Fang Gao

In vivo biodistribution and urinary excretion of mesoporous silica nanoparticles: effects of particle size and PEGylation.

The in vivo biodistribution and urinary excretion of spherical mesoporous silica nanoparticles (MSNs) are evaluated by tail-vein injection in ICR mice, and the effects of the particle size and PEGylation are investigated. The results indicate that both MSNs and PEGylated MSNs of different particle sizes (80-360 nm) distribute mainly in the liver and spleen, a minority of them in the lungs, and a few in the kidney and heart. The PEGylated MSNs of smaller particle size escape more easily from capture by liver, spleen, and lung tissues, possess longer blood-circulation lifetime, and are more slowly biodegraded and correspondingly have a lower excreted amount of degradation products in the urine. Neither MSNs nor PEGylated MSNs cause tissue toxicity after 1 month in vivo.

A pH-responsive mesoporous silica nanoparticles-based multi-drug delivery system for overcoming multi-drug resistance

A type of pH-responsive nano multi-drug delivery systems (nano-MDDSs) with uniform particle size (100xa0±xa013xa0nm) and excellent monodispersity was developed by in situ co-self-assembly among water-insoluble anti-cancer drug (doxorubicin, DOX), surfactant micelles (CTAB) as chemosensitiver and silicon species forming drugs/surfactant micelles-co-loaded mesoporous silica nanoparticles (drugs@micelles@MSNs or DOX@CTAB@MSNs) via a micelles-MSNs self-assembly mechanism. The nano-MDDS DOX@CTAB@MSNs had a highly precise pH-responsive drug release behavior both inxa0vitro and inxa0vivo, and exhibited high drug efficiencies against drug-resistant MCF-7/ADR cells as well as drug-sensitive MCF-7 cells by the MSNs-mediated transmembrane delivery, the sustained drug release and the high anti-cancer and multi-drug resistance (MDR)-overcoming efficiencies. The MDR-overcoming mechanism was proved to be a synergistic cell cycle arrest/apoptosis-inducing effect resulted from the chemosensitization of the surfactant CTAB. These results demonstrated a very promising nano-MDDS for the pH-responsive controlled drug release and the cancer MDR overcoming.

Nanoemulsion improves the oral absorption of candesartan cilexetil in rats: Performance and mechanism

Candesartan cilexetil (CC), an inactive prodrug of candesartan, was rapidly hydrolyzed into active candesartan during absorption in the gastrointestinal (GI) tract to achieve antihypertensive effects. However, CC exhibited incomplete intestinal absorption with low oral bioavailability due to its poor aqueous solubility. In this work, a novel CC loaded nanoemulsion (CCN) was designed to improve the intestinal absorption. CCN was prepared by a modified emulsification-solvent evaporation technique. The physicochemical characteristics of CCN were characterized, and the intestinal absorption was investigated as well. The experimental results indicated that CCN was nanometer-sized droplets (35.5±5.9nm) with negative potential (-6.45±0.36mV), and the absorption of CCN was significantly improved in total intestinal tract compared with free CC solution. Moreover, CCN could be internalized into the enterocytes by clathrin-mediated endocytosis pathway, and thereafter transported into systemic circulation via both portal vein and lymphatic pathway. The concentration of active candesartan in rat plasma was determined by LC-MS-MS method. The experimental results showed that the area under the concentration-time curve (AUC(0-t)) of candesartan was improved over 10-fold after CC was incorporated into CCN. The overall results implicated that the nanoemulsion was very effective for enhancing the oral absorption of insoluble CC, and CCN showed the great potential for clinical application.

The characteristics and mechanism of simvastatin loaded lipid nanoparticles to increase oral bioavailability in rats

Simvastatin (SV), a cholesterol-lowering agent, has been widely used in the treatment of hypercholesterolemia, dyslipidemia and coronary heart disease, but SV shows the low oral bioavailability due to its poor aqueous solubility and extensive metabolism by cytochrome-3A system in intestinal guts and liver. In this work, SV loaded lipid nanoparticles (SLNs) with different components were designed to enhance its oral bioavailability, and the plasma concentration of SV and its active metabolite (simvastatin acid, SVA) was determined by LC-MS-MS method. The experimental results showed that SLNs were spherical nano-sized particles with high encapsulation efficiency (>95%). The in situ intestinal absorption indicated that the absorption of SLNs was greatly improved compared with that of free SV, and the absorption was changed with the site of the intestinal segments. SLNs could be uptaken into the enterocytes through both clathrin and caveolae mediated endocytosis pathways. The oral bioavailability of SV after its incorporation into the lipid nanoparticles was improved by 3.37-fold for SLNs I and 2.55-fold for SLNs II compared with that from free SV in rats, and that of the SVA was significantly enhanced as well. As a result, lipid nanoparticles could be a promising delivery system to enhance the oral bioavailability of simvastatin.

Solid lipid nanoparticles loading candesartan cilexetil enhance oral bioavailability: in vitro characteristics and absorption mechanism in rats

UNLABELLEDnCandesartan cilexetil (CC) is widely used for the treatment of hypertension and heart failure, but it shows very poor aqueous solubility and very low oral absorption. In this work, CC-loaded solid lipid nanoparticles (CLNs) were successfully developed to improve the oral bioavailability. The physicochemical properties of CLNs were characterized, and the pharmacokinetic behavior of CLNs was evaluated in rats. CLNs exhibited nanometer-sized spherical particles with high entrapment efficiency (91.33%). The absorption of CLNs in the stomach was only 2.8% of that in intestine. Moreover, CLNs could be internalized into the enterocytes and then transported into the systemic circulation via the portal circulation and intestinal lymphatic pathway. The pharmacokinetic results indicated that the oral bioavailability of candesartan was obviously improved over 12-fold after incorporation into solid lipid nanoparticles. These results demonstrated that solid lipid nanoparticles have great potential for increasing oral bioavailability of lipophilic drugs such as CC.nnnFROM THE CLINICAL EDITORnCandesartan cilexetil is a potent angiotensin receptor inhibitor with low bioavailability due to poor aqueous solubility. In this work, solid lipid nanoparticles were used to improve the oral bioavailability 12-fold compared to standard preparation in rats, suggesting that a similar approach might be effective in future human applications.

Bile salts enhance the intestinal absorption of lipophilic drug loaded lipid nanocarriers: Mechanism and effect in rats

The purpose of this study was to elucidate the effect and possible mechanism of bile salts on the intestinal absorption of lipophilic drug loaded lipid nanocarriers in rats. Effects of sodium cholate (SC) on the characteristics, intestinal absorption, cellular uptake in Caco-2 cell monolayers and intestinal lymphatic transport of candesartan cilexetil loaded lipid nanocarriers (CLN) were investigated to clarify the possible mechanism. The intestinal absorption of candesartan from CLN was evidently improved over 16-fold compared with free drug suspension, and further significantly enhanced 1.79-fold after the addition of SC. The cellular uptake of CLN in Caco-2 cell monolayers at 37̊C and its colocalization with endoplasmic reticulum were obviously increased in the presence of SC. Moreover, the intestinal lymphatic transport of CLN was obviously enhanced by SC. These results implicated that bile salts could improve the cellular uptake of CLN in Caco-2 cell monolayers via the active processes and promote the intestinal absorption of CLN through the intestinal lymphatic pathway. Therefore, bile salts could be an important physiological factor affecting the intestinal absorption of lipophilic drugs loaded lipid nanocarriers.

A self-assembled nanodelivery system enhances the oral bioavailability of daidzein: in vitro characteristics and in vivo performance

AIMnA self-assembled nano-based delivery system was designed and developed to increase the oral bioavailability of poor hydrophilic and lipophilic daidzein.nnnMETHODSnDaidzein was firstly combined with lecithin to form the daidzein-lecithin complex, then self-assembled into micelles (DLMs) with lecithin and sodium bile. The physiochemical properties and intestinal absorption of DLMs were characterized, and the pharmacokinetic behavior was evaluated in rats.nnnRESULTSnDLMs exhibited nanometer-sized particles. DLMs were mainly distributed in the stomach and proximal intestine after oral administration. The intestinal absorption of DLMs was significantly improved, and DLMs could be absorbed via both endocytosis and passive transport. The AUC(0-t) value of daidzein in rats treated with DLMs was ninefold greater than that of free daidzein suspension.nnnCONCLUSIONnThe presented delivery system could provide a new promising strategy for enhancing the oral bioavailability of drugs with poor hydrophilicity and lipophilicity.

Nano-based Drug Delivery System Enhances the Oral Absorption of Lipophilic Drugs with Extensive Presystemic Metabolism

Oral administration remains the most preferred route for the treatment of many diseases due to its convenience and adaptability. However, the presystemic metabolism may be an important barrier that prevents lipophilic drugs from achieving their pharmacological effects following oral delivery. Nano-based drug delivery system provides an effective strategy to reduce the presystemic metabolism and increase the systemic exposure of lipophilic drugs. In this review, we described the physiological factors affecting the presystemic metabolism of lipophilic drugs, intestinal transport of nanosystems, strategy of nanosystems to avoid the presystemic metabolism, and the current application of various oral nanosystems including lipid and polymeric nanocarriers. The nano-based drug delivery system has a lot of potential for reducing the presystemic metabolism and enhancing the bioavailability of orally administrated lipophilic drugs.