<i>In vivo</i> tumor diagnosis and photodynamic therapy <i>via</i> tumoral pH-responsive polymeric micelles

Koo, Heebeom,Lee, Hyejung,Lee, Sojin,Min, Kyung Hyun,Kim, Min Sang,Lee, Doo Sung,Choi, Yongseok,Kwon, Ick Chan,Kim, Kwangmeyung,Jeong, Seo Young Royal Society of Chemistry 2010 Chemical communications Vol.46 No.31

<P>We report protoporphyrin IX (PpIX) encapsulated pH-responsive micelles for cancer treatment. This system showed pH-responsive micellization/demicellization transition at tumoral acidic pH and enabled <I>in vivo</I> tumor diagnosis and therapy simultaneously.</P> <P>Graphic Abstract</P><P>A tumor tissue targeted system with tumoral pH-responsive micelles and photosensitizer (PpIX) was developed. This enables efficient tumor diagnosis and photodynamic therapy simultaneously. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c0cc01413c'> </P>

Polymeric Nanoparticles and Hydrogels for Therapy

Heebeom Koo(구희범) 한국고분자학회 2021 한국고분자학회 학술대회 연구논문 초록집 Vol.46 No.1

In this century, nanoparticles (NPs) have been given a great amount of attention by biomedical researchers. NPs can disperse hydrophobic drugs stably in aqueous conditions without aggregation. Importantly, their physicochemical properties, including size and surface charge, can easily be modified by adjusting the component molecules or fabrication method. NPs can delay the early release of drugs in order to allow enough time for therapeutic action. Along with NPs, hydrogel is also another representative material for biomedical applications. Hydrogels are three-dimensional network that contain large amount of water, and have used for drug delivery, cell therapy, and tissue engineering. In our recent studies, polymeric NPs and hydrogels have shown promising results in hearing loss and vocal cord paralysis, respectively.

In Vivo Targeted Delivery of Nanoparticles for Theranosis

Koo, Heebeom,Huh, Myung Sook,Sun, In-Cheol,Yuk, Soon Hong,Choi, Kuiwon,Kim, Kwangmeyung,Kwon, Ick Chan American Chemical Society 2011 Accounts of chemical research Vol.44 No.10

<P>Therapy and diagnosis are two major categories in the clinical treatment of disease. Recently, the word “theranosis” has been created, combining the words to describe the implementation of these two distinct pursuits simultaneously. For successful theranosis, the efficient delivery of imaging agents and drugs is critical to provide sufficient imaging signal or drug concentration in the targeted disease site. To achieve this purpose, biomedical researchers have developed various nanoparticles composed of organic or inorganic materials. However, the targeted delivery of these nanoparticles in animal models and patients remains a difficult hurdle for many researchers, even if they show useful properties in cell culture condition.</P><P>In this Account, we review our strategies for developing theranostic nanoparticles to accomplish in vivo targeted delivery of imaging agents and drugs. By applying these rational strategies, we achieved fine multimodal imaging and successful therapy. Our first strategy involves physicochemical optimization of nanoparticles for long circulation and an enhanced permeation and retention (EPR) effect. We accomplished this result by testing various materials in mouse models and optimizing the physical properties of the materials with imaging techniques. Through these experiments, we developed a glycol chitosan nanoparticle (CNP), which is suitable for angiogenic diseases, such as cancers, even without an additional targeting moiety. The in vivo mechanism of this particle was examined through rationally designed experiments. In addition, we evaluated and compared the biodistribution and target-site accumulation of bare and drug-loaded nanoparticles.</P><P>We then focus on the targeting moieties that bind to cell surface receptors. Small peptides were selected as targeting moieties because of their stability, low cost, size, and activity per unit mass. Through phage display screening, the interleukin-4 receptor binding peptide was discovered, and we combined it with our nanoparticles. This product accumulated efficiently in atherosclerotic regions or tumors during both imaging and therapy. We also developed hyaluronic acid nanoparticles that can bind efficiently to the CD44 antigen receptors abundant in many tumor cells. Their delivery mechanism is based on both physicochemical optimization for the EPR effect and receptor-mediated endocytosis by their hyaluronic acid backbone.</P><P>Finally, we introduce the stimuli-responsive system related to the chemical and biological changes in the target disease site. Considering the relatively low pH in tumors and ischemic sites, we applied pH-sensitive micelle to optical imaging, magnetic resonance imaging, anticancer drug delivery, and photodynamic therapy. In addition, we successfully evaluated the in vivo imaging of enzyme activity at the target site with an enzyme-specific peptide sequence and CNPs.</P><P>On the basis of these strategies, we were able to develop self-assembled nanoparticles for in vivo targeted delivery, and successful results were obtained with them in animal models for both imaging and therapy. We anticipate that these rational strategies, as well as our nanoparticles, will be applied in both the diagnosis and therapy of many human diseases. These theranostic nanoparticles are expected to greatly contribute to optimized therapy for individual patients as personalized medicine, in the near future.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/achre4/2011/achre4.2011.44.issue-10/ar2000138/production/images/medium/ar-2011-000138_0003.gif'></P>

Controlled Detachment of Chemically Glued Cells

Koo, Heebeom,Hahn, Sei Kwang,Yun, Seok Hyun American Chemical Society 2016 Bioconjugate chemistry Vol.27 No.11

<P>We demonstrate a chemically detachable cell glue system based on linkers containing disulfide bonds as well as functional groups for metabolic glycoengineering and bioorthogonal click chemistry. Azide groups are generated on the cell surface by metabolic glycoengineering, and they are further modified into tetrazine (Tz) or trans-cyclooctene (TCO) using rationally designed cross-linkers. When the Tz-modified and TCO-modified cells are mixed together, cell gluing between these two cell groups is established by Tz-TCO click chemistry. This artificial cell cell adhesion can be broken by the administration of glutathione (5 mM), which triggers the degradation of disulfide bonds. Both the gluing and detachment processes are rapid (<10 min) and minimally cytotoxic.</P>

DNA Amplification in Neutral Liposomes for Safe and Efficient Gene Delivery

Lee, Sangmin,Koo, Heebeom,Na, Jin Hee,Lee, Kyung Eun,Jeong, Seo Young,Choi, Kuiwon,Kim, Sun Hwa,Kwon, Ick Chan,Kim, Kwangmeyung American Chemical Society 2014 ACS NANO Vol.8 No.5

<P>In general, traditional gene carriers contain strong cationic charges to efficiently load anionic genes, but this cationic character also leads to destabilization of plasma membranes and causes severe cytotoxicity. Here, we developed a PCR-based nanofactory as a safe gene delivery system. A few template plasmid DNA can be amplified by PCR inside liposomes about 200 nm in diameter, and the quantity of loaded genes highly increased by more than 8.8-fold. The liposome membrane was composed of neutral lipids free from cationic charges. Consequently, this system is nontoxic, unlike other traditional cationic gene carriers. Intense red fluorescent protein (RFP) expression in CHO-K1 cells showed that the amplified genes could be successfully transfected to cells. Animal experiments with the luciferase gene also showed <I>in vivo</I> gene expression by our system without toxicity. We think that this PCR-based nanofactory system can overcome the toxicity problem that is the critical limitation of current gene delivery to clinical application.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancac3/2014/ancac3.2014.8.issue-5/nn501106a/production/images/medium/nn-2014-01106a_0002.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/nn501106a'>ACS Electronic Supporting Info</A></P>

Chemical Tumor-Targeting of Nanoparticles Based on Metabolic Glycoengineering and Click Chemistry

Lee, Sangmin,Koo, Heebeom,Na, Jin Hee,Han, Seung Jin,Min, Hyun Su,Lee, So Jin,Kim, Sun Hwa,Yun, Seok Hyun,Jeong, Seo Young,Kwon, Ick Chan,Choi, Kuiwon,Kim, Kwangmeyung American Chemical Society 2014 ACS NANO Vol.8 No.3

<P>Tumor-targeting strategies for nanoparticles have been predominantly based on optimization of physical properties or conjugation with biological ligands. However, their tumor-targeting abilities remain limited and insufficient. Furthermore, traditional biological binding molecules have intrinsic limitations originating from the limited amount of cellular receptors and the heterogeneity of tumor cells. Our two-step <I>in vivo</I> tumor-targeting strategy for nanoparticles is based on metabolic glycoengineering and click chemistry. First, an intravenous injection of precursor-loaded glycol chitosan nanoparticles generates azide groups on tumor tissue specifically by the enhanced permeation and retention (EPR) effect followed by metabolic glycoengineering. These ‘receptor-like’ chemical groups then enhance the tumor-targeting ability of drug-containing nanoparticles by copper-free click chemistry <I>in vivo</I> during a second intravenous injection. The advantage of this protocol over traditional binding molecules is that there are significantly more binding molecules on the surface of most tumor cells regardless of cell type. The subsequent enhanced tumor-targeting ability can significantly enhance the cancer therapeutic efficacy in animal studies.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancac3/2014/ancac3.2014.8.issue-3/nn406584y/production/images/medium/nn-2013-06584y_0012.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/nn406584y'>ACS Electronic Supporting Info</A></P>

Behavior of Nanoparticles in the eye

Hyungwon MOON,Heebeom KOO,Hyunkoo HAN,Jinhee NA,Kwangmeyung KIM,Hyuncheol KIM 한국생물공학회 2011 한국생물공학회 학술대회 Vol.2011 No.10

The Movement of Glycol Chitosan Nanoparticles in Rat Vitreous and Retina

Hyounkoo Han,Heebeom Koo,Jin Hee Na,Kwangmeyung Kim,Hyuncheol Kim 한국생물공학회 2011 한국생물공학회 학술대회 Vol.2011 No.4

Precise Targeting of Liver Tumor Using Glycol Chitosan Nanoparticles: Mechanisms, Key Factors, and Their Implications

Na, Jin Hee,Koo, Heebeom,Lee, Sangmin,Han, Seung Jin,Lee, Kyung Eun,Kim, Sunjin,Lee, Haeshin,Lee, Seulki,Choi, Kuiwon,Kwon, Ick Chan,Kim, Kwangmeyung American Chemical Society 2016 MOLECULAR PHARMACEUTICS Vol.13 No.11

<P>Herein, we elucidated the mechanisms and key factors for the tumor-targeting ability of nanoparticles that presented high targeting efficiency for liver tumor. We used several different nanoparticles with sizes of 200-300 nm, including liposome nanoparticles (LNPs), polystyrene nanoparticles (PNPs) and glycol chitosan-5 beta-cholanic acid nanoparticles (CNPs). Their sizes are suitable for the enhanced permeation and retention (EPR) effect in literature. Different in vitro characteristics, such as the particle structure, stability, and bioinertness, were carefully analyzed with and without serum proteins. Also, pH-dependent tumor cell uptakes of nanoparticles were studied using fluorescence microscopy. Importantly, CNPs had sufficient stability and bioinertness to maintain their nanoparticle structure in the bloodstream, and they also presented prolonged circulation time in the body (blood circulation half-life T-1/2 = about 12.2 h), compared to the control nanoparticles. Finally, employing liver tumor bearing mice, we also observed that CNPs had excellent liver tumor targeting ability in vivo, while LNPs and PNPs demonstrated lower tumor-targeting efficiency due to the nonspecific accumulation in normal liver tissue. Liver tumor models were produced by laparotomy and direct injection of HT29 tumor cells into the left lobe of the liver of athymic nude mice. This study provides valuable information concerning the key factors for the tumor-targeting ability of nanoparticles such as stability, bioinertness, and rapid cellular uptake at targeted tumor tissues.</P>

Nano-sized metabolic precursors for heterogeneous tumor-targeting strategy using bioorthogonal click chemistry <i>in vivo</i>

Lee, Sangmin,Jung, Seulhee,Koo, Heebeom,Na, Jin Hee,Yoon, Hong Yeol,Shim, Man Kyu,Park, Jooho,Kim, Jong-Ho,Lee, Seulki,Pomper, Martin G.,Kwon, Ick Chan,Ahn, Cheol-Hee,Kim, Kwangmeyung IPC Science and Technology Press 2017 Biomaterials Vol.148 No.-

<P><B>Abstract</B></P> <P>Herein, we developed nano-sized metabolic precursors (Nano-MPs) for new tumor-targeting strategy to overcome the intrinsic limitations of biological ligands such as the limited number of biological receptors and the heterogeneity in tumor tissues. We conjugated the azide group-containing metabolic precursors, triacetylated <I>N</I>-azidoacetyl-<SMALL> <I>D</I> </SMALL>-mannosamine to generation 4 poly(amidoamine) dendrimer backbone. The nano-sized dendrimer of Nano-MPs could generate azide groups on the surface of tumor cells homogeneously regardless of cell types via metabolic glycoengineering. Importantly, these exogenously generated ‘artificial chemical receptors’ containing azide groups could be used for bioorthogonal click chemistry, regardless of phenotypes of different tumor cells. Furthermore, in tumor-bearing mice models, Nano-MPs could be mainly localized at the target tumor tissues by the enhanced permeation and retention (EPR) effect, and they successfully generated azide groups on tumor cells <I>in vivo</I> after an intravenous injection. Finally, we showed that these azide groups on tumor tissues could be used as ‘artificial chemical receptors’ that were conjugated to bioorthogonal chemical group-containing liposomes via <I>in vivo</I> click chemistry in heterogeneous tumor-bearing mice. Therefore, overall results demonstrated that our nano-sized metabolic precursors could be extensively applied to new alternative tumor-targeting technique for molecular imaging and drug delivery system, regardless of the phenotype of heterogeneous tumor cells.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>