The feasibility of oral targeted drug delivery: Gut immune to particulates?

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.

Paclitaxel-lipid prodrug liposomes for improved drug delivery and breast carcinoma therapy

Paclitaxel(PTX)is widely applied for the treatment of unresectable and metastasis breast carcinoma as well as other cancers,whereas its efficacy is always impeded by poor solubility.Liposomes are one kind of the most successful drug carriers which are capable of solubilizing PTX and improving patients’tolerance owing to excellent biocompatibility and biodegradability.However,poor compatibility between PTX and liposomes compromises the stability,drug loading and anti-tumor capacity of liposomal formulations.To address this issue,three lipids with various chain lengths,namely,myristic acid(MA,14C),palmitic acid(PA,16C)and stearic acid(SA,18C),were conjugated to PTX via ester bonds and the synthesized prodrugs with high lipophilicity were further formulated into liposomes,respectively.All liposomes show high stability and drug loadings,as well as sustained drug release.The chain lengths of lipids are negatively correlated with drug release and enzymatic conversion rates,which further impact the pharmacokinetics,tumor accumulation,and anti-tumor efficacy of liposomal PTX.Neither rapid nor slow drug release facilitates high tumor accumulation as well as anti-tumor efficacy of PTX.Among all liposomes,PTX-PA-loaded liposomes show the longest circulation and highest tumor accumulation of PTX and exert the most potent anti-tumor capacities in vivo,owing to its moderate drug release and enzymatic conversion rate.Witnessing its superior safety,PTX-PA liposomes hold potential for further clinical translation.

PLGA-based implants for sustained delivery of peptides/proteins:Current status,challenge and perspectives

Peptide and protein drugs with therapeutic effects suffer from their short half-life and low stability,albeit their high efficiency and specificity.To overcome these demerits,long-acting drug delivery systems have been developed,wherein poly(lactic-co-glycolic acid)(PLGA)implants are most preferred owing to their excellent biodegradability and biocompatibility.Dozens of PLGA based products have been approved since1986,when the first product,named Decapeptyl R,successfully marched into market.To meet the increasing demand for delivering various peptides and proteins,different kinds of technologies have been developed for lab-scale fabrication or industrial manufacture.This review aims to introduce recent advances of PLGA implants,and give a brief summary of fundamental properties of PLGA,fabrication technologies of peptides/proteins-loaded PLGA implants as well as factors influencing the drug release processes.Moreover,challenges and future perspectives are also highlighted.

The intragastrointestinal fate of paclitaxel-loaded micelles:Implications on oral drug delivery

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.

Editorial of Special Issue of Hot Topic Reviews in Drug Delivery

Research in the cross-disciplines of drug delivery is developing at an accelerated speed never seen before,as witnessed by the soaring number of yearly publications.A quick search of the database of Web of Science by utilizing the keyword"drug delivery"gives a total number of 251,538,3385,13484,48550,129263 and 338627 publications by the year range of 1900e1960,1961e1970,1971e1980,1981e1990,1991e2000,2001e2010and 2011e2020,respectively.More impressively,there seems to be no sign of deceleration.

Current research trends of nanomedicines

Owing to the inherent shortcomings of traditional therapeutic drugs in terms of inadequate therapeutic efficacy and toxicity in clinical treatment,nanomedicine designs have received widespread attention with significantly improved efficacy and reduced non-target side effects.Nanomedicines hold tremendous theranostic potential for treating,monitoring,diagnosing,and controlling various diseases and are attracting an unfathomable amount of input of research resources.Against the backdrop of an exponentially growing number of publications,it is imperative to help the audience get a panorama image of the research activities in the field of nanomedicines.Herein,this review elaborates on the development trends of nanomedicines,emerging nanocarriers,in vivo fate and safety of nanomedicines,and their extensive applications.Moreover,the potential challenges and the obstacles hindering the clinical translation of nanomedicines are also discussed.The elaboration on various aspects of the research trends of nanomedicines may help enlighten the readers and set the route for future endeavors.

Biomimetic thiamine- and niacin-decorated liposomes for enhanced oral delivery of insulin

Biomimetic nanocarriers are emerging as efficient vehicles to facilitate dietary absorption of biomacromolecules. In this study, two vitamins, thiamine and niacin, are employed to decorate liposomes loaded with insulin, thus facilitating oral absorption via vitamin ligand–receptor interactions. Both vitamins are conjugated with stearamine, which works to anchor the ligands to the surface of liposomes.Liposomes prepared under optimum conditions have a mean particle size of 125–150 nm and an insulin entrapment efficiency of approximately 30%–36%. Encapsulation into liposomes helps to stabilize insulin due to improved resistance against enzymatic disruption, with 60% and 80% of the insulin left after 4 h when incubated in simulated gastric and intestinal fluids, respectively, whereas non-encapsulated insulin is broken down completely at 0.5 h. Preservation of insulin bioactivity against preparative stresses is validated by intra-peritoneal injection of insulin after release from various liposomes using the surfactant Triton X-100. In a diabetic rat model chemically induced by streptozotocin, both thiamine-and niacindecorated liposomes showed a comparable and sustained mild hypoglycemic effect. The superiority of decorated liposomes over conventional liposomes highlights the contribution of vitamin ligands. It is concluded that decoration of liposomes with thiamine or niacin facilitates interactions with gastrointestinal vitamin receptors and thereby facilitates oral absorption of insulin-loaded liposomes.

Oral delivery of proteins and peptides:Challenges, status quo and future perspectives

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.

In vivo dissolution of poorly water-soluble drugs:Proof of concept based on fluorescence bioimaging

In vitro-in vivo correlation(IVIVC)of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients.Nevertheless,in vivo dissolution profles have never been accurately portrayed.The current practice of IVIVC has to resort to in vivo absorption fractions(Fa).In this proof-of-concept study,in vivo dissolution of a model poorly watersoluble drug fenofbrate(FNB)was investigated by fuorescence bioimaging.FNB crystals were frst labeled by near-infrared fuorophores with aggregation-caused quenching properties.The dyes illuminated FNB crystals but quenched immediately and absolutely once been released into aqueous media,enabling accurate monitoring of residual drug crystals.The linearity established between fuorescence and crystal concentration justifed reliable quantifcation of FNB crystals.In vitro dissolution was frst measured following pharmacopoeia monograph protocols with well-documented IVIVC.The synchronicity between fuorescence and in vitro dissolution of FNB supported using fuorescence as a measure for determination of dissolution.In vitro dissolution correlated well with in vivo dissolution,acquired by either live or ex vivo imaging.The newly established IVIVC was further validated by correlating both in vitro and in vivo dissolution with Faobtained from pharmacokinetic data.

The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers

The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin(DOX)-loaded methoxy polyethylene glycol-polycaprolactone(mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration;DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.

Near-infrared fluorophores with absolute aggregation-caused quenching and negligible fluorescence re-illumination for in vivo bioimaging of nanocarriers

Environment-responsive fluorophores with aggregation-caused quenching(ACQ)properties have been applied to track nanocarriers with reduced artefacts caused by unbound or free fluorophores but suffer from incomplete fluorescence quenching and significant re-illumination,which undermine bioimaging accuracy.Herein,through structural modifications to reinforce the hydrophobicity,planarity and rigidity of fluorophores with an aza-BODIPY framework,probes featuring absolute ACQ(aACQ)and negligible re-illumination are developed and evaluated in various nanocarriers.aACQ probes,FD-B21 and FD-C7,exhibit near-infrared emission,high quantum yield,photostability,water sensitivity,and negligible re-illumination in blood,plasma and 1%Tween-80 in contrast to ACQ probe P2 and conventional probe DiR.All nanocarriers can be labeled efficiently by the tested fluorophores.Polymeric micelles(PMs)labeled by different aACQ probes manifest similar biodistribution patterns,which however differ from that of DiR-labeled PMs and could be ascribed to the appreciable re-illumination of DiR.Significantly lower re-illumination is also found in aACQ probes(2%-3%)than DiR(20%-40%)in Caco-2,Hela,and Raw264.7 cells.Molecular dynamics simulations unravel the molecular mechanisms behind aggregation and re-illumination,supporting the hypothesis of planarity dependency.It is concluded that aACQ fluorophores demonstrate excellent water sensitivity and negligible fluorescence re-illumination,making themselves useful tools for more accurate bioimaging of nanocarriers.

Ionic liquid-based in situ dynamically self-assembled cationic lipid nanocomplexes(CLNs)for enhanced intranasal siRNA delivery

This research aims to develop a non-invasive strategy for small interfering RNA(siRNA)nasal delivery based on ionic liquids(ILs)and cationic lipid(2,3-dioleoyloxy-propyl)-trimethylammonium-chloride(DOTAP).Other than the classical role of penetration enhancer,ILs also acted as superior solvents to simultaneously load siRNA and DOTAP,forming siRNA-DOTAP-ILs(siRNA-DILs)formulations.During nasal mucosa penetration,DOTAP and ILs components self-assembled into cationic lipid nanocomplexes to load siRNA for enhanced in situ transfection.The siRNA-DILs demonstrated resistance against RNase,significant mucosa penetration,prolonged nasal retention,and satisfying gene-silencing efficacy at lower dosage.Meanwhile,DILs were also able to deliver KCa3.1-targeted siRNA effectively for the treatment of allergic rhinitis in rat model by nasal route.Thus,DILs have great potentials to deliver biological macromolecules across nasal mucosa by in situ dynamic self-assembly.

Adapting liposomes for oral drug delivery

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.

Gastrointestinal lipolysis and trans-epithelial transport of SMEDDS via oral route

Self-microemulsifying drug delivery systems(SMEDDSs)have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules.However,information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare.Aggregation-caused quenching(ACQ)fuorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs,because the released probes during lipolysis are quenched upon contacting water.Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models,meanwhile Neoral?was used as a control.The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey frst order kinetic law of lipolysis.The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs.Ex vivo imaging of main tissues and histological examination confrm the trans-epithelial transportation of the SMEDDS droplets.Approximately 2%-4%of the given SMEDDSs are transported via the lymph route following epithelial uptake,while liver is the main termination.Caco-2 cell lines confrm the cellular uptake and trans-epithelial transport.In conclusion,a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract,permeate across the epithelia,translocate via the lymph,and accumulate mainly in the liver.

Editorial: Persistent endeavors for the enhancement of dissolution and oral bioavailability

More than 50%of marketed drugs and 90%drug candidates are believed to be poorly water-soluble, and these figures keep growing due to input of new drug entities into the pool, thanks to the fast development in drug discovery. It has long been recognized that poor solubility poses problems of retarded dissolution rate and thereby poor bioavailability.

An update on oral drug delivery via intestinal lymphatic transport

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.

The influence of nanoparticle shape on bilateral exocytosis from Caco-2cells

Nanoparticles are easily to be taken up by cells but hard to be transported across epithelia, which plays an important role in absorption and toxicity. This paper aims to elucidate the effect of nanoparticle shape on bilateral exocytosis of Caco-2 cells. The fluorescent resonance energy transfer(FRET) probes(DiO and Dil)were utilized to label nanospheres and nanorods for determining and tracking nanoparticles. The results showed that more nanorods were internalized into Caco-2 cells than nanospheres. But the apical exocytosis rate of nanospheres from Caco-2 cells was faster than that of nanorods significantly. In addition, only less than 2% of intact nanoparticles were transported across monolayers for both nanoparticles, but the exocytosis behaviors between them was absolutely different. Compared to nanospheres, nanorods preferred basolateral exocytosis to apical exocytosis. Therefore, the shape is a critical parameter in cellular uptake and transport, even intracellular fate, which should be primarily considered in design of oral nanoparticles.

Permeation into but not across the cornea:Bioimaging of intact nanoemulsions and nanosuspensions using aggregation-caused quenching probes

Nanoemulsions(NEs) and nanosuspensions(NSs) show great potential in enhancing the ocular bioavailability of therapeutics through topical delivery. However, transocular fate of intact NEs and NSs is still inconclusive. In this study, an aggregation-caused quenching fluorescent probe is used to track precorneal retention and transocular transportation of intact NEs and NSs, while coumarin 6 is used to mimick the cargo. NEs show superior precorneal retention to NSs. Both the two types of nanocarriers can permeate into but not across the cornea. The smaller NEs(100 nm) permeate better into the cornea than the bigger ones(210 nm). Nanocarriers in the cornea serves as depots. The released cargo molecules can penetrate across the cornea and diffuse into the lens. Moreover, the conjunctiva-scleral route may be potential to deliver drugs to the back of the eye, In conclusion, the study provides useful tools and information in the field of transocular transportation of nanoparticles.

Ionic co-aggregates(ICAs)based oral drug delivery:Solubilization and permeability improvement

Due to the overwhelming percentage of poorly water-soluble drugs,pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement.Salts consisting of lipophilic fatty acid anions and hydrophilic choline cations are found to be surface active and able to form ionic co-aggregates(ICAs)in water.Choline oleate-based ICAs significantly enhance oral absorption of paclitaxel(PTX)as compared with cremophor EL-based micelles(MCs).Aggregation-caused quenching probes enable tracking of intact ICAs in in vivo transport and cellular interaction.Prolonged intestinal retention of ICAs than MCs implies stronger solubilizing capability in vivo.Ex vivo imaging of major organs and intestinal tracts suggests transepithelial transport of intact ICAs.Cellular studies support the enhanced absorption of PTX and transmembrane transport of intact ICAs.In conclusion,ICAs,consisting of lipophilic ions and hydrophilic counter-ions,are of great potential in delivery of poorly water-soluble drugs by enhancing solubility and permeability.

Rod-like mesoporous silica nanoparticles facilitate oral drug delivery via enhanced permeation and retention effect in mucus

The physiochemical characteristics of nanoparticles affect their in vitro and in vivo performance significantly,such as diameter,surface chemistry,and shape.This paper disclosed the effect of enhanced permeation and retention(EPR)in mucus caused by nanoparticle shape on improving oral absorption.The spherical and rod-like mesoporous silica nanoparticles(MSNs)were used to evaluate shape effect of EPR in mucus.Fenofibrate was loaded in MSNs as model drug.The in vitro release of fenofibrate from MSNs was dependent on nanoparticle shapes,but faster than that of raw drug.The drug release slowed down with the increase of aspect ratio due to longer channels in rod-like MSNs with higher aspect ratio.However,in vivo study showed that the oral bioavailability of fenofibrate was the highest after loading in rod-like MSNs with aspect ratio of 5.The in vitro study of mechanisms revealed that superior mucus diffusion ability of rod-like MSNs with aspect ratio of 5 was conductive to higher bioavailability.Meanwhile,more rod-like MSNs with higher aspect ratio were able to diffuse into mucus and reside there compared to spherical and short counterparts,which demonstrated higher aspect ratio was beneficial to EPR effect of nanoparticles in mucus.This study provides significant implication in rational oral drug carrier design.