Miaorong Yu

Dual-functional liposome for tumor targeting and overcoming multidrug resistance in hepatocellular carcinoma cells

The purpose of this study was to design and evaluate the dual-functional liposome (LPG) with synthetic polymeric nano-biomaterial (Gal-P123) that targets cancer cells and reverses multidrug resistance (MDR) in hepatocellular carcinoma (HCC) cells. The mitoxantrone (MX) loaded LPG (MX-LPG) was about 100 nm in diameter, spherically shaped, and had an encapsulation efficiency of 97.3%. The cytotoxicity and cellular uptake of MX-LPG were evaluated in HCC Huh-7 cells. BCRP-overexpressing MDCKII/BCRP cells were used to certify the inhibitory effect of LPG on drug efflux transporter. Compared with MX, MX-LPG had 2.3-fold higher cytotoxicity in Huh-7 cells and a 14.9-fold increase in cellular MX accumulation in MDCKII/BCRP cells. The pharmacokinetic study in rats showed that LPG significantly prolonged the circulation time and enhanced the bioavailability of MX. Moreover, MX-LPG increased antitumor activity and improved selectivity in BALB/c mice bearing orthotopic xenograft HCC tumors.

Orally active-targeted drug delivery systems for proteins and peptides

Introduction: In the past decade, extensive efforts have been devoted to designing ‘active targeted’ drug delivery systems (ATDDS) to improve oral absorption of proteins and peptides. Such ATDDS enhance cellular internalization and permeability of proteins and peptides via molecular recognition processes such as ligand–receptor or antigen−antibody interaction, and thus enhance drug absorption. Areas covered: This review focuses on recent advances with orally ATDDS, including ligand–protein conjugates, recombinant ligand–protein fusion proteins and ligand-modified carriers. In addition to traditional intestinal active transport systems of substrates and their corresponding receptors, transporters and carriers, new targets such as intercellular adhesion molecule-1 and β-integrin are also discussed. Expert opinion: ATDDS can improve oral absorption of proteins and peptides. However, currently, no clinical studies on ATDDS for proteins and peptides are underway, perhaps due to the complexity and limited knowledge of transport mechanisms. Therefore, more research is warranted to optimize ATDDS efficiency.

Advances in the transepithelial transport of nanoparticles

The intestinal epithelium represents a barrier to the delivery of nanoparticles (NPs). It prevents intact NPs from efficiently crossing the mucosa to access the circulation, thus limiting the successful application of NP-based oral drug delivery. Recent advances in nanotechnology have provided promising solutions to this challenge. This review describes the potential intestinal absorption pathways of NPs, including the transenterocytic pathway, paracellular pathway and M-cell-mediated pathway. NP properties that influence transcytosis are summarized; and the biodistribution of NPs after oral absorption is described and the future prospects of novel NPs are explored.

Enhanced transport of nanocage stabilized pure nanodrug across intestinal epithelial barrier mimicking Listeria monocytogenes

Ligand grafted nanoparticles have been shown to enhance drug transport across epithelium barrier and are expected to improve drug delivery. However, grafting of these ligands to the surface of pure nanodrug, i.e., nanocrystals (NCs), is a critical challenge due to the shedding of ligands along with the stabilizer upon high dilution or dissolving of the drug. Herein, a non-sheddable nanocage-like stabilizer was designed by covalent cross-linking of poly(acrylic acid)-b-poly(methyl acrylate) on drug nanocrystal surface, and a ligand, wheat germ agglutinin (WGA), was successfully anchored to the surface of itraconazole (ITZ) NCs by covalent conjugation to the nanocage (WGA-cage-NCs). The cellular study showed that large amount of WGA-cage-NCs were adhered to Caco-2 cell membrane, and invaded into cells, resulting in a higher drug uptake than that of ordinary NCs (ONCs). After oral administration to rats, WGA-cage-NC were largely accumulated on the apical side of epithelium cells, facilitating drug diffusing across epithelium barrier. Interestingly, WGA-cage-NCs were capable of invading rat intestinal villi and reaching to lamina propria by transcytosis across goblet cells, which behaved like a foodborne pathogen, Listeria monocytogenes. The WGA-cage-NCs showed an improved oral bioavailability, which was 17.5- and 2.41-folds higher than that of coarse crystals and ONCs, respectively. To our best knowledge, this may represent the first report that a functional ligand was successfully anchored to the surface of pure nanodrug by using a cage-like stabilizer, showing unique biological functions in gastrointestinal tract and having an important significance in oral drug delivery.

Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers

To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.Penetration of the mucus and tumor interstitial matrix is an important consideration for drug delivery devices. Here, the authors report on a study into the optimization of rigidity for the transport of nanoparticles through biological hydrogels using core-shell polymer-lipid nanoparticles.

A poly-L-glutamic acid functionalized nanocomplex for improved oral drug absorption

Poor permeability of the intestinal epithelium limits the oral absorption of many drugs. Here, a poly-l-glutamic acid (PGA)-based functional ternary nanocomplex (TC) is reported for enhancing the intestinal absorption of poorly permeable drug doxorubicin hydrochloride (Dox·HCl). The particle size and zeta potential of TC were 189.3 ± 13.7 nm and -29.1 ± 7.4 mV, respectively. The TC was shown to be more stable under simulated gastrointestinal changing pH or electrolyte content conditions than the binary nanocomplex Dox·HCl/PGA. Cellular uptake and the apparent permeability coefficient value (Papp) of the TC were determined to be 5.2- and 4.6-fold higher than that of Dox·HCl solutions, respectively. Mechanistic studies showed that active endocytosis caused by specific interactions between γ-glutamyl terminal groups of PGA and membrane-bound γ-glutamyl transferase contributed much to the TC-dependent Dox·HCl absorption. Studies on the rat model also demonstrated the highest efficiency for Dox·HCl absorption by the TC throughout the intestinal tract, with 2.6- and 4.2-fold higher Cmax and AUC0-24h values compared to Dox·HCl solutions. In conclusion, the TC is a promising carrier for improving Dox·HCl intestinal absorption, and the rational design of carriers with functional polymer PGA could implement the efficient active absorption of poorly permeable drugs.

Advances in particle shape engineering for improved drug delivery

Spherical particles such as liposomes and microspheres are the most common and extensively applied drug vehicles. However, researchers have come to realize the superiority of nonspherical nanoparticles. Actually, in human bodies red blood cells, gut biotics and many well-known pathogens have distinct shapes. It can be reasonably inferred that particle shape plays a pivotal part in human bodies. In this review, we summarize the recent studies about the effect of shape on delivery processes such as cellular uptake, tissue penetration and biodistribution. The underlying mechanisms that are relevant to the phenomena revealed, owing to experimental and computational modern techniques, will be addressed, and we shall provide future perspectives on particle design to improve the efficacy of drug delivery.

Enhanced digestion inhibition and mucus penetration of F127-modified self-nanoemulsions for improved oral delivery

Self-nanoemulsifying systems (SNEs) have excellent ability to improve the solubility of poorly water-soluble drugs (PWSD). However, SNEs are likely to be degraded in gastrointestinal (GIT) when their surface is recognized by lipase/co-lipase enzyme complex, resulting in rapid release and precipitation of encapsulated drugs. The precipitates are then captured and removed by intestinal mucus, reducing the delivery efficacy of SNEs. Herein, the amphiphilic polymer Pluronic® F127 was incorporated into long and short-chain triglycerides (LCT, SCT) based SNEs to diminish the recognition and therefore minimized their degradation by enzymes and clearance by mucus. The SNEs were characterized in terms of particle size, zeta potential and stability. Ex vivo multiple particles tracking studies were performed by adding particle solution into fresh rat mucus. Cellular uptake of SNEs were conducted by using E12 cells, the absorption and distribution in small intestine were also studied after oral administration in male Sprague-Dawley (SD) rats. The in vitro digestion rate of SNEs were found to be in following order SCT-SNE > SCT-F127-SNE > LCT-SNE > LCT-F127-SNE. Moreover, the LCT-F127-SNE was found to be most effective in enhancing cellular uptake, resulting in 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. After incubating the SNE with E12 cells, the LCT-F127-SNE exhibited the highest amount regarding both mucus penetration and cellular uptake, with an uptake amount number (via bicinchoninic acid (BCA) analysis) of 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. The in vivo results revealed that orally administered LCT-F127-SNE could significantly increase the bioavailability of Cyclosporine A (CsA), which was approximately 2.43-fold, 1.33-fold and 1.80-fold higher than that of SCT-SNE, SCT-F127-SNE and LCT-SNE, respectively. We address in this work that F127-modified SNEs have potentials to improve oral drug absorption by significantly reducing gastrointestinal enzymatic degradation and simultaneously enhancing mucus penetration.

Supersaturated polymeric micelles for oral silybin delivery: the role of the Soluplus–PVPVA complex

Increasing the degree of supersaturation of drugs and maintaining their proper stability are very important in improving the oral bioavailability of poorly soluble drugs by a supersaturated drug delivery system (SDDS). In this study, we reported a complex system of Soluplus–Copovidone (Soluplus–PVPVA) loaded with the model drug silybin (SLB) that could not only maintain the stability of a supersaturated solution but also effectively promote oral absorption. The antiprecipitation effect of the polymers on SLB was observed using the solvent-shift method. In addition, the effects of the polymers on absorption were detected by cellular uptake and transport experiments. The mechanisms by which the Soluplus–PVPVA complex promotes oral absorption were explored by dynamic light scattering, transmission electron microscopy, fluorescence spectra and isothermal titration calorimetry analyses. Furthermore, a pharmacokinetic study in rats was used to demonstrate the advantages of the Soluplus–PVPVA complex. The results showed that Soluplus and PVPVA spontaneously formed complexes in aqueous solution via the adsorption of PVPVA on the hydrophilic-hydrophobic interface of the Soluplus micelle, and the Soluplus–PVPVA complex significantly increased the absorption of SLB. In conclusion, the Soluplus–PVPVA complex is a potential SDDS for improving the bioavailability of hydrophobic drugs.

Wheat germ agglutinin nanocage stabilized drug nanocrystals cross intestinal epithelium barrier via goblet cells

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