UNIQUE ORAL DRUG DELIVERY SYSTEM

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.

Milk-derived exosomes exhibit versatile effects for improved oral drug delivery

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.

A “cluster bomb” oral drug delivery system to sequentially overcome the multiple absorption barriers

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.

Rational design of oral drugs targeting mucosa delivery with gut organoid platforms

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.

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.

Influence of solvent mixtures on HPMCAS-celecoxib microparticles prepared by electrospraying

Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different solubility for CEL and HPMCAS were used to induce changes in the polymer structural conformation of the microparticles. The performance of the prepared microparticles was evaluated by studying the solid state from, particle size and morphology, radial drug distribution and drug release. CEL was amorphous in all electrosprayed HPMCAS microparticles. The particle size and morphology was dependent on the solubility of HPMCAS in the solvent mixture used with poorer solvents resulting in smaller microparticles with rougher appearance. The CEL distribution on the particles surface was relatively homogeneous and similar for all microparticles. Drug release from the microparticles was observed at a higher rate depending on the solubility of HPMCAS in the solvent used for electrospraying, and in all cases an at least 4-fold higher rate was observed compared with the crystalline drug. Drug precipitation from the supersaturated solution was inhibited by HPMCAS for all microparticles based on its parachute effect while crystalline CEL did not reach supersaturation. This study demonstrated that electrospraying can be used to produce microparticles with tailored properties for pharmaceutical application by adjusting solvent selection.

Preparation and evaluation of sustained-release solid dispersions co-loading gastrodin with borneol as an oral brain-targeting enhancer

Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain.However,stomach irritation may occur when high doses of borneol are used.In the present work,gastrodin,the main bioactive ingredient of the traditional Chinese drug“Tianma”(Rhizoma Gastrodiae)was used as a model drug to explore reasonable application of borneol.Sustained-release solid dispersions(SRSDs)for co-loading gastrodin and borneol were prepared using ethylcellulose as a sustained release matrix and hydroxy-propyl methylcellulose as a retarder.The dispersion state of drug within the SRSDs was analyzed by using scanning electron microscopy,differential scanning calorimetry,and powder X-ray diffractometry.The results indicated that both gastrodin and borneol were molecularly dispersed in an amorphous form.Assay of in vitro drug release demonstrated that the dissolution profiles of gastrodin and borneol from the SRSDs both fitted the Higuchi model.Subsequently,gastric mucosa irritation and the brain targeting of the SRSDs were evaluated.Compared with the free mixture of gastrodin and borneol,brain targeting of SRSDs was slightly weaker(brain targeting index:1.83 vs.2.09),but stomach irritation obviously reduced.Sustained-release technology can be used to reduce stomach irritation caused by borneol while preserving sufficient transport capacity for oral brain-targeting drug delivery.

Oral nano-formulation improves pancreatic islets dysfunction via lymphatic transport for antidiabetic treatment

Type 2 diabetes mellitus(T2DM)therapy is facing the challenges of long-term medication and gradual destruction of pancreatic isletβ-cells.Therefore,it is timely to develop oral prolonged action formulations to improve compliance,while restoringβ-cells survival and function.Herein,we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property,which combined apical sodiumdependent bile acid transporter-mediated intestinal uptake and lymphatic transportation.In this system,taurocholic acid(TCA)modified poly(lactic-co-glycolic acid)(PLGA)was employed to achieve pancreas location,hydroxychloroquine(HCQ)was loaded to execute therapeutic efficacy,and 1,2-dilauroyl-sn-glycero-3-phosphocholine(DLPC)was introduced as stabilizer together with synergist(PLGA-TCA/DLPC/HCQ).In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction,thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day.In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress,remodeled the inflammatory pancreas microenvironment,and activated PI3K/AKT signaling pathway without obvious toxicity.This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment.

Membrane fusion reverse micelle platforms as potential oral nanocarriers for efficient internalization of free hydrophilic peptides

Orally administered peptides or proteins are garnering increasing preference owing to their superiority in terms of patient compliance and convenience.However,the development of oral protein formulations has stalled due to the low bioavailability of macromolecules that encounter the aggressive gastrointestinal environment and harsh mucus villi barrier.Herein,we propose an ideal reverse micelle/self-emulsifying drug delivery system(RM/SEDDS)nanoplatform that is capable of improving the oral bioavailability of hydrophilic peptides by preventing enzymatic degradation and enhancing mucosal permeability.Upon the passage through the mucus,the self-emulsifying drug delivery system with optimal surface properties effectively penetrates the viscoelastic mucosal barrier,followed by the exposure of the inner reverse micelle amphipathic vectors,which autonomously form continua with the lipidic cell membrane and facilitate the internalization of drugs.This membrane-fusion mechanism inaugurates a new way for hydrophilic peptide delivery in the free form,circumventing the traditional impediments of the cellular internalization of nanocarriers and subsequent poor release of drugs.And more importantly,reverse micelles are not spatially specific to the laden drugs,which enables their delivery for a myriad of peptide clinical drugs.In conclusion,as an exquisitely designed nanoplatform,RM/SEDDS overcomes multiple physiological barriers and opens a new path for drug cellular entry,providing new prospects for the development of oral drug delivery systems.

Study the lipidoid nanoparticle mediated genome editing protein delivery using 3D intestinal tissue model

Lipid nanoparticles are promising carriers for oral drug delivery.For bioactive cargos with intracellular targets,e.g.gene-editing proteins,it is essential for the cargo and carrier to remain complexed after crossing the epithelial layer of intestine in order for the delivery system to transport the cargos inside targeted cells.However,limited studies have been conducted to verify the integrity of cargo/carrier nanocomplexes and their capability in facilitating cargo delivery intracellularly after the nanocomplex crossing the epithelial barrier.Herein,we used a traditional 2D transwell system and a recently developed 3D tissue engineered intestine model and demonstrated the synthetic lipid nanoparticle(carrier)and protein(cargo)nanocomplexes are able to cross the epithelial layer and deliver the protein cargo inside the underneath cells.We found that the EC16-63 LNP efficiently encapsulated the GFP-Cre recombinase,penetrated the intestinal monolayer cells in both the 2D cell culture and 3D tissue models through temporarily interrupting the tight junctions between epithelial layer.After transporting across the intestinal epithelia,the EC16-63 and GFP-Cre recombinase nanocomplexes can enter the underneath cells to induce gene recombination.These results suggest that the in vitro 3D intestinal tissue model is useful for identifying effective lipid nanoparticles for potential oral drug delivery.

Neonatal Fc receptor-targeted lignin-encapsulated porous silicon nanoparticles for enhanced cellular interactions and insulin permeation across the intestinal epithelium

Oral insulin delivery could change the life of millions of diabetic patients as an effective,safe,easy-to-use,and affordable alternative to insulin injections,known by an inherently thwarted patient compliance.Here,we designed a multistage nanoparticle(NP)system capable of circumventing the biological barriers that lead to poor drug absorption and bioavailability after oral administration.The nanosystem consists of an insulin-loaded porous silicon NP encapsulated into a pH-responsive lignin matrix,and surface-functionalized with the Fc fragment of immunoglobulin G,which acts as a targeting ligand for the neonatal Fc receptor(FcRn).The developed NPs presented small size(211±1 nm)and narrow size distribution.The NPs remained intact in stomach and intestinal pH conditions,releasing the drug exclusively at pH 7.4,which mimics blood circulation.This formulation showed to be highly cytocompatible,and surface plasmon resonance studies demonstrated that FcRn-targeted NPs present higher capacity to interact and being internalized by the Caco-2 cells,which express FcRn,as demonstrated by Western blot.Ultimately,in vitro permeability studies showed that Fc-functionalized NPs induced an increase in the amount of insulin that permeated across a Caco-2/HT29-MTX co-culture model,showing apparent permeability coefficients(Papp)of 2.37×106 cm/s,over the 1.66×106 cm/s observed for their non-functionalized counterparts.Overall,these results demonstrate the potential of these NPs for oral delivery of anti-diabetic drugs.

Fabrication of deoxycholic acid-modified polymeric micelles and their transmembrane transport

Oral administration is the best way for the most patients due to the good compliance,and intestinal epithelium is the main barrier of oral drug absorption.In order to overcome the small intestine epithelial barrier to orally deliver water-insoluble drugs,deoxycholic acid(DA),a substrate of the intestinal bile acid transporters,conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide)(DA-PEOz-PLA)was designed and synthesized,and deoxycholic acid-modified polymeric micelles composed of DA-PEOz-PLA and mPEG-PLA were fabricated to encapsulate model drug coumarin 6(C6)based on intestinal bile acid pathway.The structure of DA-PEOz-PLA was confirmed using 1 H NMR and TLC,and the molecular weight measured by GPC was 10034 g/mol with a PDI of 1.51.The C6-loaded polymeric micelles with drug loading content of 0.085%were characterized to have 40.11 nm in diameter and uniform spherical morphology observed by TEM.Furthermore,the deoxycholic acid-modified polymeric micelles were demonstrated to further enhance the transmembrane transport efficiency.The mechanic study evidenced that anchorage of deoxycholic acid onto the micelles surface enriched their transcellular transport pathway.Therefore,the designed deoxycholic acid-modified polymeric micelles might have a promising potential for oral delivery of water-insoluble drugs.