Zhenhai Zhang

Solid lipid nanoparticles modified with stearic acid–octaarginine for oral administration of insulin

The aim of this study was to design and characterize solid lipid nanoparticles (SLNs) modified with stearic acid–octaarginine (SA-R8) as carriers for oral administration of insulin (SA-R 8-Ins-SLNs). The SLNs were prepared by spontaneous emulsion solvent diffusion methods. The mean particle size, zeta potential, drug loading, and encapsulation efficiency of the SA-R8-Ins-SLNs were 162 nm, 29.87 mV, 3.19%, and 76.54%, respectively. The zeta potential of the SLNs changed dramatically, from −32.13 mV to 29.87 mV, by binding the positively charged SA-R8. Morphological studies of SA-R8-Ins-SLNs using transmission electron microscopy showed that they were spherical. In vitro, a degradation experiment by enzymes showed that SLNs and SA-R8 could partially protect insulin from proteolysis. Compared to the insulin solution, the SA-R8-Ins-SLNs increased the Caco-2 cell’s internalization by up to 18.44 times. In the in vivo studies, a significant hypoglycemic effect in diabetic rats over controls was obtained, with a SA-R8-Ins-SLN pharmacological availability value of 13.86 ± 0.79. These results demonstrate that SA-R8-modified SLNs promote the oral absorption of insulin.

Solid dispersion of berberine–phospholipid complex/TPGS 1000/SiO2: preparation, characterization and in vivo studies

Berberine (Ber), an isoquinoline alkaloid, arouses wide interests in many researchers in recent years because of its numerous new pharmacological actions. However Bers low oral bioavailability restricts its wide application. In this study, a solid dispersion (BPTS-SD) composed of berberine-phospholipid complex (BPC), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS 1000) and SiO₂ was prepared by simple solvent evaporation technique. BPC was employed to improve the liposolubility of Ber, and SiO₂ was used to improve the flowability of BPTS-SD, while TPGS 1000 played a dual role: firstly, as a solid dispersion carrier to improve the dissolution rate of BPC and secondly, as a P-glycoprotein (P-gp) inhibitor to enhance the intestinal absorption of Ber. FTIR, DSC and SEM analysis proved the formation of BPC and BPTS-SD. Po/w of BPC successfully increased from 0.25 to 8.75. In vitro dissolution study showed that the cumulative dissolution percentages of BPTS-SDs were nearly 2.67-4.78-folds of BPC. Single-pass intestinal perfusion studies showed that the absorption of Ber in BPC was increased nearly 1.4-2.0-folds compared to that of Ber which was mainly due to the improved liposolubility, and further increased by BPTS-SD around 0.1-1.3-folds compared to that of BPC through the P-gp inhibition of TPGS 1000. Significant improvements in Cmax and AUC₀→t of BPC and BPTS-SD were obtained in pharmacokinetic study (the highest improvement in oral relative bioavailability of BPTS-SD-1 was 322.66% of Ber). All these results indicated that BPTS-SD can be a promising drug delivery system to improve their oral bioavailability for the Bers analogues. In particular this solid dispersion can be prepared just by a simple method and has a strong feasibility for industrialization.

Studies on lactoferrin nanoparticles of gambogic acid for oral delivery

Abstract Purpose: Lactoferrin (Lf), a mammalian cationic iron-binding glycoprotein belonging to the transferrin (Tf) family, has been widely used in a variety of fields ranging from treating infant diarrhea and supporting newborn growth to food and pharmaceutical applications. In this study, Lf nanoparticles were firstly used as carriers of gambogic acid (GA) to enhance oral absorption and anti-cancer activity, hence reducing the related toxic effect. Methods: Gambogic acid-lactoferrin nanoparticles (GL-NPs) were prepared by the nanoparticle albumin-bound (NAB) technology. The formed nanoparticles were characterized by DSC, TEM, etc. In situ intestinal perfusion experiment was performed to clarify the absorption mechanism of GL-NPs. Furthermore in vivo and in vitro anti-tumor activities of GL-NPs were also investigated. Results: GL-NPs was successfully prepared with about 150 nm mean size, +20 mV ζ potential, 92.3 ± 7.2% encapsulation efficiency and 9.04 ± 0.7% DL; GL-NPs also exhibited a better stability and a desirable slow release in vitro experiment. The results of in situ intestinal perfusion showed a transformation of GA absorption from passive diffusion into active transport or facilitated diffusion by GL-NPs. MTT assay of GL-NPs showed almost an equal anti-proliferative effect with arginine solution of GA (Arg-GA) in HepG2 cell. The inhibitory rate against S180 tumor mice after oral administration of GL-NPs was up to 86.01% which was1.39-folds of intravenous injection of Arg-GA. Conclusion: The in vitro results showed that the NAB technology was feasible for industrial production of Lf nanoparticles and the in vivo results proved that the effective GL-NPs is a promising approach for the oral delivery of GA. These obtained research works have also paved the preliminary way for the study of Lf as an oral drug delivery carrier.

A Biomimetic Chitosan Derivates: Preparation, Characterization and Transdermal Enhancement Studies of N-Arginine Chitosan

A novel arginine-rich chitosan (CS) derivates mimicked cell penetration peptides; N-Arginine chitosan (N-Arg-CS) was prepared by two reaction methods involving activated L-arginine and the amine group on the chitosan. FTIR spectra showed that arginine was chemically coupled with CS. Elemental analysis estimated that the degrees of substitution (DS) of arginine in CS were 6%, 31.3% and 61.5%, respectively. The drug adefovir was chosen as model and its permeation flux across excised mice skin was investigated using a Franz diffusion cell. The results showed that the most effective enhancer was 2% (w/v) concentration of 10 kDa N-Arg-CS with 6% DS. At neutral pH, the cumulative amount of adefovir permeated after 12 hours was 2.63 ± 0.19 mg cm−2 which was 5.83-fold more than adefovir aqueous solution. Meanwhile N-Arg-CS was 1.83, 2.22, and 2.45 times more effective than Azone, eucalyptus and peppermint, respectively. The obtained results suggest that N-Arg-CS could be a promising transdermal enhancer.

Preparation and evaluation of icariside II-loaded binary mixed micelles using Solutol HS15 and Pluronic F127 as carriers

Abstract An effective anti-cancer drug, icariside II (IS), has been used to treat a variety of cancers in vitro. However, its poor aqueous solubility and permeability lead to low oral bioavailability. The aim of this work was to use Solutol®HS15 and Pluronic F127 as surfactants to develop novel mixed micelles to enhance the oral bioavailability of IS by improving permeability and inhibiting efflux. The IS-loaded mixed micelles were prepared using the method of ethanol thin-film hydration. The physicochemical properties, dissolution property, oral bioavailability of the male SD rats, permeability and efflux of Caco-2 transport models, and gastrointestinal safety of the mixed micelles were evaluated. The optimized IS-loaded mixed micelles showed that at 4:1 ratio of Solutol®HS15 and Pluronic F127, the particle size was 12.88 nm with an acceptable polydispersity index of 0.172. Entrapment efficiency (94.6%) and drug loading (9.7%) contributed to the high solubility (11.7 mg/mL in water) of IS, which increased about 900-fold. The SF-IS mixed micelle release profile showed a better sustained release property than that of IS. In Caco-2 cell monolayer models, the efflux ratio dramatically decreased by 83.5%, and the relative bioavailability of the mixed micelles (AUC0–∞) compared with that of IS (AUC0–∞) was 317%, indicating potential for clinical application. In addition, a gastrointestinal safety assay also provided reliable clinical evidence for the safe use of this micelle.

Preparation and evaluation of berberine alginate beads for stomach-specific delivery.

The purpose of this research was to prepare floating calcium alginate beads of berberine for targeting the gastric mucosa and prolonging their gastric residence time. The floating beads were prepared by suspending octodecanol and berberine in sodium alginate (SA) solution. The suspension was then dripped into a solution of calcium chloride. The hydrophobic and low-density octodecanol enhanced the sustained-release properties and floating ability of the beads. The bead formulation was optimized for different weight ratios of octodecanol and SA and evaluated in terms of diameter, floating ability and drug loading, entrapment and release. In vitro release studies showed that the floating and sustained release time were effectively increased in gastric media by addition of octodecanol. In vivo studies with rats showed that a significant increase in gastric residence time of beads had been achieved.

The studies of N-Octyl-N-Arginine-Chitosan coated liposome as an oral delivery system of Cyclosporine A

An amphiphilic polymer N‐Octyl‐N‐Arginine‐Chitosan (OACS) was synthesized to coat the Cyclosporine A (CsA) liposomes (CL) to decrease the destruction of liposomes in gastrointestinal tract (GI) tract and improve its oral absorption.

Design, synthesis and evaluation of multi-functional tLyP-1-hyaluronic acid-paclitaxel conjugate endowed with broad anticancer scope

A novel tLyP-1-HA-PTX conjugate is designed for combining the solubilization capacity of Paclitaxel (PTX) and tumor tissue targeting - penetration effect of hyaluronic acid (HA) as well as cell penetration peptide (tLyP-1). In addition, through modifying by tLyP-1, the anticancer scope of tLyP-1-HA-PTX conjugate was expanded from tumor cells expressing CD44 receptors to those of expressing NRP1 receptors. In vitro antitumor ability of tLyP-1-HA-PTX conjugate and cellular uptake tests were conducted to testify the tumor-targeting behavior of the conjugates. The results showed that both HA-PTX and tLyP-1-HA-PTX conjugates gained better solubility, better stability and specific tumor sites ability and showed high safety in vitro cytotoxicity tests. The tLyP-1-HA-PTX conjugate was especially endowed with efficient cell-penetrating and tumor NRP1 receptor targeting ability and compensate for the decreasing of uptake caused by suppression of CD44 receptor, which is more significant when NRP1 receptor is highly expressed.

TPGS-modified liposomes for the delivery of ginsenoside compound K against non-small cell lung cancer: formulation design and its evaluation in vitro and in vivo.

This work aimed at preparing ginsenoside compound K (GCK)‐loaded liposomes modified with TPGS (GCKT‐liposomes) to enhance solubility and targeting capability of GCK, as well as inhibit the efflux of GCK from tumour cells.

Preparation and antitumor evaluation of self-assembling oleanolic acid-loaded Pluronic P105/D-α-tocopheryl polyethylene glycol succinate mixed micelles for non-small-cell lung cancer treatment

Oleanolic acid (OA) is a triterpenoid found in various fruits and vegetables and used in traditional Chinese medicine. OA plays a crucial role in the treatment of several cancers, but poor water solubility, low permeability, and significant efflux have limited its widespread clinical use. Vitamin E-d-α-tocopheryl polyethylene glycol succinate (vitamin E-TPGS) and Pluronic P105 were used to improve the solubility and permeability and to decrease the efflux of OA. OA-loaded mixed micelles were prepared by ethanol thin-film hydration. The physicochemical properties of the micelles, including zeta potential, morphology, particle size, solubility, drug loading, and drug entrapment efficiency were characterized. OA release from micelles was slower than that from the free drug system. OA uptake by A549 non-small-cell lung cancer (NSCLC) cells was enhanced by the micelles. A tumor model was established by injecting A549 cells into nude mice. In vivo imaging showed that OA-micelles could accumulate in the tumors of nude mice. Additionally, smaller tumor size and increased expression of pro-apoptotic proteins were observed in OA-micelle-treated mice, indicating that OA-micelles are more effective than free OA in treating cancer. In vitro experiments were performed using two NSCLC cell lines (A549 and PC-9). Cytotoxicity evaluations showed that the half-maximal inhibitory concentrations of free OA and OA-micelles were 36.8±4.8 and 20.9±3.7 μM, respectively, in A549 cells and 82.7±7.8 and 56.7±4.7 μM, respectively, in PC-9 cells. Apoptosis assays revealed that the apoptotic rate of OA-micelle-treated A549 and PC-9 cells was higher than that of cells treated with the same concentration of free OA. Wound healing and transwell assays showed that migration and invasion were significantly suppressed in OA-micelle-treated cells. Immunofluorescence and Western blot analyses confirmed that the epithelial–mesenchymal transition was reversed in OA-micelle-treated cells. Mixed micelles are a promising nano-drug delivery system for lung cancer treatment.