Visible light-induced apoptosis activatable nanoparticles of photosensitizer-DEVD-anticancer drug conjugate for targeted cancer therapy

Um, Wooram,Park, Jooho,Ko, Hokyung,Lim, Seungho,Yoon, Hong Yeol,Shim, Man Kyu,Lee, Sangmin,Ko, Young Ji,Kim, Min Ju,Park, Jae Hyung,Lim, Dong-Kwon,Byun, Youngro,Kwon, Ick Chan,Kim, Kwangmeyung Elsevier 2019 Biomaterials Vol.224 No.-

<P><B>Abstract</B></P> <P>The therapeutic efficacy of photodynamic therapy (PDT) in cancer treatment is attributed to the conversion of tumor oxygen into reactive singlet oxygen (<SUP>1</SUP>O<SUB>2</SUB>) using photosensitizers. However, poor tissue penetration and rapid oxygen depletion have limited the effectiveness of PDT. Therefore, we have developed visible light-induced apoptosis activatable nanoparticles of the photosensitizer (Ce6)-caspase 3 cleavable peptide (<I>Asp-Glu-Val-Asp</I>, DEVD)-anticancer drug monomethyl auristatin E (MMAE) conjugate, resulting in Ce6-DEVD-MMAE nanoparticles. The average size of self-assembled Ce6-DEVD-MMAE nanoparticles was 90.8 ± 18.9 nm. Compared with conventional PDT based on high-energy irradiation, the new therapy uses lower-energy irradiation to induce apoptosis of cancer cells, and activation of caspase 3 to successfully cleave the anticancer drug MMAE from the Ce6-DEVD-MMAE nanoparticles, resulting in strong cytotoxic effects in cancer cells. Notably, the one-time activation of MMAE in the Ce6-DEVD-MMAE nanoparticles further amplified the cytotoxic effect resulting in additional cell death in the absence of visible light irradiation. Furthermore, Ce6-DEVD-MMAE nanoparticles passively accumulated in the targeted tumor tissues <I>via</I> enhanced permeation and retention (EPR) effect in mice with squamous cell carcinoma (SCC7). The high levels of toxicity were retained after exposure to lower-energy irradiation. However, Ce6-DEVD-MMAE nanoparticles did not show any toxicity in the absence of exposure to visible light irradiation, in contrast to the toxicity of free MMAE (1–10 nM). Thus, the light-induced therapeutic strategy based on apoptotic activation of Ce6-DEVD-MMAE nanoparticles can be used to treat solid tumors inaccessible to conventional PDT.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Hydrophilized Titanium Dioxide Nanoparticles as Sonosensitizers for Cancer Eradication

Wooram UM,Dong Gil YOU,Veerasikku Gopal DEEPAGAN,Jae Hyung PARK 한국고분자학회 2016 한국고분자학회 학술대회 연구논문 초록집 Vol.41 No.2

A charge-switchable, four-armed polymeric photosensitizer for photodynamic cancer therapy

Lee, Chung-Sung,Park, Wooram,Jo, Young Um,Na, Kun The Royal Society of Chemistry 2014 Chemical communications Vol.50 No.33

<P>A water-soluble, charge-switchable, four-armed polymeric photosensitizer (C4P-PS), in which charge switching is pH dependent, has been designed as a new class of photosensitizer for photodynamic cancer therapy.</P> <P>Graphic Abstract</P><P>A water-soluble, charge-switchable, four-armed polymeric photosensitizer (C4P-PS), in which charge switching is pH dependent, has been designed as a new class of photosensitizer for photodynamic cancer therapy. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c4cc00746h'> </P>

Laser-Induced CO₂ Generation from Gold Nanorod-Containing Poly(propylene carbonate)-Based Block Polymer Micelles for Ultrasound Contrast Enhancement

Lee, Jaewon,Jo, Sung Duk,Chung, Haejun,Um, Wooram,Chandrasekar, Rohith,Choi, Yun Hwa,Shalaev, Vladimir M.,Won, You-Yeon American Chemical Society 2018 ACS APPLIED MATERIALS & INTERFACES Vol.10 No.31

<P>Poly(propylene carbonate) (PPC) decomposes at high temperature to release CO<SUB>2</SUB>. This CO<SUB>2</SUB>-generation temperature of PPC can be reduced down to less than 80 °C with the aid of a photoacid generator (PAG). In the present work, we demonstrate that using an additional helper component, surface plasmonic gold nanorods (GNRs), the PPC degradation reaction can also be initiated by infrared (IR) irradiation. For this purpose, a PPC-containing nanoparticle formulation was developed in which PPC-based amphiphilic block copolymers (BCPs), poly(poly(ethylene glycol) methacrylate-<I>b</I>-propylene carbonate-<I>b</I>-poly(ethylene glycol) methacrylate) (PPEGMA-PPC-PPEGMA), were self-assembled with GNRs and PAG molecules via solvent exchange. Under IR irradiation, GNRs produce heat that can cause PPC to decompose into CO<SUB>2</SUB>, and PAG (after UV pretreatment) catalyzes this PPC degradation process. Two PPEGMA-PPC-PPEGMA materials were used for this study: PPEGMA<SUB>7.3K</SUB>-PPC<SUB>5.6K</SUB>-PPEGMA<SUB>7.3K</SUB> (“G7C6G7”) and PPEGMA<SUB>2.1K</SUB>-PPC<SUB>5.6K</SUB>-PPEGMA<SUB>2.1K</SUB> (“G2C6G2”). Addition of CTAB-coated GNRs dispersed in water to a G2C6G2 solution in DMF produced individually G2C6G2-encapsulated GNRs, whereas the same solvent exchange procedure resulted in the formation of polymer-coated GNR clusters when G7C6G7 was used as the encapsulating material. GNR/G2C6G2 NPs exhibited a surface plasmon resonance peak at 697 nm. The clustered morphology of G7C6G7-encapsulated GNRs caused a blue shift of the absorbance maximum to 511 nm. As a consequence, GNR/G2C6G2 NPs showed a greater absorbance/heat generation rate under IR irradiation than did GNR/G7C6G7 NPs. The IR-induced CO<SUB>2</SUB> generation rate was about 4.2 times higher with the GNR/G2C6G2+PAG sample than that with the GNR/G7C6G7+PAG sample. Both GNR/G7C6G7+PAG and GNR/G2C6G2+PAG systems produced ultrasound contrast enhancement effects under continuous exposure to IR light for >20 min; contrast enhancement was more spatially uniform for the GNR/G2C6G2+PAG sample. These results support the potential utility of PPC as a CO<SUB>2</SUB>-generating contrast agent in ultrasound imaging applications.</P> [FIG OMISSION]</BR>

Anti-Trop2 antibody-conjugated bioreducible nanoparticles for targeted triple negative breast cancer therapy

Son, Soyoung,Shin, Sol,Rao, N. Vijayakameswara,Um, Wooram,Jeon, Jueun,Ko, Hyewon,Deepagan, V.G.,Kwon, Seunglee,Lee, Jun Young,Park, Jae Hyung Elsevier 2018 International journal of biological macromolecules Vol.110 No.-

<P><B>Abstract</B></P> <P>Trop2, a transmembrane glycoprotein, has emerged as a biomarker for targeted cancer therapy since it is overexpressed in 80% of triple negative breast cancer (TNBC) patients. For the site-specific delivery of the anticancer drug into TNBC, anti-Trop2 antibody-conjugated nanoparticles (ST-NPs) were prepared as the potential nanocarrier, composed of carboxymethyl dextran (CMD) derivatives with bioreducible disulfide bonds. Owing to its amphiphilicity, the CMD derivatives were self-assembled into nano-sized particles in an aqueous condition. Doxorubicin (DOX), chosen as a model anticancer drug, was effectively encapsulated into the nanoparticles. DOX-loaded ST-NPs (DOX-ST-NPs) rapidly released DOX in the presence of 10mM glutathione (GSH), whereas the DOX release is significantly retarded in the physiological condition (PBS, pH 7.4). Confocal microscopic images and flow cytometry analysis demonstrated that DOX-ST-NPs were selectively taken up by MDA-MB-231 as the representative Trop2-expressing TNBC cells. Consequently, DOX-ST-NPs exhibited higher toxicity to Trop2-positive MDA-MB-231 cancer cells, compared to DOX-loaded control nanoparticles without the disulfide bond or anti-Trop2 antibody. Overall, ST-NPs might be a promising carrier of DOX for targeted TNBC therapy.</P>

Long-Circulating Au-TiO₂ Nanocomposite as a Sonosensitizer for ROS-Mediated Eradication of Cancer

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>

Dextran sulfate nanoparticles as a theranostic nanomedicine for rheumatoid arthritis

Heo, Roun,You, Dong Gil,Um, Wooram,Choi, Ki Young,Jeon, Sangmin,Park, Jong-Sung,Choi, Yuri,Kwon, Seunglee,Kim, Kwangmeyung,Kwon, Ick Chan,Jo, Dong-Gyu,Kang, Young Mo,Park, Jae Hyung IPC Science and Technology Press 2017 Biomaterials Vol.131 No.-

<P><B>Abstract</B></P> <P>With the aim of developing nanoparticles for targeted delivery of methotrexate (MTX) to inflamed joints in rheumatoid arthritis (RA), an amphiphilic polysaccharide was synthesized by conjugating 5β-cholanic acid to a dextran sulfate (DS) backbone. Due to its amphiphilic nature, the DS derivative self-assembled into spherical nanoparticles (220 nm in diameter) in aqueous conditions. The MTX was effectively loaded into the DS nanoparticles (loading efficiency: 73.0%) by a simple dialysis method. Interestingly, the DS nanoparticles were selectively taken up by activated macrophages, which are responsible for inflammation and joint destruction, via scavenger receptor class A-mediated endocytosis. When systemically administrated into mice with experimental collagen-induced arthritis (CIA), the DS nanoparticles effectively accumulated in inflamed joints (12-fold more than wild type mice (WT)), implying their high targetability to RA tissues. Moreover, the MTX-loaded DS nanoparticles exhibited significantly improved therapeutic efficacy against CIA in mice compared to free MTX alone. Overall, the data presented here indicate that DS nanoparticles are potentially useful nanomedicines for RA imaging and therapy.</P>

Carrier-free nanoparticles of cathepsin B-cleavable peptide-conjugated doxorubicin prodrug for cancer targeting therapy

Shim, Man Kyu,Park, Jooho,Yoon, Hong Yeol,Lee, Sangmin,Um, Wooram,Kim, Jong-Ho,Kang, Sun-Woong,Seo, Joung-Wook,Hyun, Soo-Wang,Park, Jae Hyung,Byun, Youngro,Kwon, Ick Chan,Kim, Kwangmeyung Elsevier 2019 Journal of controlled release Vol.294 No.-

<P><B>Abstract</B></P> <P>Cancer nanomedicine using nanoparticle-based delivery systems has shown outstanding promise in recent decades for improving anticancer treatment. However, limited targeting efficiency, low drug loading efficiency and innate toxicity of nanoparticles have caused severe problems, leaving only a few available in the clinic. Here, we newly developed carrier-free nanoparticles of cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly; FRRG)-conjugated doxorubicin (DOX) prodrug (FRRG-DOX) that formed a stable nanoparticle structure with an average diameter of 213 nm in aqueous condition. The carrier-free nanoparticles of FRRG-DOX induced cytotoxicity against cathepsin B-overexpressed tumor cells whereas the toxicity was minimized in normal cells. In particular, the FRRG-DOX nanoparticles showed the successful tumor-targeting ability and enhanced therapeutic efficiency in human colon adenocarcinoma (HT-29) tumor-bearing mice <I>via</I> enhanced permeation and retention (EPR) effect. Furthermore, FRRG-DOX nanoparticles did not present any severe toxicity, such as non-specific cell death and cardiac toxicity, in normal tissues due to minimal expression of cathepsin B. This carrier-free nanoparticles of FRRG-DOX can solve the unavoidable problems of current nanomedicine, such as lower targeting efficiency, toxicity of nanoparticles themselves, and difficulty in mass production that are fatally caused by natural and synthetic nano-sized carriers.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Comparison of <i>in vivo</i> targeting ability between cRGD and collagen-targeting peptide conjugated nano-carriers for atherosclerosis

Kim, Manse,Sahu, Abhishek,Kim, Gi Beom,Nam, Gi Hoon,Um, Wooram,Shin, So Jin,Jeong, Yong Yeon,Kim, In-San,Kim, Kwangmeyung,Kwon, Ick Chan,Tae, Giyoong Elsevier 2018 Journal of controlled release Vol.269 No.-

<P><B>Abstract</B></P> <P>Atherosclerosis plaque is a major cause of cardiovascular diseases across the globe and a silent killer. There are no physical symptoms of the disease in its early stage and current diagnostic techniques cannot detect the small plaques effectively or safely. Plaques formed in blood vessels can cause serious clinical problems such as impaired blood flow or sudden death, regardless of their size. Thus, detecting early stage of plaques is especially more important to effectively reduce the risk of atherosclerosis. Nanoparticle based delivery systems are recognized as a promising option to fight against this disease, and various targeting ligands are typically used to improve their efficiency. So, the choice of appropriate targeting ligand is a crucial factor for optimal targeting efficiency. cRGD peptide and collagen IV targeting peptide, which binds with the α<SUB>v</SUB>β<SUB>3</SUB> integrin overexpressed in the neovasculature of the plaque and collagen type IV present in the plaque, respectively, are frequently used for the targeting of nanoparticles. However, at present no study has directly compared these two peptides. Therefore, in this study, we have prepared cRGD or collagen IV targeting (Col IV-tg-) peptide conjugated and iron oxide nanoparticle (IONP) loaded Pluronic based nano-carriers for systemic comparison of their targeting ability towards <I>in vivo</I> atherosclerotic plaque in Apolipoprotein E deficient (<I>Apo E</I> <SUP>−/−</SUP>) mouse model. Nano-carriers with similar size, surface charge, and IONP loading content but with different targeting ligands were analyzed through <I>in vitro</I> and <I>in vivo</I> experiments. Near infrared fluorescence imaging and magnetic resonance imaging techniques as well as Prussian blue staining were used to compare the accumulation of different ligand conjugated nano-caariers in the aorta of atherosclerotic mice. Our results indicate that cRGD based targeting is more efficient than Col IV-tg-peptide in the early stage of atherosclerosis.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Deep tissue penetration of nanoparticles using pulsed-high intensity focused ultrasound

You Dong Gil,Yoon Hong Yeol,Jeon Sangmin,Um Wooram,손세진,Park Jae Hyung,권익찬,김광명 나노기술연구협의회 2017 Nano Convergence Vol.4 No.30

Recently, ultrasound (US)-based drug delivery strategies have received attention to improve enhanced permeation and retention (EPR) effect-based passive targeting efficiency of nanoparticles in vitro and in vivo conditions. Among the US treatment techniques, pulsed-high intensity focused ultrasound (pHIFU) have specialized for improving tissue penetration of various macromolecules and nanoparticles without irreversible tissue damages. In this study, we have demonstrated that pHIFU could be utilized to improve tissue penetration of fluorescent dye-labeled glycol chitosan nanoparticles (FCNPs) in femoral tissue of mice. pHIFU could improve blood flow of the targeted-blood vessel in femoral tissue. In addition, tissue penetration of FCNPs was specifically increased 5.7-, 8- and 9.3-folds than that of non-treated (0 W pHIFU) femoral tissue, when the femoral tissue was treated with 10, 20 and 50 W of pHIFU, respectively. However, tissue penetration of FCNPs was significantly reduced after 3 h post-pHIFU treatment (50 W). Because overdose (50 W) of pHIFU led to irreversible tissue damages, including the edema and chapped red blood cells. These overall results support that pHIFU treatment can enhance the extravasation and tissue penetration of FCNPs as well as induce irreversible tissue damages. We expect that our results can provide advantages to optimize pHIFU-mediated delivery strategy of nanoparticles for further clinical applications.