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In situ diselenide-crosslinked polymeric micelles for ROS-mediated anticancer drug delivery
Deepagan, V.G.,Kwon, S.,You, D.G.,Nguyen, V.Q.,Um, W.,Ko, H.,Lee, H.,Jo, D.G.,Kang, Y.M.,Park, J.H. IPC Science and Technology Press 2016 Biomaterials Vol.103 No.-
<P>Stimuli-responsive micelles have emerged as the drug carrier for cancer therapy since they can exclusively release the drug via their structural changes in response to the specific stimuli of the target site. Herein, we developed the in situ diselenide-crosslinked micelles (DCMs), which are responsive to the abnormal ROS levels of tumoral region, as anticancer drug carriers. The DCMs were spontaneously derived from selenol-bearing triblock copolymers consisting of polyethylene glycol (PEG) and poly peptide derivatives. During micelle formation, doxorubicine (DOX) was effectively encapsulated in the hydrophobic core, and diselenide crosslinks were formed in the shell. The DCMs maintained their structural integrity, at least for 6 days in physiological conditions, even in the presence of destabilizing agents. However, ROS-rich conditions triggered rapid release of DOX from the DOX-encapsulating DCMs (DOX-DCMs) because the hydrophobic diselenide bond was cleaved into hydrophilic selenic acid derivatives. Interestingly, after their systemic administration into the tumor-bearing mice, DOX-DCMs delivered significantly more drug to tumors (1.69-fold and 3.73-fold higher amount compared with their non-crosslinked counterparts and free drug, respectively) and effectively suppressed tumor growth. Overall, our data indicate that DCMs have great potential as drug carriers for anticancer therapy. (C) 2016 Elsevier Ltd. All rights reserved.</P>
Amphiphilic polysialic acid derivatives: synthesis, characterization, and in-vitro cytotoxicity.
Deepagan, V G,Thambi, Thavasyappan,Ko, Hyewon,Kang, Young Mo,Park, Jae Hyung American Scientific Publishers 2013 Journal of Nanoscience and Nanotechnology Vol.13 No.11
<P>Polysialic acid (PSA), a natural hydrophilic polysaccharide, is a potential alternative to poly(ethylene glycol) as the hydrophilic constituent of the polymeric amphiphiles for biomedical applications. In this study, amphiphilic block copolymers were prepared based on PSA as the hydrophilic block and polycaprolactone (PCL) as the hydrophobic block. The block copolymers formed micelles with spherical shapes in an aqueous environment. The average sizes of the nanoparticles were in the range of 270-390 nm, depending on the block length of PCL. The zeta potential values of the micelles were approximately -20 mV due to the negatively charged carboxylic acids of PSA. The nanoparticles showed good stability for five days in a physiological solution (pH 7.4), and had low critical micelle concentration values (1.68-8.54 microg/ml). The in-vitro cytotoxicity tests confirmed that the PSA-PCL micelles had little cytotoxicity. All these results suggest that the PSA-PCL block copolymers can form nano-sized micelles with high stability and low toxicity, implying their high potential for biomedical application.</P>
Intracellularly Activatable Nanovasodilators To Enhance Passive Cancer Targeting Regime
Deepagan, V. G.,Ko, Hyewon,Kwon, Seunglee,Rao, N. Vijayakameswara,Kim, Sang Kyoon,Um, Wooram,Lee, Sohee,Min, Jiwoong,Lee, Jeongjin,Choi, Ki Young,Shin, Sol,Suh, Minah,Park, Jae Hyung American Chemical Society 2018 NANO LETTERS Vol.18 No.4
<P>Conventional cancer targeting with nanoparticles has been based on the assumed enhanced permeability and retention (EPR) effect. The data obtained in clinical trials to date, however, have rarely supported the presence of such an effect. To address this challenge, we formulated intracellular nitric oxide-generating nanoparticles (NO-NPs) for the tumor site-specific delivery of NO, a well-known vasodilator, with the intention of boosting EPR. These nanoparticles are self-assembled under aqueous conditions from amphiphilic copolymers of poly(ethylene glycol) and nitrated dextran, which possesses inherent NO release properties in the reductive environment of cancer cells. After systemic administration of the NO-NPs, we quantitatively assessed and visualized increased tumor blood flow as well as enhanced vascular permeability than could be achieved without NO. Additionally, we prepared doxorubicin (DOX)-encapsulated NO-NPs and demonstrated consequential improvement in therapeutic efficacy over the control groups with considerably improved DOX intratumoral accumulation. Overall, this proof of concept study implies a high potency of the NO-NPs as an EPR enhancer to achieve better clinical outcomes.</P> [FIG OMISSION]</BR>
Deepagan, V. G.,You, Dong Gil,Um, Wooram,Ko, Hyewon,Kwon, Seunglee,Choi, Ki Young,Yi, Gi-Ra,Lee, Jun Young,Lee, Doo Sung,Kim, Kwangmeyung,Kwon, Ick Chan,Park, Jae Hyung American Chemical Society 2016 NANO LETTERS Vol.16 No.10
<P>Although sonodynamic therapy (SDT) has emerged as a potential alternative to conventional photo dynamic therapy, the low quantum yield of the sonosensitizer such as TiO2 nanoparticles (NPs) is still a major concern. Here, we have developed hydrophilized Au-TiO2 nano composites (HAu-TiO2 NCs) as sonosensitizers for improved SDT. The physicochemical properties of HAu-TiO2 NCs were thoroughly studied and compared with their counterparts without gold deposition. Upon exposure of HAu-TiO2 NCs to ultrasoUnd, a large quantity of reactive oxygen species (ROS) were generated, leading to complete suppression of tumor growth after their systemic administration in vivo. Overall, it was evident that the composites of gold with TiO2 NPs significantly augmented the levels of ROS generation, implying their potential as SDT agents for Cancer therapy.</P>
PEGylated Gold Nanoprobe Bearing the Diselenide Bond for ROSResponsive Fluorescence Imaging
VEERASIKKUGOPAL DEEPAGAN,Pramod Kumar EK,서영덕,박재형 한국고분자학회 2018 Macromolecular Research Vol.26 No.7
Reactive oxygen species (ROS)-sensitive imaging can be used to distinguish ROS-rich diseased tissues from normal tissues. Herein, we developed a selective H2O2 concentration-dependent on-off gold nanoprobe and demonstrated its in vitro fluorescence imaging application using activated macrophages cells. The nanoprobe was prepared by covalent conjugation of polyethylene glycol and fluorescein dyes on gold nanoparticle surface through a H2O2-sensitive diselenide linker. The nanoprobes were well-dispersed in aqueous solution and inactive in H2O2-deficient conditions, ascribed to fluorescence resonance energy transfer between dye and gold nanoparticles. Once the nanoprobe was exposed to an H2O2-rich environment, it was quickly activated by diselenide bond dissociation, leading to fluorophore release from its surfaces. Overall, gold nanoprobe with the diselenide linker might be a potential candidate for ROS imaging.
Bioreducible polymersomes for intracellular dual-drug delivery
Thambi, Thavasyappan,Deepagan, V. G.,Ko, Hyewon,Lee, Doo Sung,Park, Jae Hyung The Royal Society of Chemistry 2012 Journal of materials chemistry Vol.22 No.41
<P>Stimuli-sensitive polymersomes, composed of amphiphilic block copolymers, have emerged as a promising nanocarrier for triggered release of anticancer drugs. In this study, we synthesized a bioreducible, amphiphilic triblock copolymer based on poly(ethylene glycol)-<I>b</I>-poly(lysine)-<I>b</I>-poly(caprolactone) bearing a disulfide bond (PEG-<I>b</I>-PLys-SS-PCL). Owing to its unique amphiphilicity, the copolymer formed self-assembled polymersomes (256 nm diameter) under aqueous conditions. These polymersomes were stable in physiological solution (pH 7.4), whereas they readily disintegrated under a reductive environment similar to an intracellular condition. The polymersomes could simultaneously encapsulate the hydrophobic camptothecin (CPT) in their membrane and the hydrophilic doxorubicin·hydrochloride (DOX·HCl) in their aqueous cores. The polymersomes released the drugs in a sustained manner under physiological conditions (pH 7.4), whereas the drug release rates dramatically increased in a reductive environment at 10 mM glutathione. From <I>in vitro</I> cytotoxicity tests, it was found that dual drug-loaded polymersomes showed significantly higher cytotoxicity to SCC7 cancer cells than those with the single drug. These results suggest that the polymersomes bearing the bioreducible linker have high potential as carriers for intracellular dual-drug delivery.</P> <P>Graphic Abstract</P><P>Bioreducible polymersomes bearing the disulfide bond have potential as the dual-drug carrier that can release the drug specifically at the intracellular level. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c2jm34546c'> </P>
Ultrasmall gold nanosatellite-bearing transformable hybrid nanoparticles for deep tumor penetration
Son, Soyoung,Deepagan, Veerasikku G.,Shin, Sol,Ko, Hyewon,Min, Jiwoong,Um, Wooram,Jeon, Jueun,Kwon, Seunglee,Lee, Eun Sook,Suh, Minah,Lee, Doo Sung,Park, Jae Hyung Elsevier 2018 Acta Biomaterialia: structure-property-function re Vol.79 No.-
<P><B>Abstract</B></P> <P>Since delivering drugs to an entire tumoral region leads to high therapeutic efficacy and good prognosis, achieving deep tumoral penetration of drugs is a major issue in cancer treatment. In this regard, conventional nanomedicines (>50 nm) have shown limitations in cancer therapy, primarily attributed to the heterogeneous distribution of drugs because of the physiological barrier of the tumor interstitial space. To address this issue, we prepared transformable hybrid nanoparticles (TNPs) consisting of a pH-responsive nanocarrier (PEG-PBAE) and doxorubicin (DOX)-conjugated ultrasmall (<3 nm) gold nanoparticles (nanosatellites). It has been shown that PEG-PBAE can serve as a reservoir for nanosatellites and release them in mildly acidic conditions (pH 6.5), mimicking the tumor microenvironment. When DOX-loaded TNPs (DOX-TNPs) were intravenously injected into tumor-bearing mice, they successfully accumulated and dissociated at the extracellular level of the tumor, leading to the disclosure of nanosatellites and free DOX. While the free DOX accumulated in tumor tissue near blood vessels, the deeply diffused nanosatellites were taken up by the tumor cell, followed by the release of DOX via cleavage of pH-responsive ester linkages in the nanosatellites at the intracellular level. Consequently, the DOX-TNPs effectively suppressed tumor growth through improved tumor penetration of DOX, suggesting their promising potential as a cancer nanomedicine.</P> <P><B>Statement of Significance</B></P> <P>Deep tumor penetration of anticancer drug is an important issue for high therapeutic efficacy. If the drugs cannot reach cancer cells in a sufficient concentration, their effectiveness will be limited. In this regard, conventional nanomedicine showed only modest therapeutic efficacy since they cannot deliver their payloads to the deep site of tumor tissue. This heterogeneous distribution of the drug is primarily attributed to the physiological barriers of the tumor microenvironment, including a dense extracellular matrix. To surmount this challenge, we developed tumor acidity-triggered transformable nanoparticles. By encapsulating doxorubicin-conjugated ultrasmall gold nanosatellites into the nanoparticles, the drug was not significantly bound to genetic materials, resulting in its minimal sequestration near the vasculature and deep tumor penetration. Our strategy could resolve not only the poor penetration issue of the drug but also its restricted tumor accumulation, suggesting the potential as an effective nanotherapeutics.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>