Sangyong Jon

Superparamagnetic Iron Oxide Nanoparticle–Aptamer Bioconjugates for Combined Prostate Cancer Imaging and Therapy

ThemajorshortcomingofCombidexisitsinabilitytodetectPCadiseaseoutsideofthelymphnodes.Herein, we report the development of a novel, multifunc-tional, thermally cross-linked SPION (TCL-SPION) that can bothdetect PCa cells, and deliver targeted chemotherapeuticagents directly to the PCa cells. We previously reported theuseoftheA10RNAaptamer (Apt), which bindstheextracellu-lar domain of the prostate-specific membrane antigen (PSMA),to engineer targeted nanoparticles for PCa therapy and imag-ing.

Co-delivery of hydrophobic and hydrophilic drugs from nanoparticle-aptamer bioconjugates.

Apromisingapplicationofnanoparticle(NP)drugdeliverysystemsisthetargeteddeliveryoftherapeuticagentsinacell-,tissue-,ordisease-specificmanner.Thisgoalmaybeachieved by the surface-modification of NPs with antibodies,nucleic acid ligands (aptamers; Apt), peptides, or small mole-cules that bind to antigens present on the target cells or tis-sues.

Preparation and characterization of water-soluble albumin-bound curcumin nanoparticles with improved antitumor activity

Curcumin (CCM), a yellow natural polyphenol extracted from turmeric (Curcuma longa), has potent anti-cancer properties as has been demonstrated in various human cancer cells. However, the widespread clinical application of this efficient agent in cancer and other diseases has been limited by its poor aqueous solubility and bioavailability. In this study, we prepared novel CCM-loaded human serum albumin (HSA) nanoparticles (CCM-HSA-NPs) for intravenous administration using albumin bound technology. Field emission scanning electron microscopy (FE-SEM) and dynamic light scattering (DLS) investigation confirmed a narrow size distribution in the 130-150nm range. Furthermore, CCM-HSA-NPs showed much greater water solubility (300-fold) than free CCM, and on storage, the biological activity of CCM-HSA-NPs was preserved with negligible activity loss. In vivo distributions and vascular endothelial cells transport studies demonstrated the superiority of CCM-HSA-NPs over CCM. Amounts of CCM in tumors after treatment with CCM-HSA-NPs were about 14 times higher at 1h after injection than that achieved by CCM. Furthermore, vascular endothelial cell binding of CCM increased 5.5-fold, and transport of CCM across a vascular endothelial cell monolayer by Transwell testing was 7.7-fold greater for CCM-HSA-NPs than CCM. Finally, in vivo antitumor tests revealed that CCM-HSA-NPs (10 or 20mg/kg) had a greater therapeutic effect (50% or 66% tumor growth inhibition vs. PBS-treated controls) than CCM (18% inhibition vs. controls) in tumor xenograft HCT116 models without inducing toxicity. We attribute this potent antitumor activity of CCM-HSA-NPs to enhanced water solubility, increased accumulation in tumors, and an ability to traverse vascular endothelial cell.

Image-guided prostate cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles.

CG-rich duplex containing prostate-specific membrane antigen (PSMA) aptamer-conjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPIONs) is reported as prostate cancer-specific nanotheranostic agents. These agents are capable of prostate tumor detection in vivo by magnetic resonance imaging (MRI) and selective delivery of drugs to the tumor tissue, simultaneously. The prepared PSMA-functionalized TCL-SPION via a hybridization method (Apt-hybr-TCL-SPION) exhibited preferential binding towards target prostate-cancer cells (LNCaP, PSMA+) in both in vitro and in vivo when analyzed by T(2) -weighted MRI. After Dox molecules were loaded onto the Apt-hybr-TCL-SPION through the intercalation of Dox to the CG-rich duplex containing PSMA aptamer as well as electrostatic interaction between the Dox-and-polymer coating layer of the nanoparticles, the resulting Dox@Apt-hybr-TCL-SPION showed selective drug-delivery efficacy in the LNCaP xenograft mouse model. These results suggest that Dox@Apt-hybr-TCL-SPION has potential for use as novel prostate cancer-specific nanotheranostics.

In vivo antitumor effects of chitosan-conjugated docetaxel after oral administration

The purpose of this study is to evaluate in vivo antitumor efficacy and subacute toxicity of docetaxel (DTX) prodrug comprising a conjugate between DTX and low molecular weight chitosan (LMWC) after oral administration. DTX was covalently attached to LMWC via a cleavable linker so as to be released from LMWC-DTX conjugate in body. In vitro cytotoxicity of LMWC-DTX conjugate was evaluated by MTT assay against two human cancer cell lines, showing similar IC(50) values to the parent DTX. The pharmacokinetic data of the conjugate after oral administration revealed that half-life in blood circulation was increased by approximately 15-fold and AUC((0-infinity)) was 3.8-6.2 times higher in comparison with the intravenously injected DTX (i.v.). In vivo antitumor efficacy was evaluated in nude mice bearing human non-small cell lung carcinoma (NCI-H358) and glioblastoma (U87MG), respectively. The orally administered LMWC-DTX conjugate (10 mg DTX equivalent/kg) showed comparable antitumor efficacy to the same dose of DTX (i.v.) for both NCI-H358 and U87MG models, but revealed much lower subacute toxicity as seen in body weight loss and hematological toxicity.

Magnetically responsive polymeric microparticles for oral delivery of protein drugs

PurposeProtein drugs cannot be delivered efficiently through oral routes. To address this challenge, we evaluated the effect of prolonged gastrointestinal transit on the bioavailability of insulin carried by magnetically responsive microparticles in the presence of an external magnetic field.MethodsMagnetite nanocrystals and insulin were coencapsulated into poly(lactide-co-glycolide) (PLGA) microparticles and their effects on hypoglycemia were evaluated in mice in the presence of a circumferentially applied external magnetic field.ResultsA single administration of 100xa0U/kg of insulin–magnetite–PLGA microparticles to fasted mice resulted in a reduction of blood glucose levels of up to 43.8% in the presence of an external magnetic field for 20xa0h (bioavailability = 2.77 ± 0.46 and 0.87 ± 0.29% based on glucose and ELISA assay, respectively), significantly higher than similarly dosed mice without a magnetic field (bioavailability = 0.66 ± 0.56 and 0.30 ± 0.06%, based on glucose and ELISA assay, respectively).ConclusionsA substantially improved hypoglycemic effect was observed in mice that were orally administered with insulin–magnetite–PLGA microparticles in the presence of an external magnetic field, suggesting that magnetic force can be used to improve the efficiency of orally delivered protein therapeutics.

Bioinspired Colorimetric Detection of Calcium(II) Ions in Serum Using Calsequestrin-Functionalized Gold Nanoparticles†

Seeing is sensing: Calsequestrin (CSQ) functionalized gold nanoparticles undergo calcium-dependent CSQ polymerization, which results in a clear color change (see picture) together with precipitation. The sensing system is specific for Ca(2+) ions and the differences between normal and disease-associated abnormal (hypercalcemia) Ca(2+) ion levels in serum can be distinguished with the naked eye.

Amphiphilic polymer-coated hybrid nanoparticles as CT/MRI dual contrast agents

We describe hybrid nanoparticles, composed of iron oxide and gold nanoparticles, as potential dual contrast agents for both computed tomography (CT) and magnetic resonance imaging (MRI). The hybrid nanoparticles are synthesized by thermal decomposition of mixtures of Fe-oleate and Au-oleylamine complexes. Using a nano-emulsion method, the nanoparticles are coated with amphiphilic poly(DMA-r-mPEGMA-r-MA) to impart water-dispersity and antibiofouling properties. An inxa0vitro phantom study shows that the hybrid nanoparticles have high CT attenuation, because of the constituent gold nanoparticles, and afford a good MR signal, attributable to the contained iron oxide nanoparticles. Intravenous injection of the hybrid nanoparticles into hepatoma-bearing mice results in high contrast between the hepatoma and normal hepatic parenchyma in both CT and MRI. These results suggest that the hybrid nanoparticles may be useful as CT/MRI dual contrast agents for inxa0vivo hepatoma imaging.

Antibiofouling amphiphilic polymer-coated superparamagnetic iron oxide nanoparticles: synthesis, characterization, and use in cancer imaging in vivo†

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used as T2-contrast agents for magnetic resonance imaging (MRI). Herein we develop various antibiofouling amphiphilic polymer-coated SPIONs using a one-step nanoemulsion method. This methodology yielded ultrasmall polymer-coated SPIONs, of average diameter less than 30 nm, which were stable under physiological conditions. In vitrocell cytotoxicity tests revealed that no SPION showed toxicity even at relatively high concentrations. In vivo MRI with Lewis lung carcinoma (LLC) tumor-bearing mice resulted in an approximately 30% T2 signal drop in tumor tissues, indicating that the SPIONs reached such tissues via passive targeting. In summary, the ultrasmall, stable, amphiphilic polymer-coated SPIONs can be used as MRI contrast agents for cancer imaging.

Integrin-targeting thermally cross-linked superparamagnetic iron oxide nanoparticles for combined cancer imaging and drug delivery

We report multifunctional nanoparticles that are capable of cancer targeting and simultaneous cancer imaging and therapy. The nanoparticles are composed of cyclic arginine-glycine-aspartic acid (cRGD) peptide ligand bioconjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) that enable loading of the anticancer drug doxorubicin (Dox). The cyclic RGD-conjugated TCL-SPION (cRGD_TCL-SPION) had a mean hydrodynamic size of 34 ± 8 nm with approximately 0.39 wt% of cyclic RGD attached to the surface of the nanoparticles. The cRGD_TCL-SPION exhibited preferential binding towards target cancer cells (U87MG, integrin α(v)β(3)+) when analyzed by T(2)-weighted magnetic resonance (MR) imaging. When Dox was loaded onto the polymeric coating layers of cRGD_TCL-SPION via ionic interaction, the resulting Dox-loaded cRGD_TCL-SPION (Dox@cRGD_TCL-SPION) showed much higher cytotoxicity in U87MG cells than Dox@TCL-SPION lacking cRGD (IC(50) value of 0.02 µM versus 0.12 µM). These results suggest that Dox@cRGD_TCL-SPION has potential for use as an integrin-targeted, combined imaging and therapeutic agent.