0.8%-1%),and Caco-2/HT29-MTX(0.58%-1%)cell monolayers further verified the absorption of micelles and their subsequent transport;however,more TPGS micelles transported across cell monolayers than other groups.Moreover,the histological examination also confirmed that micelles ente red the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other groups.Thus,these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug,upta ke by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other groups.In conclusion,these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.展开更多
Orally administered drug entities have to survive the harsh gastrointestinal environment,penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation.Whereas the gastroint...Orally administered drug entities have to survive the harsh gastrointestinal environment,penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation.Whereas the gastrointestinal stability can be well maintained by taking proper measures,hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism.The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway.Intestinal lymphatic transport is emerging as a promising pathway to this end.In this review,we intend to provide an updated overview on the rationale,strategies,factors and applications involved in intestinal lymphatic transport.There are mainly two pathways for peroral lymphatic transportdthe chylomicron and the microfold cell pathways.The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.展开更多
Efficient oral delivery of drugs treating brain diseases has long been a challenging topic faced by the drug delivery community. Fortunately, polyester nanoparticles offer certain solutions to this problem. This revie...Efficient oral delivery of drugs treating brain diseases has long been a challenging topic faced by the drug delivery community. Fortunately, polyester nanoparticles offer certain solutions to this problem. This review article firstly describes the main obstacles faced by oral administered brain targeting, including:(1)instability in the gastrointestinal tract;(2) poor penetration of the intestinal mucosa and epithelium;(3)blood clearance;and(4) restriction by the BBB. Then the key factors influencing brain-targeting efficiency of orally administered polyester nanoparticles are also discussed, such as size, shape and surface properties. Finally, recent brain-targeting delivery strategies using oral polyester nanoparticles as carriers and their effects on brain drugs transport are reviewed, and the delivery ‘as a whole’ strategy of polyester nanoparticles will provide new insight for oral brain-targeting delivery. And by combination of multiple strategies, both the stability and permeability of polyester nanoparticles can be greatly improved for oral brain drug delivery.展开更多
As endogenous courier vesicles,exosomes play crucial roles in macromolecule transmission and intercellular communication.Therefore,exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the...As endogenous courier vesicles,exosomes play crucial roles in macromolecule transmission and intercellular communication.Therefore,exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years.However,few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration.Additionally,the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown.Herein,insulin-loaded milk-derived exosomes(EXO@INS)were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats.Surprisingly,EXO@INS(50 and 30 IU/kg)elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin.Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake,pH adaptation during gastrointestinal transit,nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration.This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.展开更多
Oral drugs have been widely used in clinical therapy, but their developments were severely limited by the side effects of drug exposure as well as the multiple biological barriers. In this study, we constructed a “cl...Oral drugs have been widely used in clinical therapy, but their developments were severely limited by the side effects of drug exposure as well as the multiple biological barriers. In this study, we constructed a “cluster bomb” oral drug delivery system (DOX@PFeL@L100) with core-shell structure to overcome the complex absorption barriers. The inner core termed as “bomb” that contains a lot of ultra-small diameter Fe_(3)O_(4) nanoparticles (DOX@PFeL NPs) loaded with doxorubicin (DOX) and modified with l-valine, which can efficiently penetrate the epithelial cells via PePT1 receptor mediated endocytosis. The outer shell of this “cluster bomb” is a layer of pH-sensitive polymer (Eudragit®L100) that can be served as a pH-responsive switch and effectively control the “bomb” release in the intestinal microenvironment to improve the antitumor efficiency by the Fenton like reaction of DOX and Fe^(2+)/Fe^(3+). This study demonstrates that the “cluster comb” oral drug delivery system can sequentially overcome the multiple biological barriers, providing a safe and effective approach for tumor therapy.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.
文摘The objective of this study is to utilize the pH sensitivity of modified silica nanoparticles (SNIL) by imidazole-based ionic liquid for oral delivery of insulin. In the first time, the imidazole was covalently attached to the 3-trimethoxysily-lpropyl chloride with replacement of all the chlorine atoms. Then, a silica nanoparticle was modified by N-(3-trimeth-oxysilylpropyl) imidazole. The nanocapsule (NCIL) was achieved after the etching of the modified silica nanoparticle template with hydrofluoric acid. The nanoparticles connected through an ionic liquid-like network were characterized by FTIR and SEM. Insulin was entrapped in these carriers and the in vitro release profiles were established separately in both enzyme-free simulated gastric and intestinal fluids (SGF, pH 1) and (SIF, pH 7.4), respectively. When these drug-loaded nanoparticles was placed in physiological buffer solution (pH 7.4), a partial negative surface charge on the modified silica nanoparticle was generated due to the deprotonation of silanol groups, and the strong electrostatic repulsion triggered a sustained release of the loaded molecules.
文摘Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.
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funded by the National Natural Science Foundation of China(No.81960717)the project of academic and technical leaders in major disciplines in Jiangxi Province(No.20212BCJL23060)+2 种基金the Guangxi science and technology base and talent project(No.Guike AD20238058)the Jiangxi University of Chinese Medicine science and technology innovation team development program(Nos.CXTD-22004,CXTD-22008)the PhD startup foundation of the Affiliated Hospital of Jiangxi University of Chinese Medicine(No.23KYQDZJ02)。
文摘Oral administration is the most acceptable route of drug delivery at this stage due to its convenience,safety,and non-invasiveness.However,drugs given orally are exposed to a complex gastrointestinal environment,causing a tremendous challenge for their successful absorption into the circulation.Over the past decades,researchers have developed various novel pharmaceutical technologies to improve oral absorption,among which the vesicular drug delivery system(like liposomes,niosomes and transfersomes)has received extensive attention.Encouragingly,there have been several investigations confirming the improved effect of vesicular drug delivery systems on oral drug absorption.Nevertheless,the clinical translation of oral vesicular drug delivery systems has been less impressive than implied by the positive results,and few vesicular formulations for oral use have been marketed yet.Against this background,this article provides an overview of the current applications and challenges associated with the vesicular delivery systems available for oral drug delivery,specifically liposomes,niosomes,transfersomes,chitosomes and bilosomes.The composition,formation mechanism,drug delivery advantages and application cases of these carriers in oral drug delivery are summarized.The possible mechanisms by which vesicular carriers enhance oral drug absorption are analyzed in terms of the in vivo process of oral drugs.Further,the challenges that oral vesicular carriers now face,such as safety,undefined in vivo fate,and scale-up production,are summarized,while possible strategies to deal with them are indicated.By reviewing the aforementioned,it can facilitate a more comprehensive knowledge of vesicular systems that can be used for oral drug delivery,providing a theoretical basis and reference for the design of oral formulations.
基金supported by National Natural Science Foundation of China grants(Nos.82073000,51973136,81902779,and 82173326)Science Foundation of Sichuan Province(No.2022YFS0289,China)Interdisciplinary innovation project of West China College of Stomatology,Sichuan University(RD-03-202004,China).
文摘Circular RNAs(circRNAs)are ideal biomarkers of oral squamous cell carcinoma(OSCC)because of their highly stable closed-loop structure,and they can act as microRNA(miRNA)sponges to regulate OSCC progression.By analyzing clinical samples,we identified circCPNE1,a dysregulated circRNA in OSCC,and its expression level was negatively correlated with the clinical stage of OSCC patients.Gain-of-function assays revealed the tumor-suppressive effect of circCPNE1,which was then identified as a miR-330-3p sponge.MiR-330-3p was recognized as a tumor promoter in multiple studies,consistent with our finding that it could promote the proliferation,migration,and invasion of OSCC cells.These results indicated that selective inhibition of miR-330-3p could be an effective strategy to inhibit OSCC progression.Therefore,we designed cationic polylysine-cisplatin prodrugs to deliver antagomiR-330-3p(a miRNA inhibitory analog)via electrostatic interactions to form PP@miR nanoparticles(NPs).Paratumoral administration results revealed that PP@miR NPs effectively inhibited subcutaneous tumor progression and achieved partial tumor elimination(2/5),which confirmed the critical role of miR-330-3p in OSCC development.These findings provide a new perspective for the development of OSCC treatments.
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financially supported by National Natural Science Foundation of China (81573363 and 81690263)National Key Basic Research Program (2015CB931800)
文摘Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes,oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract,difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.
基金This work was supported by NIH(Nos.NS095817(J.Z.)and 18TPA34170180(J.Z.))the National Natural Science Foundation of China(NSFC)(Nos.31770614(C.M.),21233003(L.F.),and 21573019(L.F.)).
文摘Oral drug delivery,which requires surviving the harsh environment in the gastrointestinal(Gl)tract and penetrating the intestinal epithelium,has not bee n achieved using simple formulatio n nan oparticles(NPs).Medici nal natural products(MNPs)have bee n widely used in traditi onal medicine for disease management through oral consumption.However,most pharmacologically active compounds within MNPs do not have the properties suitable for oral applicatio ns.We hypothesize that some MNPs contain n atural nano materials that can convert those compounds into oral formulations by forming NPs.After screening 66 MNPs,we identified five classes of small molecules that form NPs,many of which are capable of efficient drug encapsulation and Gl penetration.We show that one of them,dehydrotrametenolic acid(DTA),is capable of mediating oral delivery for effective disease treatment.We determined that DTA NPs assemble through hydrogen bonding and penetra怕the Gl tract via apical sodium-depe ndent bile acid tran sporter.Our study reveals a no vel class of single comp orient,small molecule-assembled NPs for oral drug delivery,and suggests a n ovel approach to modernizi ng MNPs through nano material discovery.
基金supported by the National Natural Science Foundation of China(Nos.81872815,81872826,82030107,81690263)Science and Technology Commission of Shanghai Municipality(No.19XD1400300)。
文摘The goal of the present study is to elucidate the intragastrointestinal fate of micellar delivery systems by monitoring fluorescently labeled different micelles and the model drug paclitaxel(PTX).Both in vitro and ex vivo leakage studies showed fast PTX release in fluids while micelles remained intact,except in fedstate simulated intestinal fluid and fasted-state pig intestinal fluid,thus referring to the intact absorption of micelles and PTX leakage in the gastrointestinal tract with D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)micelles showing higher stability than other micelles.All groups of micelles were absorbed intact in Caco-2 and Caco-2/HT29-MTX cell models and the absorption of TPGS micelles was found to be higher than other micelles.The transport of the micelles across Caco-2/Raji(1.6%-3.5%),Caco-2(0.8%-1%),and Caco-2/HT29-MTX(0.58%-1%)cell monolayers further verified the absorption of micelles and their subsequent transport;however,more TPGS micelles transported across cell monolayers than other groups.Moreover,the histological examination also confirmed that micelles ente red the enterocytes and were transported to basolateral tissues and TPGS showed the stronger ability of penetration than other groups.Thus,these results are succinctly presenting the absorption of intact micelles in GIT confirmed by imaging evidence with prior leakage of the drug,upta ke by enterocytes and the transport of micelles that survive the digestion by enterocytes and mainly by microfold cells in material nature dependent way with TPGS showing better results than other groups.In conclusion,these results identify the mechanism by which the gastrointestinal tract processes micelles and point to the likely use of this approach in the design of micelles-based therapies.
基金supported by the National Natural Science Foundation of China(Nos.81872815,82030107,and 81690263)Science and Technology commission of Shanghai Municipality(No.19XD1400300,China)
文摘Orally administered drug entities have to survive the harsh gastrointestinal environment,penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation.Whereas the gastrointestinal stability can be well maintained by taking proper measures,hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism.The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway.Intestinal lymphatic transport is emerging as a promising pathway to this end.In this review,we intend to provide an updated overview on the rationale,strategies,factors and applications involved in intestinal lymphatic transport.There are mainly two pathways for peroral lymphatic transportdthe chylomicron and the microfold cell pathways.The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.
基金supported by the National Key R&D Program of China (No. 2020YFE0201700)the National Mega-project for Innovative Drugs (No. 2019ZX09721001)+3 种基金the National Natural Science Foundation of China (No. 81673378)the Liaoning Revitalization Talents Program (No. XLYC1908031)the Project of Liaoning Provincial Department of Education (No. 2019LQN07)the PhD Research Startup Foundation of Liaoning Province (No. 2020-BS-128)。
文摘Efficient oral delivery of drugs treating brain diseases has long been a challenging topic faced by the drug delivery community. Fortunately, polyester nanoparticles offer certain solutions to this problem. This review article firstly describes the main obstacles faced by oral administered brain targeting, including:(1)instability in the gastrointestinal tract;(2) poor penetration of the intestinal mucosa and epithelium;(3)blood clearance;and(4) restriction by the BBB. Then the key factors influencing brain-targeting efficiency of orally administered polyester nanoparticles are also discussed, such as size, shape and surface properties. Finally, recent brain-targeting delivery strategies using oral polyester nanoparticles as carriers and their effects on brain drugs transport are reviewed, and the delivery ‘as a whole’ strategy of polyester nanoparticles will provide new insight for oral brain-targeting delivery. And by combination of multiple strategies, both the stability and permeability of polyester nanoparticles can be greatly improved for oral brain drug delivery.
基金We gratefully acknowledge financial support from the National Science Foundation for Distinguished Young Scholars(81625023,China)the National Natural Science Foundation of China(81872818)the Major Research Plan of National Natural Science Foundation of China(81690261).
文摘As endogenous courier vesicles,exosomes play crucial roles in macromolecule transmission and intercellular communication.Therefore,exosomes have drawn increasing attention as biomimetic drug-delivery vehicles over the past few years.However,few studies have investigated the encapsulation of peptide/protein drugs into exosomes for oral administration.Additionally,the mechanisms underlying their biomimetic properties as oral delivery vehicles remain unknown.Herein,insulin-loaded milk-derived exosomes(EXO@INS)were fabricated and the in vivo hypoglycemic effect was investigated on type I diabetic rats.Surprisingly,EXO@INS(50 and 30 IU/kg)elicited a more superior and more sustained hypoglycemic effect compared with that obtained with subcutaneously injected insulin.Further mechanism studies indicated that the origin of excellent oral-performance of milk-derived exosomes combined active multi-targeting uptake,pH adaptation during gastrointestinal transit,nutrient assimilation related ERK1/2 and p38 MAPK signal pathway activation and intestinal mucus penetration.This study provides the first demonstration that multifunctional milk-derived exosomes offer solutions to many of the challenges arising from oral drug delivery and thus provide new insights into developing naturally-equipped nanovehicles for oral drug administration.
基金supported by the National Natural Science Foundation of China (Nos. 81773276, 81972907, 81874304, and U1804183)Key Scientific Research Project (Education Department of Henan Province)(No. 20HASTIT049)Modern Analysis and Computer Center of Zhengzhou University。
文摘Oral drugs have been widely used in clinical therapy, but their developments were severely limited by the side effects of drug exposure as well as the multiple biological barriers. In this study, we constructed a “cluster bomb” oral drug delivery system (DOX@PFeL@L100) with core-shell structure to overcome the complex absorption barriers. The inner core termed as “bomb” that contains a lot of ultra-small diameter Fe_(3)O_(4) nanoparticles (DOX@PFeL NPs) loaded with doxorubicin (DOX) and modified with l-valine, which can efficiently penetrate the epithelial cells via PePT1 receptor mediated endocytosis. The outer shell of this “cluster bomb” is a layer of pH-sensitive polymer (Eudragit®L100) that can be served as a pH-responsive switch and effectively control the “bomb” release in the intestinal microenvironment to improve the antitumor efficiency by the Fenton like reaction of DOX and Fe^(2+)/Fe^(3+). This study demonstrates that the “cluster comb” oral drug delivery system can sequentially overcome the multiple biological barriers, providing a safe and effective approach for tumor therapy.