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author:("Jon, sangong")
1.  Effect of PEG Pairing on the Efficiency of Cancer-Targeting Liposomes 
Theranostics  2015;5(7):746-754.
Standardized poly(ethylene glycol)-modified (PEGylated) liposomes, which have been widely used in research as well as in pre-clinical and clinical studies, are typically constructed using PEG with a molecular weight of 2000 Da (PEG2000). Targeting ligands are also generally conjugated using various functionalized PEG2000. However, although standardized protocols have routinely used PEG2000, it is not because this molecular weight PEG has been optimized to enhance tumor uptake of nanoparticles. Herein, we investigated the effect of various PEG lipid pairings—that is, PEG lipids for targeting-ligand conjugation and PEG lipids for achieving 'stealth' function—on in vitro cancer cell- and in vivo tumor-targeting efficacy. A class of high-affinity peptides (aptides) specific to extra domain B of fibronectin (APTEDB) was used as a representative model for a cancer-targeting ligand. We synthesized a set of aptide-conjugated PEGylated phospholipids (APTEDB‑PEG2000‑DSPE and APTEDB‑PEG1000‑DSPE) and then paired them with methoxy-capped PEGylated phospholipids with diverse molecular weights (PEG2000, PEG1000, PEG550, and PEG350) to construct various aptide-conjugated PEGylated liposomes. The liposomes with APTEDB‑PEG2000/PEG1000 and APTEDB‑PEG1000/PEG550 pairings had the highest uptake in EDB-positive cancer cells. Furthermore, in a U87MG xenograft model, APTEDB‑PEG2000/PEG1000 liposomes retarded tumor growth to the greatest extent, followed closely by APTEDB‑PEG1000/PEG550 liposomes. Among the PEGylated liposomes tested, pairs in which the methoxy-capped PEG length was about half that of the targeting ligand-displaying PEG exhibited the best performance, suggesting that PEG pairing is a key consideration in the design of drug-delivery vehicles.
PMCID: PMC4402498  PMID: 25897339
aptides · liposomes · cancer therapy · poly(ethylene glycol) · drug delivery · extra domain B of fibronectin
2.  MRI of Breast Tumor Initiating Cells Using the Extra Domain-B of Fibronectin Targeting Nanoparticles 
Theranostics  2014;4(8):845-857.
The identification of breast tumor initiating cells (BTICs) is important for the diagnosis and therapy of breast cancers. This study was undertaken to evaluate whether the extra domain-B of fibronectin (EDB-FN) could be used as a new biomarker for BTICs and whether EDB-FN targeting superparamagnetic iron oxide nanoparticles (SPIONs) could be used as a magnetic resonance imaging (MRI) contrast agent for BTIC imaging in vitro and in vivo. BTICs (NDY-1) exhibited high EDB-FN expression, whereas non-BTICs (MCF-7, BT-474, SUM-225, MDA-MB-231) did not exhibit EDB-FN expression. Furthermore, Cy3.3-labeled EDB-FN specific peptides (APTEDB) showed preferential binding to the targeted NDY-1 cells. To construct an EDB-FN targeted imaging probe, APTEDB was covalently attached to a thermally cross-linked SPION (TCL-SPION) to yield APTEDB-TCL-SPION. In the in vitro MRI of cell phantoms, selective binding of APTEDB-TCL-SPION to NDY-1 cells was evident, but little binding was observed in MCF-7 cells. After the intravenous injection of APTEDB-TCL-SPION into the NDY-1 mouse tumor xenograft model, a significant decrease in the signal within the tumor was observed in the T2*-weighted images; however, there was only a marginal change in the signal of non-targeting SPIONs such as APTscramble-TCL-SPION or TCL-SPION. Taken together, we report for the first time that EDB-FN was abundantly expressed in BTICs and may therefore be useful as a new biomarker for identifying BTICs. Our study also suggests that APTEDB-TCL-SPION could be used as an MRI contrast agent for BTIC imaging.
PMCID: PMC4063982  PMID: 24955145
Breast tumor initiating cells; Extra domain-B of fibronectin; Aptides; Superparamagnetic iron oxide nanoparticles; Magnetic resonance imaging.
3.  Distribution and accumulation of Cy5.5-labeled thermally cross-linked superparamagnetic iron oxide nanoparticles in the tissues of ICR mice 
Journal of Veterinary Science  2013;14(4):473-479.
Free Cy5.5 dye and Cy5.5-labeled thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) have been routinely used for in vivo optical imaging. However, there is little information about the distribution and accumulation of free Cy5.5 dye and Cy5.5-labeled TCL-SPION in the tissues of mice. Free Cy5.5 dye (0.1 mg/kg body weight) and Cy5.5-labeled TCL-SPION (15 mg/kg body weight) were intravenously injected into the tail vein of ICR mice. The biodistribution and accumulation of the TCL-SPION and Cy5.5 were observed by ex vivo optical imaging and fluorescence signal generation at various time points over 28 days. Cy5.5 dye fluorescence in various organs was rapidly eliminated from 0.5 to 24 h post-injection. Fluorescence intensity of Cy5.5 dye in the liver, lung, kidney, and stomach was fairly strong at the early time points within 1 day post-injection. Cy5.5-labeled TCL-SPION had the highest fluorescence density in the lung at 0.5 h post-injection and decreased rapidly over time. Fluorescence density in liver and spleen was maintained over 28 days. These results suggest that TCL-SPION can be useful as a carrier of therapeutic reagents to treat diseases by persisting for long periods of time in the body.
PMCID: PMC3885742  PMID: 24366671
accumulation; biodistribution; Cy5.5 dye; thermally cross-linked superparamagnetic iron oxide nanoparticles; toxicity
4.  Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy 
Theranostics  2012;2(1):3-44.
Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications.
PMCID: PMC3263514  PMID: 22272217
Multifunctional nanoparticles; magnetic nanoparticles; targeting ligand; bioconjugation; surface engineering; long circulation
5.  Comparison of Two Ultrasmall Superparamagnetic Iron Oxides on Cytotoxicity and MR Imaging of Tumors 
Theranostics  2012;2(1):76-85.
Purpose: This study was performed to compare the cytotoxicity and magnetic resonance (MR) contrast in diverse cultured cells and xenograft tumors models of two ultra-small superparamagnetic iron oxides (USPIOs), thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) and monocrystalline iron oxide nanoparticles (MION-47).
Materials and methods: Transmission electron microscopy (TEM) images and R2 relaxivity values of the TCL-SPION and MION-47 were obtained and the cell viability and cell growth velocity of treated and untreated human fibroblasts and human umbilical vein endothelial cells (HUVEC) were evaluated. The effect of TCL-SPION and MION-47 on the secretion of interlukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), the production of nitric oxides and the mitochondrial membrane potentials in murine macrophage cells (RAW264.7) was compared. Human hepatocellular carcinoma cells (HepG2, 5x105) were subcutaneously injected into nude mice (BALB/c) and in vivo MR imaging of tumors before and after injection with TCL-SPION or MION-47 (12.5 mg Fe/kg) was performed on a 1.5 Tesla MRI scanner.
Results: On TEM images, the average core diameter of TCL-SPION was 9 nm whereas that of MION-47 was 5 nm. TCL- SPION (345.0 ± 6.2 mM-1sec-1) had higher relaxivity (R2) than MION-47 (130.7 ± 1.1 mM-1sec-1). Significant changes in cell viability and growth were not found in human fibroblasts and HUVEC exposed to TCL-SPION and MION-47. However, IL-6 and TNF-α secretions increased dose-dependently and significantly in the macrophages treated with MION-47 or TCL-SPION. TCL-SPION had a lower stimulatory effect on IL-6 secretions than did MION-47 (P <0.05) and nitric oxides were produced in the macrophages by MION-47 but not TCL-SPION. A change in the mitochondrial membrane potential of the macrophages was observed 24 hours after the exposure, and MION-47 induced more collapses of the mitochondrial membrane potential than did TCL-SPION. In the in vivo MR imaging, 33.0 ± 1.3% and 7.5 ± 0.4% signal intensity decrease on T2*-weighted images was observed in the tumors injected with TCL-SPION and MION-47, respectively.
Conclusion: Due to the modified surface properties and larger core size of its iron oxide nanoparticles, TCL-SPION achieves lower cytotoxicity and better tumor MR contrast than MION-47. Our study suggests that TCL-SPION may be used as a new platform for tumor imaging and therapy monitoring.
PMCID: PMC3263518  PMID: 22272221
Ultra-small superparamagnetic iron oxides; Magnetic resonance imaging; TCL-SPION; MION-47; Tumor targeting.
6.  Magnetic Nanoparticle-Based Theranostics 
Theranostics  2012;2(1):122-124.
This theme issue provides a timely collection of studies on magnetic nanoparticle-based imaging, bio-sensing, therapy and/or their combinations.
PMCID: PMC3267387  PMID: 22287992
Magnetic nanoparticles; biomedical imaging; biosensor; hyperthermia; gene/drug delivery

Results 1-7 (7)