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105. Polymer Thin Film–Induced Tumor Spheroids Acquire Cancer Stem Cell–like Properties

Author

Choi, Minsuk, primary, Yu, Seung J., additional, Choi, Yoonjung, additional, Lee, Hak R., additional, Lee, Eunbeol, additional, Lee, Eunjung, additional, Lee, Yumi, additional, Song, Junhyuk, additional, Son, Jin G., additional, Lee, Tae G., additional, Kim, Jin Y., additional, Kang, Sukmo, additional, Baek, Jieung, additional, Lee, Daeyoup, additional, Im, Sung G., additional, and Jon, Sangyong, additional

Published
2018
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116. Nanoparticles targeting extra domain B of fibronectin-specific to the atherosclerotic lesion types III, IV, and V-enhance plaque detection and cargo delivery

Author

Yu, Mikyung, primary, Ortega, Carleena A., additional, Si, Kevin, additional, Molinaro, Roberto, additional, Schoen, Frederick J., additional, Leitao, Renata F. C., additional, Xu, Xiaoding, additional, Mahmoudi, Morteza, additional, Ahn, Suyeon, additional, Liu, Jerry, additional, Saw, Phei Er, additional, Lee, In-Hyun, additional, Brayner, Mirna M. B., additional, Lotfi, Azita, additional, Shi, Jinjun, additional, Libby, Peter, additional, Jon, Sangyong, additional, and Farokhzad, Omid C., additional

Published
2018
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121. Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism inLdlr −/−Mice

Author

Yu, Mikyung, primary, Amengual, Jaume, additional, Menon, Arjun, additional, Kamaly, Nazila, additional, Zhou, Felix, additional, Xu, Xiaoding, additional, Saw, Phei Er, additional, Lee, Seung‐Joo, additional, Si, Kevin, additional, Ortega, Carleena Angelica, additional, Choi, Won Il, additional, Lee, In‐Hyun, additional, Bdour, Yazan, additional, Shi, Jinjun, additional, Mahmoudi, Morteza, additional, Jon, Sangyong, additional, Fisher, Edward A., additional, and Farokhzad, Omid C., additional

Published
2017
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125. Parallel microfluidic synthesis of size-tunable polymeric nanoparticles using 3D flow focusing towards in vivo study

Author

Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Mechanical Engineering, Koch Institute for Integrative Cancer Research at MIT, Lim, Jong-Min, Bertrand, Nicolas, Valencia, Pedro Miguel, Rhee, Minsoung, Langer, Robert S, Jon, Sangyong, Karnik, Rohit, Farokhzad, Omid C., Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Mechanical Engineering, Koch Institute for Integrative Cancer Research at MIT, Lim, Jong-Min, Bertrand, Nicolas, Valencia, Pedro Miguel, Rhee, Minsoung, Langer, Robert S, Jon, Sangyong, Karnik, Rohit, and Farokhzad, Omid C.

Abstract

Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility in physicochemical properties of NPs compared to bulk synthesis methods. However, applications of microfluidic synthesis are typically limited to in vitro studies due to low production rates. Herein, we report the parallelization of NP synthesis by 3D hydrodynamic flow focusing (HFF) using a multilayer microfluidic system to enhance the production rate without losing the advantages of reproducibility, controllability, and robustness. Using parallel 3D HFF, polymeric poly(lactide-co-glycolide)-b-polyethyleneglycol (PLGA-PEG) NPs with sizes tunable in the range of 13-150 nm could be synthesized reproducibly with high production rate. As a proof of concept, we used this system to perform in vivo pharmacokinetic and biodistribution study of small (20 nm diameter) PLGA-PEG NPs that are otherwise difficult to synthesize. Microfluidic parallelization thus enables synthesis of NPs with tunable properties with production rates suitable for both in vitro and in vivo studies.

Published
2017

129. Substituent Effects in BODIPY in Live Cell Imaging

Author

Mulay, Sandip V., primary, Yudhistira, Tesla, additional, Choi, Minsuk, additional, Kim, Youngsam, additional, Kim, Jinjoo, additional, Jang, Yoon Jeong, additional, Jon, Sangyong, additional, and Churchill, David G., additional

Published
2016
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136. Enhanced Doubly Activated Dual Emission Fluorescent Probes for Selective Imaging of Glutathione or Cysteine in Living Systems

Author

Mulay, Sandip V., Kim, Youngsam, Choi, Minsuk, Lee, Dong Yun, Choi, Jonghoon, Lee, Yunho, Jon, Sangyong, and Churchill, David G.

Abstract

The development of novel fluorescent probes for monitoring the concentration of various biomolecules in living systems has great potential for eventual early diagnosis and disease intervention. Selective detection of competitive species in biological systems is a great challenge for the design and development of fluorescent probes. To improve on the design of fluorescent coumarin-based biothiol sensing technologies, we have developed herein an enhanced dual emission doubly activated system (DACP-1and the closely related DACP-2) for the selective detection of glutathione (GSH) through the use of one optical channel and the detection of cysteine (Cys) by another channel. A phenylselenium group present at the 4-position completely quenches the fluorescence of the probe via photoinduced electron transfer to give a nonfluorescent species. Probes are selective for glutathione (GSH) in the red region and for cysteine/homocysteine (Cys/Hcy) in the green region. When they were treated with GSH, DACP-1and DACP-2showed strong fluorescence enhancement in comparison to that for closely related species such as amino acids, including Cys/Hcy. Fluorescence quantum yields (ΦF) increased for the red channel (<0.001 to 0.52 (DACP-1) and 0.48 (DACP-2)) and green channel (Cys) (<0.001 to 0.030 (DACP-1) and 0.026 (DACP-2)), respectively. Competing fluorescent enhancements upon addition of closely related species were negligible. Fast responses, improved water solubility, and good cell membrane permeability were all properly established with the use of DACP-1and DACP-2. Live human lung cancer cells and fibroblasts imaged by confocal microscopy, as well as live mice tumor model imaging, confirmed selective detection.

Published
2024
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137. Targeted Cancer Therapy Using Fusion Protein of TNFα and Tumor-Associated Fibronectin-Specific Aptide

Author

Jeon, Hyungsu, Kim, Daejin, Choi, Minsuk, Kang, Sukmo, Kim, Jin Yong, Kim, Sunghyun, and Jon, Sangyong

Abstract

Tumor necrosis factor-α has shown potent antitumor effects in preclinical and clinical studies. However, severe side effects at less than therapeutic doses have limited its systemic delivery, prompting the need for a new strategy for targeted delivery of the protein to tumors. Here, we report a fusion protein of mouse tumor necrosis factor (TNF)-α (mTNFα) and a cancer-targeting, high-affinity aptide and investigate its therapeutic efficacy in tumor-bearing mice. A fusion protein consisting of mTNFα, a linker, and an aptide specific to extra domain B (EDB) of fibronectin (APTEDB), designated mTNFα-APTEDB, was successfully produced by expression in Escherichia coli. mTNFα-APTEDBretained specificity and affinity for its target, EDB. In mice bearing EDB-overexpressing fibrosarcomas, mTNFα-APTEDBshowed greater efficacy in inhibiting tumor growth than mTNFα alone or mTNFα linked to a nonrelevant aptide, without causing an appreciable loss in body weight. Moreover, in vivoantitumor efficacy was further significantly increased by combination treatment with the chemotherapeutic drug, melphalan, suggesting a synergistic effect attributable to enhanced drug uptake into the tumor as a result of TNFα-mediated enhanced vascular permeability. These results suggest that a fusion protein of mTNFα with a cancer-targeting peptide could be a new anticancer therapeutic option for ensuring potent antitumor efficacy after systemic delivery.

Published
2024
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138. Antibody-Assisted Delivery of a Peptide–Drug Conjugate for Targeted Cancer Therapy

Author

Kim, Hyungjun, Hwang, Dobeen, Choi, Minsuk, Lee, Soyoung, Kang, Sukmo, Lee, Yonghyun, Kim, Sunghyun, Chung, Junho, and Jon, Sangyong

Abstract

A number of cancer-targeting peptide-drug conjugates (PDCs) have been explored as alternatives to antibody-drug conjugates (ADCs) for targeted cancer therapy. However, the much shorter circulation half-life of PDCs compared with ADCs in vivo has limited their therapeutic value and thus their translation into the clinic, highlighting the need to develop new approaches for extending the half-life of PDCs. Here, we report a new strategy for targeted cancer therapy of a PDC based on a molecular hybrid between an antihapten antibody and a hapten-labeled PDC. An anticotinine antibody (Abcot) was used as a model antihapten antibody. The anticancer drug SN38 was linked to a cotinine-labeled aptide specific to extra domain B of fibronectin (cot-APTEDB), yielding the model PDC, cot-APTEDB-SN38. The cotinine-labeled PDC showed specific binding to and cytotoxicity toward an EDB-overexpressing human glioblastoma cell line (U87MG) and also formed a hybrid complex (HC) with Abcotin situ, designated HC[cot-APTEDB–SN38/Abcot]. In glioblastoma-bearing mice, in situ HC[cot-APTEDB–SN38/Abcot] significantly extended the circulation half-life of cot-APTEDB-SN38 in blood, and it enhanced accumulation and penetration within the tumor and, ultimately, inhibition of tumor growth. These findings suggest that the present platform holds promise as a new, targeted delivery strategy for PDCs in anticancer therapy.

Published
2024
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139. Polymer Thin Films with Tunable Acetylcholine-like Functionality Enable Long-Term Culture of Primary Hippocampal Neurons

Author

Yu, Seungyoon B., Baek, Jieung, Choi, Minsuk, Oh, Youjin, Lee, Hak Rae, Yu, Seung Jung, Lee, Eunjung, Sohn, Jong-Woo, Im, Sung Gap, and Jon, Sangyong

Abstract

In vitroculture systems for primary neurons have served as useful tools for neuroscience research. However, conventional in vitroculture methods are still plagued by challenging problems with respect to applications to neurodegenerative disease models or neuron-based biosensors and neural chips, which commonly require long-term culture of neural cells. These impediments highlight the necessity of developing a platform capable of sustaining neural activity over months. Here, we designed a series of polymeric bilayers composed of poly(glycidyl methacrylate) (pGMA) and poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA), designated pGMA:pDMAEMA, using initiated chemical vapor deposition (iCVD). Harnessing the surface-growing characteristics of iCVD polymer films, we were able to precisely engraft acetylcholine-like functionalities (tertiary amine and quaternary ammonium) onto cell culture plates. Notably, pGD3, a pGMA:pDMAEMA preparation with the highest surface composition of quaternary ammonium, fostered the most rapid outgrowth of neural cells. Clear contrasts in neural growth and survival between pGD3 and poly-l-lysine (PLL)-coated surfaces became apparent after 30 days in vitro(DIV). Moreover, brain-derived neurotrophic factor level continuously accumulated in pGD3-cultured neurons, reaching a 3-fold increase at 50 DIV. Electrophysiological measurements at 30 DIV revealed that the pGD3 surface not only promoted healthy maturation of hippocampal neurons but also enhanced the function of hippocampal ionotropic glutamate receptors in response to synaptic glutamate release. Neurons cultured long-term on pGD3 also maintained their characteristic depolarization-induced Ca2+influx functions. Furthermore, primary hippocampal neurons cultured on pGD3 showed long-term survival in a stable state up to 90 daysfar longer than neurons on conventional PLL-coated surfaces. Taken together, our findings indicate that a polymer thin film with optimal acetylcholine-like functionality enables a long-term culture and survival of primary neurons.

Published
2024
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140. Enhanced Electron Transfer Mediated by Conjugated Polyelectrolyte and Its Application to Washing-Free DNA Detection

Author

Park, Seonhwa, Jeong, Ji-Eun, Le, Van Sang, Seo, Jeongwook, Yu, Byeongjun, Kim, Da-Young, Kwon, Se-Hun, Jon, Sangyong, Woo, Han Young, and Yang, Haesik

Abstract

Direct electron transfer between a redox label and an electrode requires a short working distance (<1–2 nm), and in general an affinity biosensor based on direct electron transfer requires a finely smoothed Au electrode to support efficient target binding. Here we report that direct electron transfer over a longer working distance is possible between (i) an anionic π-conjugated polyelectrolyte (CPE) label having many redox-active sites and (ii) a readily prepared, thin polymeric monolayer-modified indium–tin oxide electrode. In addition, the long CPE label (∼18 nm for 10 kDa) can approach the electrode within the working distance after sandwich-type target-specific binding, and fast CPE-mediated oxidation of ammonia borane along the entire CPE backbone affords high signal amplification.

Published
2024
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144. Bioengineered yeast-derived vacuoles with enhanced tissue-penetrating ability for targeted cancer therapy

Author

Gujrati, Vipul, primary, Lee, Miriam, additional, Ko, Young-Joon, additional, Lee, Sangeun, additional, Kim, Daejin, additional, Kim, Hyungjun, additional, Kang, Sukmo, additional, Lee, Soyoung, additional, Kim, Jinjoo, additional, Jeon, Hyungsu, additional, Kim, Sun Chang, additional, Jun, Youngsoo, additional, and Jon, Sangyong, additional

Published
2015
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147. Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr−/− Mice.

Author

Yu, Mikyung, Amengual, Jaume, Menon, Arjun, Kamaly, Nazila, Zhou, Felix, Xu, Xiaoding, Saw, Phei Er, Lee, Seung‐Joo, Si, Kevin, Ortega, Carleena Angelica, Choi, Won Il, Lee, In‐Hyun, Bdour, Yazan, Shi, Jinjun, Mahmoudi, Morteza, Jon, Sangyong, Fisher, Edward A., and Farokhzad, Omid C.

Published
2017
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148. A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin.

Author

Saw, Phei Er, Park, Jinho, Jon, Sangyong, and Farokhzad, Omid C.

Subjects
BREAST cancer, DRUG resistance, CANCER, PHARMACOLOGY, SMALL interfering RNA
Abstract

A major problem with cancer chemotherapy begins when cells acquire resistance. Drug-resistant cancer cells typically upregulate multi-drug resistance proteins such as P-glycoprotein (P-gp). However, the lack of overexpressed surface biomarkers has limited the targeted therapy of drug-resistant cancers. Here we report a drug-delivery carrier decorated with a targeting ligand for a surface marker protein extra-domain B(EDB) specific to drug-resistant breast cancer cells as a new therapeutic option for the aggressive cancers. We constructed EDB-specific aptide (APT EDB )-conjugated liposome to simultaneously deliver siRNA(siMDR1) and Dox to drug-resistant breast cancer cells. APT EDB -LS(Dox,siMDR1) led to enhanced delivery of payloads into MCF7/ADR cells and showed significantly higher accumulation and retention in the tumors. While either APT EDB -LS(Dox) or APT EDB -LS(siMDR1) did not lead to appreciable tumor retardation in MCF7/ADR orthotropic model, APT EDB -LS(Dox,siMDR1) treatment resulted in significant reduction of the drug-resistant breast tumor. Taken together, this study provides a new strategy of drug delivery for drug-resistant cancer therapy. [ABSTRACT FROM AUTHOR]

Published
2017
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