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PubMed2006

Extinction coefficient of gold nanoparticles with different sizes and different capping ligands.

Extinction coefficients of gold nanoparticles with core size ranging from approximately 4 to 40 nm were determined by high resolution transmission electron microscopy analysis and UV-vis absorption spectroscopic measurement. Three different types of gold nanoparticles were prepared and studied: citrate-stabilized nanoparticles in five different sizes; oleylamide-protected gold nanoparticles with a core diameter of 8 nm, and a decanethiol-protected nanoparticle with a diameter of around 4 nm. A linear relationship between the logarithms of extinction coefficients and core diameters of gold particles was found independent of the capping ligands on the particle surface and the solvents used to dissolve the nanoparticles. This linear relation may be used as a calibration curve to determine the concentration or average size of an unknown nanoparticle or nanoparticle-biomolecule conjugate sample.

Gold↗
PubMed2006

Inhibition of malarial topoisomerase II in Plasmodium falciparum by antisense nanoparticles.

New effective antimalarial agents are urgently needed due to increasing drug resistance of Plasmodium falciparum. Phosphorothioate antisense oligodeoxynucleotides (ODNs) silencing of malarial topoisomerase II gene have shown to possess promising features as anti malarial agents. In order to improve stability and to increase intracellular penetration, ODNs were complexed with the biodegradable polymer chitosan to form solid nanoparticles with an initial diameter of approximately 55 nm. The particle zetapotential depended on the chitosan/ODN mass ratio. Nanoparticles with mass ratio of 2:1 displayed a positive surface charge (+15 mV) whereas particles with 1:1 mass ratio were negatively charged (-20 mV). Additionally nanoparticles were found to protect ODNs from nuclease degradation. P. falciparum K1 strain was exposed to the chitosan/ODN-nanoparticles for 48 h in order to examine the effects of chitosan/antisense (AS) and chitosan/sense (S) oligodeoxynucleotide nanoparticles on malaria parasite growth. Both negatively and positively charged antisense nanoparticles as well as free antisense ODNs (in a final concentration of 0.5 microM) showed sequence specific inhibition compared with sense sequence controls. However, nanoparticles were much more sequence specific in their antisense effect than free ODNs. Nanoparticles with negative surface charge exhibited a significantly stronger inhibitory effect ( approximately 87% inhibition) on the parasite growth in comparison to the positive ones ( approximately 74% inhibition) or free ODNs ( approximately 68% inhibition). This is the first study demonstrating the susceptibility of P. falciparum to antisense nanoparticles.

Animals↗
PubMed2006

Formulation and cytotoxicity of doxorubicin nanoparticles carried by dry powder aerosol particles.

Regional drug delivery via dry powder inhalers offers many advantages in the management of pharmaceutical compounds for the prevention and treatment of respiratory diseases. In the present study, doxorubicin (DOX)-loaded nanoparticles were incorporated as colloidal drug delivery system into inhalable carrier particles using a spray-freeze-drying technique. The cytotoxic effects of free DOX, carrier particles containing blank nanoparticles or DOX-loaded nanoparticles on H460 and A549 lung cancer cells were assessed using a colorimetric XTT cell viability assay. The mean geometric carrier particle size of 10+/-4 microm was determined using confocal laser scanning microscopy. DOX-loaded nanoparticles had a particle size of 173+/-43 nm after re-dissolving of the carrier particles. Compared to H460 cells, A549 cells showed less sensitivity to the treatment with free DOX. The DOX-nanoparticles showed in both cell lines a higher cytotoxicity at the highest tested concentration compared to the blank nanoparticles and the free DOX. The cell uptake of free DOX and DOX delivered by nanoparticles was confirmed using confocal laser scanning microscopy. This study supports the approach of lung cancer treatment using nanoparticles in dry powder aerosol form.

Administration, Inhalation↗
PubMed2006

Long-term studies on the stability and oral bioavailability of cyclosporine A nanoparticle colloid.

The present study was geared at the long-term stability and the changes in oral bioavailability of CyA Eudragit S100 nanoparticles stabilized by suspending agents. CyA Eudragit S100 nanoparticle colloids were prepared by quasi-emulsion solvent diffusion technique and they were mixed with Xanthan gum to obtain suspended nanoparticle colloids. The suspended nanoparticle colloids were preserved at different temperatures for different period of time, as long as 18 months. During the storage period, the CyA concentration, particle size, pH and viscosity were determined. The results indicated that CyA concentration, particle size and viscosity of the colloids had no obvious change. However, the pH increased slightly from 5.5 to about 6.4. The results of bioavailability and pharmacokinetic study revealed that all formulations of nanoparticles showed higher C(max) and higher AUC(0-24) values than that of reference (Neoral). The relative bioavailability of S-CyA-S100 NP initial compared with Neoral was 162.8%. The C(max) and AUC(0-24) values of nanoparticle formulations at 12 and 18 months were both lower than that of the initial. The bioequivalency was suggested between the tested nanoparticle formulations at the initial and 12 months. It was deduced by surface analysis, TEM observation, in vitro release as well as the characteristics of Eudragit S100 that the decrease in bioavailability might be due to the pH change of the nanoparticle colloid.

Administration, Oral↗
PubMed2006

Nanoparticle encapsulation of emulsion droplets.

The overall aim of this study is to coat emulsion droplets with nanoparticles using a simple heterocoagulation process in aqueous dispersion and determine: the adsorption behavior and interfacial layer microstructure, droplet physical stability against flocculation and coalescence, and the release profile of a model lipophilic molecule (dibutylphtalate (DBP)) from within the droplets. Polydimethylsiloxane (PDMS) droplets were used as a model emulsion due to their colloidal stability in the absence of added stabilisers. Aerosil type silica nanoparticles with different hydrophobicity levels were used as the model nanoparticles. The adsorption behavior of silica nanoparticles at the droplet-water interface was studied using adsorption isotherms and SEM imaging. Adsorption of hydrophilic nanoparticles is weakly influenced by pH, but significantly influenced by salt addition, whereas for hydrophobically modified nanoparticles a balance of hydrophobic and electrostatic forces controls adsorption over a wide range of pH and salt concentrations. The coalescence kinetics (determined under coagulation conditions at high salt concentration) and the physical structure of coalesced droplets were determined from optical microscopy. Adsorbed layers of hydrophilic nanoparticles introduced a barrier to coalescence of approximately 1kT and form kinetically unstable droplet networks at high salt concentrations. The highly structured and rigid adsorbed layers significantly reduce coalescence kinetics. Significant sustained release of DBP can be achieved using rigid layers of hydrophobic silica nanoparticles at the interface. Activation energies for release are in the range 580-630 kJ mol(-1), 10 times higher than for barriers introduced by Pluronic stabilisers.

Adsorption↗
PubMed2006

Improved bioavailability of orally administered mifepristone from PLGA nanoparticles.

The objective of this study was to prepare an oral dosage formulation of mifepristone that will improve the oral bioavailability of mifepristone and sustain the release of mifepristone for at least 3 days to effectively control reproduction, especially in coyotes. Nanoparticles containing mifepristone were prepared from dl-lactide/glycolide copolymers (PLGA). Encapsulation efficiency of the nanoparticles was determined by HPLC. In vitro release study was done in 30% isopropyl alcohol in water. In vivo bioavailability study was performed in male rats. Mifepristone and drug-loaded 50/50 PLGA, M(W) 4.4kDa, nanoparticles (equivalent to 100mg/kg mifepristone) were administered orally to rats. The concentration of mifepristone in serum at different time intervals was determined by HPLC. The average sizes of 50/50 PLGA (M(W) 4.4 and 13kDa) nanoparticles containing mifepristone were 516 and 468nm, respectively. The drug encapsulation efficiency was 75.6% at 20% drug loading in 50/50 PLGA (M(W) 4.4kDa) nanoparticles. In vitro cumulative release of mifepristone from the 50/50 PLGA (M(W) 4.4 and 13kDa) nanoparticles with 20% drug loading was 60% and 48% in 72h, respectively. In vivo studies in rats demonstrated that PLGA-1A-nanoparticles increase the bioavailability of mifepristone. We are currently using the nanoparticles containing mifepristone for efficacy studies in coyotes.

2-Propanol↗
PubMed2006

Evaluation and modification of N-trimethyl chitosan chloride nanoparticles as protein carriers.

N-Trimethyl chitosan chloride (TMC) nanoparticles were prepared by ionic crosslinking of TMC with tripolyphosphate (TPP). Two model proteins with different pI values, bovine serum albumin (BSA, pI=4.8) and bovine hemoglobin (BHb, pI=6.8), were used to investigate the loading and release features of the TMC nanoparticles. TMC samples with different degrees of quaternization were synthesized to evaluate its influence on the physicochemical properties and release profiles of the nanoparticles. Sodium alginate was used to modify the TMC nanoparticles to reduce burst release. The results indicated that the TMC nanoparticles had a high loading efficiency (95%) for BSA but a low one (30%) for BHb. The particle size and zeta potential were significantly affected by the BSA concentration but not by the BHb concentration. Nanoparticles of TMC with a lower degree of quaternization showed an increase in particle size, a decrease in zeta potential and a slower drug-release profile. As for the alginate-modified nanoparticles, a smaller size and lower zeta potential were observed and the burst release of BSA was reduced. These studies demonstrated that TMC nanoparticles are potential protein carriers, and that their physicochemical properties and release profile could be optimized by means of various modifications.

Alginates↗
PubMed2006

Imidazolyl-PEI modified nanoparticles for enhanced gene delivery.

The derivatives of polyethylenimine (PEI 25 and 750kDa) were synthesized by partially substituting their amino groups with imidazolyl moieties. The series of imidazolyl-PEIs thus obtained were cross-linked with polyethylene glycol (PEG) to get imidazolyl-PEI-PEG nanoparticles (IPP). The component of hydrophobicity was introduced by grafting the lauryl groups in the maximal substituted IPP nanoparticles (IPPL). The nanoparticles were characterized with respect to DNA interaction, hydrodynamic diameter, zeta potential, in vitro cytotoxicity and transfection efficiency on model cell lines. The IPP and IPPL nanoparticles formed a loose complex with DNA compared to the corresponding native PEI, leading to more efficient unpackaging of DNA. The DNA loading capacity of IPP and IPPL nanoparticles was also lower compared to PEI. The imidazolyl substitution improved the gene delivery efficiency of PEI (750kDa) by nine- to ten-fold and PEI (25kDa) by three- to four-fold. At maximum transfection efficiency, the zeta potential of nanoparticles was positive after forming a complex with DNA. The maximum level of reporter gene expression was mediated by IPPL nanoparticles in both the series. The cytotoxicity, another pertinent problem with cationic polymers, was also negligible in case of IPP and IPPL nanoparticles.

Active Transport, Cell Nucleus↗
PubMed2006

Poly(trimethylene carbonate) and monomethoxy poly(ethylene glycol)-block-poly(trimethylene carbonate) nanoparticles for the controlled release of dexamethasone.

In this study, single emulsion and salting out methods were employed to prepare poly(trimethylene carbonate) (PTMC) and monomethoxy poly(ethylene glycol)-block-poly(trimethylene carbonate) (mPEG-PTMC) nanoparticles. Well-defined nanoparticles of a PTMC homopolymer were prepared using poly(vinyl alcohol) (PVA) as a stabilizer. The average size of the nanoparticles can be adjusted by varying the stirring speed and polymer concentration. These particles can be readily freeze-dried and redispersed, with little influence on the average particle size and size distribution. Nanoparticles based on amphiphilic mPEG-PTMC can be prepared without an additional stabilizer. In this case, the size of the obtained nanoparticles did not vary much and ranged between 95 and 120 nm. These nanoparticles could be freeze-dried and redispersed as well. Using the salting out method, dexamethasone was loaded into PTMC and mPEG-PTMC nanoparticles at a highest efficiency of respectively 54% and 88%. With the single emulsion method, the loading efficiencies were, respectively, 91% and 72%. These drug-loaded particles were stable in time for at least 20 weeks. It was found that the release of dexamethasone from these nanoparticles was diffusion-controlled and could be sustained for 14 to 60 days. Depending on the nature of the polymer employed and the preparation method, dexamethasone diffusion coefficients varied between 4.8 x 10(-18) and 22.6 x 10(-18) cm(2)/s.

Anti-Inflammatory Agents↗
PubMed2006

In vitro toxicity of silica nanoparticles in human lung cancer cells.

The cytotoxicity of 15-nm and 46-nm silica nanoparticles was investigated by using crystalline silica (Min-U-Sil 5) as a positive control in cultured human bronchoalveolar carcinoma-derived cells. Exposure to 15-nm or 46-nm SiO(2) nanoparticles for 48 h at dosage levels between 10 and 100 microg/ml decreased cell viability in a dose-dependent manner. Both SiO(2) nanoparticles were more cytotoxic than Min-U-Sil 5; however, the cytotoxicities of 15-nm and 46-nm silica nanoparticles were not significantly different. The 15-nm SiO(2) nanoparticles were used to determine time-dependent cytotoxicity and oxidative stress responses. Cell viability decreased significantly as a function of both nanoparticle dosage (10-100 microg/ml) and exposure time (24 h, 48 h, and 72 h). Indicators of oxidative stress and cytotoxicity, including total reactive oxygen species (ROS), glutathione, malondialdehyde, and lactate dehydrogenase, were quantitatively assessed. Exposure to SiO(2) nanoparticles increased ROS levels and reduced glutathione levels. The increased production of malondialdehyde and lactate dehydrogenase release from the cells indicated lipid peroxidation and membrane damage. In summary, exposure to SiO(2) nanoparticles results in a dose-dependent cytotoxicity in cultural human bronchoalveolar carcinoma-derived cells that is closely correlated to increased oxidative stress.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2006

Preparation and encapsulation of highly fluorescent conjugated polymer nanoparticles.

A facile method has been developed to prepare aqueous dispersions of encapsulated conjugated polymer nanoparticles exhibiting high fluorescence brightness. Salient features of the nanoparticles include their small diameter and spherical morphology. Encapsulation of the nanoparticles with a silica shell reduces the rate of photooxidation and allows facile attachment of functional groups for subsequent bioconjugation and nanoparticle assembly. Functionalization of the nanoparticle with amine groups followed by the addition of Au nanoparticles resulted in the formation of nanoparticle assemblies, as evidenced by the efficient quenching of the conjugated polymer fluorescence by the Au nanoparticles.

Fluorescent Dyes↗
PubMed2006

Properties of polysaccharides grafted on nanoparticles investigated by EPR.

The in vivo fate of nanoparticles developed as drug delivery systems is influenced by the surface characteristics of the colloidal particles. In the present work, surface characteristics of a series of poly(isobutylcyanoacrylate) nanoparticles prepared by redox radical emulsion polymerization with polysaccharides of different molecular weight and nature were characterized by EPR. To this aim, a spin label was grafted on the polysaccharide chains after synthesis of the nanoparticles. The percentage of label showing fast movements was evaluated from EPR spectra which were analyzed according to the Kivelson theory. The results showed that mobility depended on temperature, type, and molecular weight of the polysaccharides. Differences between nanoparticles appeared with low-molecular-weight polysaccharides, while over a defined molecular weight which depended on the nature of the polysaccharide, the spin label behaved almost the same way in the different types of nanoparticles. Paradoxically, the percentage of fast moving label was the highest when linked to the shortest chitosan, which was the most rigid polysaccharide tested in this study. Thus, it was concluded that the apparent mobility of the polysaccharide evaluated by the EPR method depended on the capacity of the polysaccharide chains to fold making possible hydrophobic interactions between the label and the nanoparticle core. The transition between the unfolded-folded regiment depended on the molecular weight and on the nature of the polysaccharide. Results of this study may be useful to improve the understanding of the nanoparticle interactions with blood proteins and complement which in turn influence the in vivo fate of nanoparticles used as drug delivery systems.

Cyanoacrylates↗
PubMed2006

Supramolecular assembly of cyclodextrin-based nanoparticles on solid surfaces for gene delivery.

In this work, a new approach for surface-mediated gene delivery based on inclusion complex formation between the solid surface and delivery vehicles is presented. beta-Cyclodextrin (CD) molecules form high-affinity inclusion complexes with adamantane. This complexation ability was used to specifically immobilize beta-CD-modified poly(ethylenimine) (CD-PEI) nanoparticles on adamantane- (AD-) modified self-assembled monolayers. To investigate the nanoparticle/surface interaction, CD-PEI-based and PEI-based nanoparticles were passed through a surface plasmon resonance flow cell containing the monolayers. CD-PEI nanoparticles are specifically immobilized on the chip surface by cyclodextrin-adamantane inclusion complex formation. Minimal nanoparticle adsorption was detected with PEI-based nanoparticles or on control surfaces. Competition studies with free cyclodextrins reveal that the multivalent interactions between CD-PEI nanoparticles and the adamantane-modified surface results in significantly higher binding affinity than single cyclodextrin-adamantane complexes. Immobilized nanoparticles were characterized by atomic force microscopy and quantified by fluorescence assay. Thus, the ability of CD-PEI nanoparticles to form inclusion complexes can be exploited to attain specific, high-affinity loading of delivery vehicles onto solid surfaces.

Adamantane↗
PubMed2006

Immunostimulatory properties of CpG-oligonucleotides are enhanced by the use of protamine nanoparticles.

The aim of this paper was to investigate if the immunostimulatory effects of CpG-oligonucleotides (CpG-ODN) can be enhanced by the use of biodegradable protamine nanoparticles (proticles). We analyzed size, surface charge, and morphology of protamine nanoparticles containing CpG-ODN with photon correlation spectroscopy and transmission electron microscopy. Immunostimulatory effects of these nanoparticles on B cells, plasmacytoid dendritic cells (PDC), peripheral blood mononuclear cells, and whole blood were studied. Cytokine production, activation of the cells in terms of upregulation of surface molecules and uptake of nanoparticles were examined. We found that the use of protamine nanoparticles significantly increased (20-fold) CpG-ODN mediated interferon (IFN)-alpha production of PDC. ODN uptake in PDC was only marginally enhanced. CpG-ODN mediated IP-10 production in whole blood was strongly enhanced by the use of nanoparticles. Apart from a slight increase in CpG-ODN-induced interleukin (IL)-6 production in B cells, other parameters like the CpG-mediated activation of B cells and PDC as well as tumor necrosis factor (TNF)-alpha production of PDC remained largely unchanged. The use of control ODN indicated that the protamine nanoparticles themselves have no immunostimulatory properties. These results strongly support the use of particulate delivery systems like biodegradable protamine nanoparticles for the development of CpG-ODN-based therapeutics.

Adjuvants, Immunologic↗
PubMed2006

Vascular targeted nanoparticles for imaging and treatment of brain tumors.

PURPOSE: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. EXPERIMENTAL DESIGN: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. RESULTS: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. CONCLUSIONS: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.

Angiography↗
PubMed2006

Transcription of giant DNA complexed with cationic nanoparticles as a simple model of chromatin.

We prepared complexes of giant double-stranded DNA with cationic nanoparticles of 10-40 nm in diameter as an artificial model of chromatin and characterized the properties of changes in their higher-order conformation. We measured the changes in transcriptional activity that accompanied the DNA conformational transitions. Complete inhibition was found at excess concentrations of nanoparticles. In contrast, at intermediate stages of DNA binding with nanoparticles, the transcription activity of DNA survived, and this strongly depended on the size of the nanoparticles. For large nanoparticles of 40 nm, a decrease in transcriptional activity can be caused by the addition of only a small amount of nanoparticles. On the other hand, there was almost no inhibition of DNA transcriptional activity with the addition of small nanoparticles (10 nm) until very high concentrations, even under conditions that induced DNA compaction as revealed by single-DNA observation. At higher concentrations of 10-nm nanoparticles, DNA transcription activity decreased abruptly until it was completely inhibited. These results are discussed in relation to the actual size of the histone core, together with the mechanism of switching of transcriptional activity in eukaryotic cells.

Bacteriophage T4↗
PubMed2006

[Effect of nanoparticle with vascular endothelial growth factor gene transferred into ischemic myocardium: experiment with rabbits].

OBJECTIVE: To evaluate the possibility and efficiency of nanoparticle as a new vector in vascular endothelial growth factor (VEGF) gene transference, and investigate the efficacy of direct gene transfer of nanoparticle with VEGF(165) gene into ischemic myocardium. METHODS: Nanoparticle-VEGF (Np/VEGF) complex was prepared with poly (D, L-lactide-co-glycolide) (PLGA) loading VEGF(165) gene and the envelopment efficiency and size of the complex were determined. The Np/VEGF was transfected into the cultured myocardial cells, RT-PCR and ELISA were used to evaluate the transfection of VEGF. Suspension of Np/VEGF was injected into the myocardial tissue of 4 rabbits. 96 hours after operation myocardial tissue was obtained, made into sections, and observed with electron microscope. New Zealand White rabbits underwent thoracotomy followed by ligation of left anterior descending coronary artery to establish ischemic models. The New Zealand White rabbits were divided into 3 groups: Np/VEGF group (n = 12, nanoparticle with VEGF(165) were injected into the cordial myocardium), blank plasmid group (n = 12, injected with blank VEGF(165) plasmid), and control group (n = 8, injected with normal saline). Ultrasonography and immunohistochemistry with factor VIII related antigen were conducted to evaluate the cardiac function and the collateral circulation of the occluded artery. One month later the rabbits were killed to observe the vascularization of capillaries in the ischemic myocardium. RESULTS: The envelopment efficiency of the Np/VEGF complex thus prepared, 50 - 300 nm in size, were 1.87% y. RT-PCR and ELISA showed that VEGF gene had been successfully transfected into myocardial cells by the nanoparticles. A great number of nanoparticles were observed in the myocardial cytoplasm and nuclei. One month after operation, the ventricular wall motor amplitude of the Np/VEGF group was 1.87 mm +/- 0.32 mm, significantly larger than those of the blank plasmid group (1.59 mm +/- 0.24 mm, P < 0.05) and control group (0.93 mm +/- 0.40 mm, P < 0.05); and the left ventricular ejection fraction of the Np/VEGF group was 60% +/- 10%, significantly higher than those of the blank plasmid group (50% +/- 6%, P < 0.05) and control group (40% +/- 8%, P < 0.05). The capillary density at low power field (x 100) of the Np/VEGF group was 57 +/- 12, significantly higher than those of the VEGF group (41 +/- 14) and control group (24 +/- 8). CONCLUSION: Nanoparticle can act as a vector to transfect specific gene in vitro and in vivo. Direct gene transfer of nanoparticle with DNA encoding VEGF into the ischemic rabbit myocardium can increase capillary number; therefore it may be a novel therapeutic approach for myocardial ischemia.

Animals↗
PubMed2006

[The pharmacokinetics of FK506 and its nanoparticles in aqueous humor of rabbits].

OBJECTIVE: To investigate the pharmacokinetics of FK506 and its nanoparticles in aqueous humor of rabbits applied with eye drops or subconjunctiva injections. METHODS: 42 New Zealand albino rabbits were divided into 2 groups. (1) Nanoparticle solution containing 10 microg FK506 was injected into subconjunctiva or dropped on conjunctival sac of rabbits (68 eyes in 34 cases). (2) Eye drops containing 20 or 40 microg FK506 without nanoparticles were dropped on conjunctival sac of rabbits (16 eyes in 8 cases). Aqueous humor was collected at different times after local administration and FK506 concentrations were measured by ELISA. Ocular pharmacokinetic parameters of FK506 were calculated by 3p87 software. RESULTS: In the solution containing nanoparticle, the effective FK506 concentration in aqueous humor could be kept up to 16 h in eye drops group. The range of FK506 concentration was between (15.50 +/- 3.39) - (2.59 +/- 0.83) ng/ml. FK506 in aqueous humor can be maintained for 96 h by injecting into subconjunctiva and FK506 concentration were between (9.62 +/- 2.19) - (2.60 +/- 0.21) ng/ml from 6 - 96 h. T(max) and C(max) in eye drops were (1.25 +/- 0.50) h and (15.52 +/- 2.37) ng/ml respectively; while T(max) and C(max) in subconjunctiva injection were (64.00 +/- 13.86) h and (10.16 +/- 1.37) ng/ml respectively. Each AUC(0-->t) was (152.44 +/- 16.74) ng.ml(-1).h(-1) and (612.48 +/- 54.39) ng.ml(-1).h(-1) respectively; each Ka was 3.790 +/- 0.730 and 0.040 +/- 0.004 respectively; and each MRT was (8.20 +/- 1.28) h and (58.53 +/- 5.42) h respectively. In the eye drops containing 20 microg or 40 microg FK506 but without nanoparticles applied in conjunctival sac of rabbits, all effective FK506 concentrations in aqueous humor could not be kept over 4 h. T(max) was 1 h and C(max) was (18.93 +/- 6.95) ng/ml in 20 microg FK506, while in 40 microg FK506 T(max) was 2h and C(max) was (28.33 +/- 1.31) ng/ml. CONCLUSION: Solution with FK506 nanoparticle dropping onto the eye or injecting into subconjunctiva could be sustained in rabbit aqueous humor for a longer time than non-nanoparticle FK506 solution, while with injecting of nanoparticle FK506 solution it could be detected with a relative low but longer effective concentration.

Administration, Topical↗