Tiantian Ye

Design, characterization, and in vitro cellular inhibition and uptake of optimized genistein-loaded NLC for the prevention of posterior capsular opacification using response surface methodology

This study was to design an innovative nanostructured lipid carrier (NLC) for drug delivery of genistein applied after cataract surgery for the prevention of posterior capsular opacification. NLC loaded with genistein (GEN-NLC) was produced with Compritol 888 ATO, Gelucire 44/14 and Miglyol 812N, stabilized by Solutol(®) HS15 by melt emulsification method. A 2(4) central composite design of 4 independent variables was performed for optimization. Effects of drug concentration, Gelucire 44/14 concentration in total solid lipid, liquid lipid concentration, and surfactant concentration on the mean particle size, polydispersity index, zeta potential and encapsulation efficiency were investigated. Analysis of variance (ANOVA) statistical test was used to assess the optimization. The optimized GEN-NLC showed a homogeneous particle size of 90.16 nm (with PI=0.33) of negatively charged surface (-25.08 mv) and high encapsulation efficiency (91.14%). Particle morphology assessed by TEM revealed a spherical shape. DSC analyses confirmed that GEN was mostly entrapped in amorphous state. In vitro release experiments indicated a prolonged and controlled genistein release for 72 h. In vitro growth inhibition assay showed an effective growth inhibition of GEN-NLCs on human lens epithelial cells (HLECs). Preliminary cellular uptake test proved a enhanced penetration of genistein into HLECs when delivered in NLC.

Liposome incorporated ion sensitive in situ gels for opthalmic delivery of timolol maleate

This study was aimed to design a liposomal based ion-sensitive in situ ophthalmic delivery system of timolol maleate (TM). The TM liposome was produced by the reverse evaporation technique coupled with pH-gradients method (REVPR), and then was incorporated into deacetylated gellan gum gels. The TM liposome was demonstrated to be a round and uniform shape in TEM pictures. Compared with the TM eye drops, the TM liposome produced a 1.93 folds increase in apparent permeability coefficients (Papp), resulting in a significant increase of the corneal penetration. The TM-loaded liposome incorporated ion sensitive in situ gels (TM L-ISG) showed longer retention time on corneal surface compared with the eye drops using gamma scintigraphy technology. Draize testing showed that TM L-ISG was non-irritant for ocular tissues. The biggest efficacy of TM L-ISG occurred 30 min after eye drops administration, and efficacy disappeared after 240min. Then, compared with the eye drops, the optimal TM L-ISG could quickly reduce the intraocular pressure and the effective time was significantly longer (P≤0.05). These results indicate that liposome incorporated ion sensitive in situ gels have a potential ability for the opthalmic delivery.

A novel oral delivery system consisting in "drug-in cyclodextrin-in nanostructured lipid carriers" for poorly water-soluble drug: vinpocetine.

The purpose of this study was to develop a new delivery system based on drug cyclodextrin (CD) complexation and loading into nanostructured lipid carriers (NLC) to improve the oral bioavailability of vinpocetine (VP). Three different CDs and three different methods to obtain solid vinpocetine-cyclodextrin-tartaric acid complexes (VP-CD-TA) were contrasted. The co-evaporation vinpocetine-β-cyclodextrin-tartaric acid loaded NLC (VP-β-CD-TA COE-loaded NLC) was obtained by emulsification ultrasonic dispersion method. VP-β-CD-TA COE-loaded NLC was suitably characterized for particle size, polydispersity index, zeta potential, entrapment efficiency and the morphology. The crystallization of drug in VP-CD-TA and NLC was investigated by differential scanning calorimetry (DSC). The in vitro release study was carried out at pH 1.2, pH 6.8 and pH 7.4 medium. New Zealand rabbits were applied to investigate the pharmacokinetic behavior in vivo. The VP-β-CD-TA COE-loaded NLC presented a superior physicochemical property and selected to further study. In the in vitro release study, VP-β-CD-TA COE-loaded NLC exhibited a higher dissolution rate in the pH 6.8 and pH 7.4 medium than VP suspension and VP-NLC. The relative bioavailability of VP-β-CD-TA COE-loaded NLC was 592% compared with VP suspension and 92% higher than VP-NLC. In conclusion, the new formulation significantly improved bioavailability of VP for oral delivery, demonstrated a perspective way for oral delivery of poorly water-soluble drugs.

Nanostructured lipid carrier surface modified with Eudragit RS 100 and its potential ophthalmic functions

This study was carried out to evaluate the ocular performance of a cationic Eudragit (EDU) RS 100-coated nanostructured lipid carrier (NLC). The genistein encapsulated NLC (GEN-NLC) was produced using the melt-emulsification technique followed by surface absorption of EDU RS 100. The EDU RS 100 increased the surface zeta potential from −7.46 mV to +13.60 mV, by uniformly forming a spherical coating outside the NLC surface, as shown by transmission electron microscopy images. The EDU RS 100 on the NLC surface effectively improved the NLC stability by inhibiting particle size growth. The obtained EDU RS 100-GEN-NLC showed extended precorneal clearance and a 1.22-fold increase in AUC (area under the curve) compared with the bare NLC in a Gamma scintigraphic evaluation. The EDU RS 100 modification also significantly increased corneal penetration producing a 3.3-fold increase in apparent permeability coefficients (Papp) compared with references. Draize and cytotoxicity testing confirmed that the developed EDU RS 100-GEN-NLC was nonirritant to ocular tissues and nontoxic to corneal cells. These results indicate that the NLC surface modified by EDU RS 100 significantly improves the NLC properties and exhibits many advantages for ocular use.

A novel gastro-floating multiparticulate system for dipyridamole (DIP) based on a porous and low-density matrix core: In vitro and in vivo evaluation

The study was aimed to develop a novel gastro-floating multiparticulate system based on a porous and low-density matrix core with excellent floatability. The gastro-floating pellets (GFP) were composed of a porous matrix core, a drug loaded layer (DIP and HPMC), a sub-coating layer (HPMC) and a retarding layer (Eudragit(®) NE 30D). The porous matrix cores were evaluated in specific. EC was chosen as the matrix membrane for its rigidity and minimal expansion to large extent. The porous matrix core was achieved by the complete release of the bulk water soluble excipient from the EC coated beads, and mannitol was selected as the optimal water soluble excipient. SEM photomicrographs confirmed the structure of porous matrix cores. The compositions of GFP were investigated and optimized by orthogonal array design. The optimized formulation could sustain the drug release for 12h and float on the dissolution medium for at least 12h without lag time to float. The pharmacokinetic study was conducted in beagle dogs, and the relative bioavailability of the test preparation was 193.11±3.43%. In conclusion, the novel gastro-floating pellets can be developed as a promising approach for the gastro-retentive drug delivery systems.

Low molecular weight heparin mediating targeting of lymph node metastasis based on nanoliposome and enzyme-substrate interaction.

The aim of our study is to develop a new function of low molecular weight heparin (LMWHEP) for targeting tumor metastatic lymph node based on LMWHEP-modified nanoliposome and LMWHEP-heparanase (HPA) interaction (LMWHEP-HPA). At First, LMWHEP-modified nanoliposomes (LMWHEP-LPs) were prepared by the electrostatic attraction and the physiochemical properties were evaluated. Then the effects of LMWHEP-HPA on the stability and drug release were investigated. In addition, the cellular uptake of LMWHEP-LPs was studied by using Hela, MCF-7, L929 and RAW264.7 cells. Finally, the targeting ability as well as the tissue distribution was examined in the mice model bearing Hela tumor lymph node metastasis. LMWHEP-LPs prepared had suitable physicochemical properties. The effect results of LMWHEP-HPA showed that LMWHEP coated on the surface of nanoliposome could be degraded by HPA. Compared with the unmodified-nanoliposome, the LMWHEP modification could improve the cellular uptake and increase the targeting ability to the metastatic lymph nodes according to LMWHEP-HPA. This study demonstrates LMWHEP is a highly promising polymer material for the targeting of tumor lymph node metastasis.

Injectable chitosan thermogels for sustained and localized delivery of pingyangmycin in vascular malformations

Pingyangmycin (PYM) is an effective drug to treat vascular malformations (VM), but can easily diffuse from the injection site, which will reduce its therapeutic effect and increase side effect. Our study was to evaluate PYM-loaded chitosan thermogels for sustained and localized embolization therapy. It was shown that in vitro release of PYM thermogels could be delayed up to 12 days. The results measured by MTT assay showed that PYM thermogels could inhibit proliferation and induce apoptosis of EA.hy926 cells in a concentration and time dependent manner. In vivo pharmacokinetics study demonstrated that compared with PYM injections, PYM thermogels had a better sustained delivery of PYM. Macroscopic observation and histological examination of rabbit ear veins displayed that after administration with PYM thermogels for 18 days, obvious venous embolization and inflammatory response could be found. These results indicate that PYM thermogels is likely to achieve excellent prospects for VM treatment.

Study on enhanced lymphatic exposure of polyamidoamin-alkali blue dendrimer for paclitaxel delivery and influence of the osmotic pressure on the lymphatic targeting

Abstract In this study, paclitaxel (PTX)-loaded polyamidoamin-alkali blue (PTX-P-AB) was prepared in order to investigate the intralymphatic targeting ability and anti-cancer effect after subcutaneous (s.c.) administration. The physicochemical properties and in vitro drug release were evaluated. The lymphatic drainage and lymph nodes (LNs) uptake were examined by pharmacokinetics and distribution recovery of PTX in plasma, LNs, injection site (IS) and tissues after s.c. injection in healthy mice and in tumor-bearing mice. The osmotic pressure of PTX-P-AB affecting the lymphatic targeting was studied. The anti-tumor activity of PTX-P-AB was investigated in mice bearing S180 metastatic tumors. Results showed that PTX-P-AB with suitable and stable physicochemical properties could be used for in vivo lymphatic studies, and displayed the more rapid lymphatic absorption, the higher AUC value in LNs, the longer LNs residence time and the higher metastasis-inhibiting rate compared with Taxol®. Enhanced lymphatic drainage from the IS and uptake into lymph by increasing the osmotic pressure of PTX-P-AB indicated that PTX-P-AB possesses the double function of lymphatic tracing and lymphatic targeting, and suggested the potential for the development of lymphatic targeting vectors and the lymphatic tracer for treatment and diagnosis.

Improved lymphatic targeting: effect and mechanism of synthetic borneol on lymph node uptake of 7-ethyl-10-hydroxycamptothecin nanoliposomes following subcutaneous administration

Abstract Borneol as a penetration enhancer is widely used in guiding other components through the biological barrier into the targeting organs or tissues. This study aimed at studying effect and mechanism of synthetic borneol (S-BO) on improving lymphatic-targeting ability of 7-ethyl-10-hydroxycamptothecin liposomes (SN-38-Lips) via increasing lymph node uptake. At first, SN-38-Lips prepared had appropriate particle distribution, drug loading property and compatible stability with S-BO. Both in vitro cellular uptake and in vivo fluorescence imaging showed that 2 and 5 mg/mL S-BO, especially 2 mg/mL S-BO, enhanced cytoplasmic fluorescence signal of SN-38-Lips in the macrophages based on phagocytosis effect. And high-intensity zone appeared in the paracortex and medulla of popliteal lymph node. SN-38-Lips were subcutaneously (s.c.) injected into the right footpad of KM rats in the dose of 4 mg/kg following s.c. injection of 1, 2 and 5 mg/mL BO suspension. The lymphatic pharmacokinetics were investigated to explore the promotion law of S-BO, and combined with tissue irritation to optimize S-BO concentrations. The results indicated that 2 mg/mL S-BO could reduce injection-site retention, and prolong residence time and increase uptake of lymph nodes, which would not cause inflammatory reaction of injection site. In conclusion, the present study may provide a basic study for improving lymphatic-targeting ability of SN-38-Lips by the S-BO regulation, and to be the helpful guidance for further study in lymphatic targeting of delivery system.