Clinical Anti-aging Efficacy of Propolis Polymeric Nanoparticles Prepared by a Temperature-induced Phase Transition Method.

BACKGROUND: Collagen forms a dermal matrix in the skin. Biosynthesis and decomposition of collagen are the major processes in skin aging. Propolis is rich in flavonoids and phenolic compounds, which are known to be effective in preventing skin aging, including the enhancement of fibroblast proliferation, activation, and growth capacity. OBJECTIVES: The aim of this study was to develop a poorly soluble propolis extract as an active ingredient in cosmetic products for anti-aging efficacy. METHODS & RESULTS: Polymeric nanoparticles containing propolis extract, polyethylene glycol 400, and poloxamer 407 were prepared via a temperature-induced phase transition method. The particle size of the polymeric nanoparticles was approximately 20.75 nm. The results of an in vitro procollagen type I carboxy-terminal peptide assay and a matrix metalloproteinase-1 inhibition assay showed that the polymeric nanoparticles increased collagen production by 19.81%-24.59% compared to blank (p < 0.05), and significantly reduced intracellular collagenase activity by 7.46%-31.52% compared to blank (p < 0.05). In a clinical trial, polymeric nanoparticles in a cosmetic formulation were applied around the eyes of 24 female subjects for 8 weeks. Five skin parameters were significantly improved after the application of the test ampoule. Visual evaluation using the Global Photo Damage Score showed a significant reduction in wrinkles after the application of the test ampoules (p < 0.001). CONCLUSIONS: This study outlines the development of stable polymeric nanoparticles containing poorly soluble propolis in a cosmetic formulation, and its efficacy in wrinkle improvement. The developed polymeric nanoparticles were effective for alleviating wrinkles and can be used for pharmaceutical applications that utilize propolis as antiseptic, anti-inflammatory, antimycotic, antifungal, antibacterial, antiulcer, anticancer, and immunomodulatory agents.

Development of Polymeric Micelles of Oleanolic Acid and Evaluation of Their Clinical Efficacy.

Oleanolic acid has been used only as a subsidiary agent in cosmetic products. The aim of the study is to show the effect of oleanolic acid as an active ingredient for the alleviation of wrinkles in humans and to develop a polymeric micelle formulation that enables poorly soluble oleanolic acid to be used as a main ingredient in cosmetic products for reducing wrinkles. The solubility of oleanolic acid was evaluated in solubilizers, surfactants, and polymers. The particle sizes and shapes of polymeric micelles containing oleanolic acid were evaluated by electrophoretic light scattering spectrophotometer and scanning electron cryomicroscopy. Encapsulation efficiency and skin permeation were measured by HPLC. Stability of the polymeric micelles stored at 40 °C for 3 months was evaluated by visual observation, particle size measurement, and oleanolic acid content measurement. Polymeric micelles in final product ampoule form were applied around the eyes of 23 female subjects for 8 weeks. Five skin parameters were evaluated by optical profilometry every 4 weeks for 8 weeks. In addition, professionals made visual observations of the skin and a human skin irritation study was conducted. Polymeric micelles of oleanolic acid with a particle size of less than 100 nm were prepared using Capryol 90® and poloxamer. The skin permeation rate of the oleanolic acid in the polymeric micelles was higher than that in the other solutions made of oleanolic acid dispersed in 2 different surfactants. No significant changes in particle size, color, or oleanolic acid content were observed, and the polymeric micelles stored at 40 °C for 3 months did not undergo phase separation. After 8 weeks of application, skin irritation had not developed and all five parameters evaluated by optical profilometry as well as the visual evaluation scores were significantly improved. This study showed that the polymeric micelles of oleanolic acid prepared in this study were stable and effective at alleviating wrinkles in humans as the principal active ingredient. Based on these findings, it is expected that polymeric micelles of oleanolic acid can be widely used in cosmetic applications.

Marbofloxacin-encapsulated microparticles provide sustained drug release for treatment of veterinary diseases.

Fluoroquinolone antibiotics with concentration-dependent killing effects and a well-established broad spectrum of activity are used commonly to treat infectious diseases caused by bacteria. However, frequent and excessive administration of these antibiotics is a serious problem, and leads to increased number of drug-resistant bacteria. Thus, there is an urgent need for novel fluoroquinolone antibiotic formulations that minimize the risk of resistance while maximizing their efficacy. In this study, we developed intramuscularly injectable polymeric microparticles (MPs) that encapsulated with marbofloxacin (MAR) and were composed of poly(D,L-lactide-co-glycolic acid) (PLGA) and poloxamer (POL). MAR-encapsulated MP (MAR-MP) had a spherical shape with particle size ranging from 80 µm to 120 µm. Drug loading efficiency varied from 55 to 85% (w/w) at increasing amount of hydrophilic agent, POL. Drug release from MAR-MP demonstrated a significant and sustained increase at increased ratios of POL to PLGA. These results indicate that MAR-MP is an improved drug delivery carrier for fluoroquinolone antibiotics, which can reduce the number of doses needed and sustain a high release rate of MAR for 2-3 days. As a novel and highly effective drug delivery platform, MAR-MP has great potential for use in a broad range of applications for the treatment of various veterinary diseases.

Ethosomes and Transfersomes for Topical Delivery of Ginsenoside Rhl from Red Ginseng: Characterization and In Vitro Evaluation.

Red ginseng (the steamed root of Panax ginseng C. A. Mayer), which contains ginsenosides as its main constituents, is frequently used to treat tumor, inflammation, diabetes, stress and acquired immunodeficiency syndrome in Asian countries. Ginsenoside Rhl, a bacterial metabolite of ginsenoside Rgl, is a protopanaxatriol type of ginsenosides. Liposomes do not deeply penetrate the skin and remain confined to the stratum corneum.Thus, new vesicular colloidal carriers such as ethosomes and transfersomes have been developed as an enhanced type of liposomes, recently. The aim of this study was to improve the topical delivery of ginsenoside Rhl isolated from red ginseng employing new vesicular system of ethosomes and transfersomes compared to conventional liposome. Characterization of ginsenoside Rhl-loaded vesicles were prepared and evaluated for particle size, zeta potential, entrapment efficiency (% EE), and transmission electron microscopy (TEM) studies. In addition, skin permeation profile was obtained using frantz diffusion cells and rat dorsal skin treated with ethosome and transfersome compared with conventional iposome. The size of vesicles range from 108.5 to 322.9 nm, and negatively charged from -20.95 to -31.37 mV. The % EE of ginsenoside Rh1 was obtained between 45.0 to 65.0%. Transfersomes provided a significantly higher skin permeation of ginsenoside Rhl compared to ethosome and conventional liposome. Therefore, based on the current study, ginsenoside Rhl-loaded transfersomes can act as a topical therapeutic effects potential.

Gold cluster-labeled thermosensitive liposmes enhance triggered drug release in the tumor microenvironment by a photothermal effect.

Stimulus-triggered drug release based on the liposomal drug delivery platform has been studied vigorously to increase drug release at the target site. Although the delivery system has been developed, an effective carrier system is needed to achieve effective therapeutic efficacy. Therefore, we focused on the development of gold cluster bound thermosensitive liposomes (G-TSL), which are capable of triggered drug release when stimulated by external near-infrared (NIR) irradiation in the tumor microenvironment. The size of doxorubicin (DOX)-loaded G-TSL (DOX/G-TSL) was 171.5 ± 8.3 nm, and the efficiency of DOX encapsulation was up to 90%. The release of DOX from DOX/G-TSL was increased 70% by NIR irradiation (1.50 W/cm(2) for 0.5 min) compared to non-gold-coated TSL. Consequentially, the gold cluster on the TSL enabled the light-controlled DOX release through the photothermal conversion of the energy of NIR-absorbed light, leading to membrane destabilization. Cell cytotoxicity of DOX/G-TSL was also increased by their NIR irradiation-triggered DOX release compared to non-NIR-irradiated DOX/G-TSL. In addition, we demonstrated the therapeutic efficacy of DOX/G-TSL against the MDA-MB-231 tumor model. The NIR-irradiated DOX/G-TSL treatment showed greater therapeutic efficacy than that of the non-NIR-irradiated DOX/G-TSL and control (p<0.05). Taken together, DOX/G-TSL has the potential for remote-triggered drug release upon stimulation with NIR irradiation in the tumor microenvironment, and may be applied to a broad range of photothermal-based disease therapies.

Therapeutic efficacy of doxorubicin delivery by a CO2 generating liposomal platform in breast carcinoma.

Drug delivery using thermosensitive liposomes (TSL) has significant potential for tumor drug targeting and can be combined with local hyperthermia to trigger drug release. Although TSL-mediated drug delivery can be effective by itself, we developed doxorubicin (DOX)-containing CO2 bubble-generating TSL (TSL-C) that were found to enhance the antitumor effects of DOX owing to the synergism between burst release of drug and hyperthermia-induced CO2 generation. An ultrasound imaging system was used to monitor hyperthermia-induced CO2 generation in TSL-C and the results revealed that hyperthermia-induced CO2 generation in TSL-C led to increased DOX release compared to that observed for non-CO2-generating TSL. Moreover, TSL-C significantly inhibited the tumor growth in MDA-MB-231 tumor-bearing mice compared to TSL (p<0.004). Taken together, we demonstrated that the TSL-C platform increased the therapeutic efficacy of cancer chemotherapy and showed the applicability of this approach to increase drug release within the tumor microenvironment. As a novel and highly effective drug delivery platform, TSL-C has great potential for use in a broad range of applications for the treatment of various human diseases. STATEMENT OF SIGNIFICANCE: We have developed a novel method for drug release from liposomes by gas (CO2) generation in tumor microenvironment. In addition, we demonstrate therapeutic efficacy in breast carcinoma. CO2-generated liposomal doxorubicin is a novel and highly attractive delivery system for anticancer drug with the potential for broad applications in human disease.

Preparation and evaluation of poly(2-hydroxyethyl aspartamide)-hexadecylamine-iron oxide for MR imaging of lymph nodes.

The purpose of this study was to synthesize biocompatible poly(2-hydroxyethyl aspartamide)-C16-iron oxide (PHEA-C16-iron oxide) nanoparticles and to evaluate their efficacy as a contrast agent for magnetic resonance imaging of lymph nodes. The PHEA-C16-iron oxide nanoparticles were synthesized by coprecipitation method. The core size of the PHEA-C16-iron oxide nanoparticles was about 5 to 7 nm, and the overall size of the nanoparticles was around 20, 60, and 150 nm in aqueous solution. The size of the nanoparticles was controlled by the amount of C16. The 3.0-T MRI signal intensity of a rabbit lymph node was effectively reduced after intravenous administration of PHEA-C16-iron oxide with the size of 20 nm. The in vitro and in vivo toxicity tests revealed the high biocompatibility of PHEA-C16-iron oxide nanoparticles. Therefore, PHEA-C16-iron oxide nanoparticles with 20-nm size can be potentially useful as T2-weighted MR imaging contrast agents for the detection of lymph nodes.

Biodistribution of newly synthesized PHEA-based polymer-coated SPION in Sprague Dawley rats as magnetic resonance contrast agent.

OBJECTIVES: The purpose of this study was to observe the pharmacokinetic behavior of newly synthesized biocompatible polymers based on polyhydroxyethylaspartamide (PHEA) to be used to coat an iron oxide core to make superparamagnetic iron oxide nanoparticles (SPION). MATERIALS AND METHODS: The isotopes [(14)C] and [(59)Fe] were used to label the polymer backbone (CLS) and iron oxide core (FLS), respectively. In addition, unradiolabeled cold superparamagnetic iron oxide nanoparticles (SPION/ULS) were synthesized to characterize particle size by dynamic light scattering, morphology by transmission electron microscopy, and in vivo magnetic resonance imaging (MRI). CLS and FLS were used separately to investigate the behavior of both the synthesized polymer and [Fe] in Sprague Dawley (SD) rats, respectively. Because radioactivity of the isotopes was different by ß for CLS and γ for FLS, synthesis of the samples had to be separately prepared. RESULTS: The mean particle size of the ULS was 66.1 nm, and the biodistribution of CLS concentrations in various organs, in rank order of magnitude, was liver > kidney > small intestine > other. The biodistribution of FLS concentrations was liver > spleen > lung > other. These rank orders show that synthesized SPION mainly accumulates in the liver. The differences in the distribution were caused by the SPION metabolism. Radiolabeled polymer was metabolized by the kidney and excreted mainly in the urine; [(59)Fe] was recycled for erythrocyte production in the spleen and excreted mainly in the feces. The MR image of the liver after intravenous injection demonstrated that [Fe] effectively accumulated in the liver and exhibited high-contrast enhancement on T2-weighted images. CONCLUSION: This newly synthesized, polymer-coated SPION appears to be a promising candidate for use as a liver-targeted, biocompatible iron oxide MR imaging agent.

Gd(III)-DOTA-modified sonosensitive liposomes for ultrasound-triggered release and MR imaging.

Ultrasound-sensitive (sonosensitive) liposomes for tumor targeting have been studied in order to increase the antitumor efficacy of drugs and decrease the associated severe side effects. Liposomal contrast agents having Gd(III) are known as a nano-contrast agent system for the efficient and selective delivery of contrast agents into pathological sites. The objective of this study was to prepare Gd(III)-DOTA-modified sonosensitive liposomes (GdSL), which could deliver a model drug, doxorubicin (DOX), to a specific site and, at the same time, be capable of magnetic resonance (MR) imaging. The GdSL was prepared using synthesized Gd(III)-DOTA-1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid. Sonosensitivity of GdSL to 20-kHz ultrasound induced 33% to 40% of DOX release. The relaxivities (r1) of GdSL were 6.6 to 7.8 mM-1 s-1, which were higher than that of MR-bester®. Intracellular uptake properties of GdSL were evaluated according to the intensity of ultrasound. Intracellular uptake of DOX for ultrasound-triggered GdSL was higher than that for non-ultrasound-triggered GdSL. The results of our study suggest that the paramagnetic and sonosensitive liposomes, GdSL, may provide a versatile platform for molecular imaging and targeted drug delivery.

Enhancement of the targeting capabilities of the Paclitaxel-loaded pluronic nanoparticles with a glycol chitosan/heparin composite.

An enhancement of tumor-targeting capability was demonstrated with paclitaxel (PTX)-loaded Pluronic nanoparticles (NPs) with immobilized glycol chitosan and heparin. The PTX-loaded Pluronic NPs were prepared as described in our previous report by means of a temperature-induced phase transition in a mixture of Pluronic F-68 and liquid polyethylene glycol (PEG; molecular weight: 400) containing PTX. The liquid PEG is used as the solubilizer of PTX, and Pluronic F-68 is the polymer that encapsulates the PTX. The glycol chitosan and heparin were immobilized on the surface of the Pluronic NPs in an aqueous medium, and a powdery form of the glycol chitosan/heparin immobilized Pluronic NPs (composite NPs) was obtained by freeze-drying. Field emission scanning electron microscopy and a particle size analyzer were used to observe the morphology and size distribution of the prepared NPs. To apply the composite NPs as a delivery system for the model anticancer drug PTX, the release pattern and pharmacokinetic parameters were observed, and the tumor growth was monitored by injecting the composite NPs into the tail veins of tumor-bearing mice. An enhancement of tumor-targeting capability of NPs was verified by using noninvasive live animal imaging technology to observe the time-dependent excretion profile, the in vivo biodistribution, circulation time, and the tumor-targeting capability of composite NPs.

Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shell-corona micelles with shell-specific redox-responsive cross-links.

A robust core-shell-corona micelle bearing redox-responsive shell-specific cross-links was evaluated as a carrier of docetaxel (DTX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-phenylalanine) (PEG-PLys-PPhe) in the aqueous phase provided the three distinct functional domains: the PEG outer corona for prolonged circulation, the PLys middle shell for disulfide cross-linking, and the PPhe inner core for DTX loading. The shell cross-linking was performed by the reaction of disulfide-containing cross-linkers with Lys moieties in the middle shells. The shell cross-linking did not change the micelle size or the spherical morphology. The shell cross-linked micelles exhibited enhanced serum stability. The DTX release from the DTX-loaded disulfide cross-linked micelles (DTX-SSCLM) was facilitated by increasing the concentration of glutathione (GSH). At an intracellular GSH level, DTX release was facilitated due to the reductive cleavage of the disulfide cross-links in the shell domains. The in vivo tissue distribution and tumor accumulation of the DTX-SSCLM that were labeled with a near-infrared fluorescence (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DTX-SSCLM exhibited enhanced tumor specificity due to the prolonged stable circulation in blood and the enhanced permeation and retention (EPR) effect compared with the DTX-loaded non-cross-linked micelles (DTX-NCLM). The DTX-SSCLM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DTX and DTX-NCLM. The domain-specific shell cross-linking that is described in this work may serve as a useful guidance for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.

Glycol chitosan/heparin immobilized iron oxide nanoparticles with a tumor-targeting characteristic for magnetic resonance imaging.

We described the preparation of the glycol chitosan/heparin immobilized iron oxide nanoparticles (composite NPs) as a magnetic resonance imaging agent with a tumor-targeting characteristic. The iron oxide nanoseeds used clinically as a magnetic resonance imaging agent were immobilized into the glycol chitosan/heparin network to form the composite NPs. To induce the ionic interaction between the iron oxide nanoseeds and glycol chitosan, gold was deposited on the surface of iron oxide nanoseeds. After the immobilization of gold-deposited iron oxide NPs into the glycol chitosan network, the NPs were stabilized with heparin based on the ionic interaction between cationic glycol chitosan and anionic heparin. FE-SEM (field emission-scanning electron microscopy) and a particle size analyzer were used to observe the formation of the stabilized composite NPs, and a Jobin-Yvon Ultima-C inductively coupled plasma-atomic emission spectrometer (ICP-AES) was used to measure the contents (%) of formed iron oxide nanoseeds as a function of reaction temperature and formed gold deposited on the iron oxide nanoparticles. We also evaluated the time-dependent excretion profile, in vivo biodistribution, circulation time, and tumor-targeting ability of the composite NPs using a noninvasive NIR fluorescence imaging technology. To observe the MRI contrast characteristic, the composite NPs were injected into the tail veins of tumor-bearing mice to demonstrate their selective tumoral distribution. The MR images were collected with conventional T(2)-weighted spin echo acquisition parameters.

Biocompatible Polyhydroxyethylaspartamide-based Micelles with Gadolinium for MRI Contrast Agents.

Biocompatible poly-[N-(2-hydroxyethyl)-d,l-aspartamide]-methoxypoly(ethyleneglycol)-hexadecylamine (PHEA-mPEG-C(16)) conjugated with 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-gadolinium (DOTA-Gd) via ethylenediamine (ED) was synthesized as a magnetic resonance imaging (MRI) contrast agent. Amphiphilic PHEA-mPEG-C(16)-ED-DOTA-Gd forms micelle in aqueous solution. All the synthesized materials were characterized by proton nuclear magnetic resonance ((1)H NMR). Micelle size and shape were examined by dynamic light scattering (DLS) and atomic force microscopy (AFM). Micelles with PHEA-mPEG-C(16)-ED-DOTA-Gd showed higher relaxivities than the commercially available gadolinium contrast agent. Moreover, the signal intensity of a rabbit liver was effectively increased after intravenous injection of PHEA-mPEG-C(16)-ED-DOTA-Gd.

Core/shell nanoparticles for pH-sensitive delivery of doxorubicin.

Core/shell nanoparticles with lipid core were prepared and characterized as pH-sensitive delivery system of anticancer drug. The lipid core is composed of drug-loaded lecithin and the polymeric shell is composed of Pluronics (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) tri-block copolymer, F-127). Based on the preparation method in the previous report by us, the freeze-drying of drug-loaded lecithin was performed in the F-127 aqueous solution containing trehalose used as a cryoprotectant to form stabilized core/shell nanoparticles. For the application of core/shell nanoparticles as a pH-sensitive drug delivery system for anticancer drug, doxorubicin was loaded into the core/shell nanoparticles and the drug loading amount and drug release behavior in response to pH change were observed.

Paclitaxel-loaded Pluronic nanoparticles formed by a temperature-induced phase transition for cancer therapy.

We prepared nanoparticles by a temperature-induced phase transition in a mixture of Pluronic F-68 and liquid PEG (polyethylene glycol, molecular weight: 400) containing paclitaxel (PTX) with a fast, simple, continuous and solvent-free process. The liquid PEG is used as solubilizer of PTX and the polymer for the encapsulation of PTX is composed of Pluronic F-68. At the phase transition temperature, the polymer mixture was changed to the liquid phase, and stirring the liquid 0 °C to form Pluronic nanoparticles. The morphology and size distribution of the prepared Pluronic nanoparticles were observed using FE-SEM and TEM, and a particle size analyzer and cryo-TEM were used to observe the shape of paclitaxel-loaded Pluronic nanoparticles in an aqueous state. To apply Pluronic nanoparticles as a delivery system for cancer therapy, the release pattern of PTX, a model anti-cancer drug, was observed and the tumor growth was monitored by injecting the PTX-loaded Pluronic nanoparticles into the tail veins of tumor-bearing mice. We also evaluated the time-dependent excretion profile, in vivo biodistribution, circulation time, and tumor targeting ability of PTX-loaded Pluronic nanoparticles using non-invasive live animal imaging technology. In the early stage within 7h of release, the loaded PTX was rapidly released and the sustained release was observed for up to 48 h. In vivo studies, PTX-loaded Pluronic nanoparticles were observed with higher anti-tumor efficacy compared with PTX formulated in Cremophor EL.

Increased stability in plasma and enhanced cellular uptake of thermally denatured albumin-coated liposomes.

Liposomes are nano-scale vesicles that can be used as one of drug carriers. The liposomes are, however, plagued by rapid opsonization of them and hence making their circulation time in bloodstream to be shortened. In this study, cationically charged liposomes of which surface was modified with bovine serum albumin (BSA) were prepared by using electrostatic interaction between cationic liposomes and anionically charged BSA molecules at higher pH than isoelectric point (pI) of BSA. The BSA-coated liposomes (BLs) were denatured by thermal treatment of BL at 100 degrees C. The thermally denatured BSA-coated liposomes (DBLs) have mean particle diameter of 109+/-1 nm. Encapsulation of model drug, doxorubicin (DOX), in the liposomes was carried out by using, so called, remote loading method and loading efficiency of DOX in liposomes was about 90%. DBL800 showed higher stability in plasma compared to Doxil. Results of intracellular uptake evaluated by flow cytometry and confocal microscopy studies showed higher intracellular uptake of DBL800 than that of Doxil. Consequently, the DBL, of which surface was complexed with denatured protein may be applicable as drug delivery carriers for increasing stability in plasma and enhanced cellular uptake efficacy of anticancer drugs.

Polyethylene glycol-complexed cationic liposome for enhanced cellular uptake and anticancer activity.

Liposomes as one of the efficient drug carriers have some shortcomings such as their relatively short blood circulation time, fast clearance from human body by reticuloendothelial system (RES) and limited intracellular uptake to target cells. In this study, polyethylene glycol (PEG)-complexed cationic liposomes (PCL) were prepared by ionic complex of cationically charged liposomes with carboxylated polyethylene glycol (mPEG-COOH). The cationic liposomes had approximately 98.6+/-1.0 nm of mean particle diameter and 45.5+/-1.1 mV of zeta potential value. While, the PCL had 110.1+/-1.2 nm of mean particle diameter and 18.4+/-0.8 mV of zeta potential value as a result of the ionic complex of mPEG-COOH with cationic liposomes. Loading efficiency of model drug, doxorubicin, into cationic liposomes or PCL was about 96.0+/-0.7%. Results of intracellular uptake evaluated by flow cytometry and fluorescence microscopy studies showed higher intracellular uptake of PCL than that of Doxil. In addition, in vitro cytotoxicity of PCL was comparable to cationic liposomes. In pharmacokinetic study in rats, PCL showed slightly lower plasma level of DOX than that of Doxil. In vivo antitumor activity of DOX-loaded PCL was comparable to that of Doxil against human SKOV-3 ovarian adenocarcinoma xenograft rat model. Consequently, the PCL, of which surface was complexed with PEG by ionic complex may be applicable as drug delivery carriers for increasing therapeutic efficacy of anticancer drugs.

Functional characterization of mesenchymal stem cells labeled with a novel PVP-coated superparamagnetic iron oxide.

Magnetic resonance imaging of cells labeled with superparamagnetic iron oxide (SPIO) could be a valuable tool for tracking transplanted cells in living organisms. Human bone marrow-derived mesenchymal stem cells (hBMMSC) were labeled with a novel polyvinyl pyrrolidone (PVP)-coated SPIO. Prussian blue staining and electron microscopy revealed that almost all of the cells were efficiently labeled with PVP-SPIO nanoparticles. There were no signs of cytotoxicity, even at concentrations of up to 1600 microg Fe/ml of the nanoparticles, and the labeled cells were successfully visualized by in vitro cellular MRI. In addition, there was no significant alteration of the phenotype or the adipo/osteo/chondrogenic differentiation potential of the cells. This was in contrast to Feridex IV labeling that led to the inhibition of hBMMSC chondrogenesis. Following intramuscular injection in a rabbit hind limb ischemia model, the intercellular migration of the labeled cells toward the ablated site was clearly tracked through in vivo MRI. The localization of the transplanted cells observed by MRI correlated well with postmortem histological studies. These results demonstrate that the novel PVP-SPIO nanoparticles appear to be efficient MR contrast agents and may enable non-invasive in vivo tracking of stem cells in experimental and clinical settings during cell therapy.

Heparin-immobilized pluronic/PVA composite microparticles for the sustained delivery of ionic drug.

Heparin-immobilized Pluronic (F-68)/Polyvinylalcohol (PVA) composite microparticles were designed and characterized for the sustained drug delivery of ionic drug. Venlafaxine, antidepressant medication, was used as a model drug. For the efficient loading of ionic drug, heparin was immobilized into F-68/PVA composite microparticles. Differential scanning calorimetry (DSC) was used to understand the intra/intermolecular interactions in the heparin-immobilized F-68/PVA composite gels containing model drug. For the application as a sustained drug delivery system, the loading amount and release pattern of loaded drug were measured using high performance liquid chromatography (HPLC).

Synthesis and characterization of PVP-coated large core iron oxide nanoparticles as an MRI contrast agent.

The purpose of this study was to synthesize biocompatible polyvinylpyrrolidone (PVP)-coated iron oxide (PVP-IO) nanoparticles and to evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The PVP-IO nanoparticles were synthesized by a thermal decomposition method and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and a superconducting quantum interface device (SQUID). The core size of the particles is about 8-10 nm and the overall size is around 20-30 nm. The measured r(2) (reciprocal of T(2) relaxation time) and r2∗ (reciprocal of T2∗ relaxation time) are 141.2 and 338.1 (s mM)(-1), respectively. The particles are highly soluble and stable in various buffers and in serum. The macrophage uptake of PVP-IO is comparable to that of Feridex as measured by a Prussian blue iron stain and phantom study. The signal intensity of a rabbit liver was effectively reduced after intravenous administration of PVP-IO. Therefore PVP-IO nanoparticles are potentially useful for T(2)-weighted MR imaging.