Cheol-Hee Ahn

Thermo-sensitive, injectable, and tissue adhesive sol–gel transition hyaluronic acid/pluronic composite hydrogels prepared from bio-inspired catechol-thiol reaction

Hyaluronic acid (HA) hydrogels are widely pursued as tissue regenerative and drug delivery materials due to their excellent biocompatibility and biodegradability. Inspired by mussel adhesion, we report here a novel class of thermo-sensitive and injectable HA/Pluronic F127 composite tissue-adhesive hydrogels applicable for various biomedical applications. HA conjugated with dopamine (HA-DN) was mixed with thiol end-capped Pluronic F127 copolymer (Plu-SH) to produce a lightly cross-linked HA/Pluronic composite gel structure based on Michael-type catechol-thiol addition reaction. The HA/Pluronic hydrogels exhibited temperature-dependent sol–gel phase transition behaviors different from Pluronic hydrogels. Rheological studies showed that the sol–gel transitions were rapid and reversible in response to temperature. The HA/Pluronic hydrogels could be injected in vivo in a sol state at room temperature using a syringe, but immediately became a robust gel state at body temperature. The in situ formed hydrogels exhibited excellent tissue-adhesion properties with superior in vivo gel stability and are potentially useful for drug and cell delivery.

Heparin‐Coated Gold Nanoparticles for Liver‐Specific CT Imaging

Since computed tomography (CT) was developed and its resolution, sensitivity, and scan speed rapidly improved, the use of CT in the diagnosis of hepatic disease has been evaluated by various investigators. In particular, liver-specific X-ray CT imaging has attracted much attention in cancer diagnosis and cancer treatment because liver metastases are a common occurrence in the history of a patient affected by various cancers. The liver is the organ most frequently involved in metastases due to its high volume of blood flow, the suitable size of sinusoids for trapping metastatic cells, and rich environment for rapid growth. The sensitivity of liver imaging needs to be guaranteed in cancer detection because diagnosis of liver metastasis at an early stage mainly relies on imaging and all liver metastases begin with a microscopic-sized tumor. However, in CT imaging, the detection of liver lesions is impossible without the use of contrast-enhancing agents, although, even then, the problem of distinguishing between small vessels and small liver tumors is an issue. For this reason, the demand for a tissue-specific X-ray contrast agent has increased, although there are a few products available they have limitations for clinical application. Although low-molecular-weight iodinated contrast agents are generally used in CT imaging, they have serious limitations in clinical applications due to their low liver uptake, rapid renal excretion, and lack of membrane permeation; this leads to renal toxicity and high viscosity of the injectable formulation. To overcome the undesirable pharmacokinetics and limitations, low-molecular-weight iodinates have been chemically conjugated to high-molecular-weight polymers or encapsulated into liposomes and polymeric micelles. These macromolecular and nanosized contrast agents display enhanced blood-circulating characteristics in vivo as well as providing liver-specific CT images. However, they still show a lower imaging resolution with respect to differentiating liver tissues from other vessels, organs, and cancers because iodine-based contrast agents inherently possess a lower X-ray absorption coefficient. Another novel inorganic nanoparticle-based CT contrast agent has been proposed. Polymer-coated bismuth sulfide (Bi2S3) nanoparticles showed high X-ray absorption compared with iodinated imaging agents, but their size and shape were not easy to [a] I.-C. Sun, J. H. Na, Dr. S. Lee, Dr. I.-C. Youn, Dr. K. Choi, Dr. I. C. Kwon, Dr. K. Kim Biomedical Research Center Korea Institute of Science and Technology 39-1 Hawolgok-dong, Seongbuk-gu, Seoul, 136-791 (Korea) Fax: (+82)2-958-5909 E-mail : kim@kist.re.kr [b] D.-K. Eun, Dr. C.-H. Ahn Research Institute of Advanced Materials (RIAM) Department of Materials Science and Engineering Seoul National University San 56-1, Sillim, Gwanak, Seoul, 151-744 (Korea) Fax: (+82)2-883-8197 E-mail : chahn@snu.ac.kr [c] I.-J. Kim Department of Chemistry, College of Science, Korea University Anam-dong, Seongbuk-gu, Seoul 136-791 (Korea) [d] Dr. C.-Y. Ko, Dr. H.-S. Kim Department of Biomedical Engineering, Yonsei University Wonju, Ganwondo, 220-710 (Korea) [e] Dr. D. Lim Silver Technology Center, Korea Institute of Industrial Technology 35-5 Hongcheon, Ipjang, Cheonan, Chungnam (Korea) [f] Dr. P. B. Messersmith Biomedical Engineering, Northwestern University 2145 Sheridan Road, Evanstron, IL 60208 (USA) [g] Dr. T. G. Park Department of Biological Sciences Korea Advanced Institute of Science Technology Daejeon 305-701 (Korea) [h] Dr. S. Y. Kim Department of Otolaryngology-Head and Neck Surgery Asan Medical Center, College of Medicine, University of Ulsan Seoul 138-736 (South Korea) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200902344.

Poly[lactic-co-(glycolic acid)]-Grafted Hyaluronic Acid Copolymer Micelle Nanoparticles for Target-Specific Delivery of Doxorubicin

PLGA-grafted HA copolymers were synthesized and utilized as target specific micelle carriers for DOX. For grafting hydrophobic PLGA chains onto the backbone of hydrophilic HA, HA was solubilized in an anhydrous DMSO by nano-complexing with dimethoxy-PEG. The carboxylic groups of HA were chemically grafted with PLGA, producing HA-g-PLGA copolymers. Resultant HA-g-PLGA self-assembled in aqueous solution to form multi-cored micellar aggregates and DOX was encapsulated during the self-assembly. DOX-loaded HA-g-PLGA micelle nanoparticles exhibited higher cellular uptake and greater cytotoxicity than free DOX for HCT-116 cells that over-expressed HA receptor, suggesting that they were taken up by the cells via HA receptor-mediated endocytosis.

PEGylated and MMP-2 Specifically DePEGylated Quantum Dots: Comparative Evaluation of Cellular Uptake

Polyethylene glycol (PEG)-immobilized quantum dot (QD) nanoparticles, which could be specifically dePEGylated in response to the presence of the matrix metalloprotease-2 (MMP-2) enzyme, were prepared. The degree of PEGylation (MW 3400) on the surface of 12 nm streptavidin-coated QDs was stoichiometrically controlled by varying the feed amount of a biotin-substrate-PEG conjugate, where the substrate contained an MMP-2 cleavable peptide sequence. A biotin-cell penetrating peptide (CPP) conjugate was also immobilized onto the surface of the PEGylated QD surface to enhance the cellular uptake after dePEGylation. It was found that more than nine PEG chains per single QD were required to effectively inhibit the cellular uptake of modified QD particles down to around 20%, as compared with that of QD without PEG chains. However, the treatment of MMP-2 enzyme in the medium resulted in a substantial enhancement in the extent of QD cellular uptake by dePEGylation with concomitant resurfacing of sterically hidden CPP moieties. This study analyzed the effects of surface PEGylation density and MMP-2 specific dePEGylation on the cellular uptake of CPP-QD nanoparticles in a quantitative manner.

Matrix Metalloproteinase Sensitive Gold Nanorod for Simultaneous Bioimaging and Photothermal Therapy of Cancer

Herein, we developed matrix metalloprotease (MMP) sensitive gold nanorods (MMP-AuNR) for cancer imaging and therapy. It was feasible to absorb NIR laser and convert into heat as well as visualize MMP activity. We showed the possibility of gold nanorods as a hyperthermal therapeutic agent and MMP sensitive imaging agent both in vitro and in vivo condition. The results suggested potential application of MMP-AuNR for simultaneous cancer diagnosis and therapy.

Targeted multimodal imaging modalities

Molecular imaging non-invasively visualizes and characterizes the biologic functions and mechanisms in living organisms at a molecular level. In recent years, advances in imaging instruments, imaging probes, assay methods, and quantification techniques have enabled more refined and reliable images for more accurate diagnoses. Multimodal imaging combines two or more imaging modalities into one system to produce details in clinical diagnostic imaging that are more precise than conventional imaging. Multimodal imaging offers complementary advantages: high spatial resolution, soft tissue contrast, and biological information on the molecular level with high sensitivity. However, combining all modalities into a single imaging probe involves problems yet to be solved due to the requirement of high dose contrast agents for a component of imaging modality with low sensitivity. The introduction of targeting moieties into the probes enhances the specific binding of targeted multimodal imaging modalities and selective accumulation of the imaging agents at a disease site to provide more accurate diagnoses. An extensive list of prior reports on the targeted multimodal imaging probes categorized by each modality is presented and discussed. In addition to accurate diagnosis, targeted multimodal imaging agents carrying therapeutic medications make it possible to visualize the theranostic effect and the progress of disease. This will facilitate the development of an imaging-guided therapy, which will widen the application of the targeted multimodal imaging field to experiments in vivo.

Pluronic/polyethylenimine shell crosslinked nanocapsules with embedded magnetite nanocrystals for magnetically triggered delivery of siRNA.

Pluronic/polyethylenimine shell crosslinked nanocapsules with embedded magnetite nanocrystals (PPMCs) were developed for magnetically triggered delivery of siRNA. The positively charged PPMCs formed stable nanosized polyelectrolyte complexes via electrostatic interactions with negatively charged siRNA-polyethylene glycol conjugate (siRNA-s-s-PEG) that was linked via a cleavable disulfide linkage. PPMC/siRNA-s-s-PEG polyelectrolyte complexes were efficiently taken up by cancer cells upon exposure to a magnet, thereby enhancing intracellular uptake and silencing effect of siRNA. The present study suggests that these novel nanomaterials could be potentially utilized for magnetically triggered delivery of various nucleic acid-based therapeutic agents.

Micellization behavior of star-block copolymers in a selective solvent: A Brownian dynamics simulation approach.

Micellization behavior of (AB)n type star-block copolymer in a selective solvent for its outer block is investigated by using a Brownian dynamics simulation. Micellar properties are compared in terms of the arm number (n) of star-block copolymer. It is observed that the critical micelle concentration (cmc) shows a minimum when the cmc is plotted against the arm number. The star-block copolymer with longer soluble block shows the cmc minimum at smaller arm number than that with shorter soluble block. Although the star-block copolymer with multiple arms forms more compact core as compared to diblock copolymer, the average aggregation number is inversely proportional to the arm number (approximately 1/n), which implies that the micelle size is invariant with the arm number. Theoretical predictions based on a simple mean field theory agree qualitatively well with the simulation results.

Stabilized polymeric micelles by electrostatic interactions for drug delivery system

Methoxy poly(ethylene glycol)-block-oligo(l-aspartic acid)-block-poly(epsilon-caprolactone) with four aspartic acid groups was synthesized with a molecular weight and M(w)/M(n) of 8930 and 1.22. Polymeric micelles were formed by dialysis and stabilized by electrostatic interactions between the carboxylic acid groups and calcium cations. The critical micelle concentration of mPEG-Asp-PCL was determined to be 0.078 mg/mL. At 0.02 mg/mL, the dissociation of micelles without ionic stabilization formed an opaque, phase-separated solution, while the stabilized micelles under the same conditions showed structural stability through ionic stabilization. The paclitaxel-loading and efficiency were 8.7% and 47.6%, respectively, and the drug loading increased the mean diameter from 73.0 nm to 87 nm, which was increased further to 96 nm after ionic fixation. Rapid releases of approximately 65% of the encapsulated paclitaxel from a non-stabilized micelle and 45% from a stabilized micelle were observed in the first 24h at pH 7.4 in a PBS solution containing 0.1 wt% Tween 80. The stabilized micelles then showed a sustained, slow release pattern over a couple of weeks, while the profile from the non-stabilized micelles reached a plateau at approximately 75% after 50h. The enhanced micelle stability independent of concentration through ionic stabilization opens a way for preparing long circulating delivery systems encapsulating water-insoluble drugs.

The effects of 8-arm-PEG-catechol/heparin shielding system and immunosuppressive drug, FK506 on the survival of intraportally allotransplanted islets.

This study proposed a double-layer shielding method of using 8-arm-PEG-catechol (PEG(8)) and N-hydroxysuccinimidyl-linked unfractionated heparin (UFH-NHS) for the prevention of instant blood-mediated inflammatory reaction (IBMIR) and immune reactions against transplanted pancreatic islets. The surface of islet was evenly covered by PEG(8) and UFH-NHS. Both viability and functionality of islets were evaluated in vitro, and the anti-coagulation effect of conjugated heparin on the islet surface was also evaluated. The inhibition effects of PEG(8)/UFH double-layer shielding system on immune reactions and IBMIR induced by transplanted islets were evaluated in an allograft model. When pancreatic islets of Sprague-Dawley (SD) rats were transplanted in the liver of F344 rats, the mean survival time (MST) of PEG(8)/UFH double-layer shielded islets (6.8 ± 1.6 days) was statistically increased, compared to that of unmodified islets (3.6 ± 1.1 days). Furthermore, when 0.5 mg/kg of FK506 was daily administered, the MST of double-layer shielded islet (15.0 ± 2.1 days) was increased by two-fold, compared to that of unmodified islets treated with the same dose of FK506 (8.0 ± 2.4 days). Therefore, a newly developed strategy of combining the PEG(8)/UFH double-layer shielding system with FK506 would certainly be effective for preventing immune activation and IBMIR against allotransplanted islets.