Hohyeon Lee

Multifunctional theranostic contrast agent for photoacoustics- and ultrasound-based tumor diagnosis and ultrasound-stimulated local tumor therapy.

Biomedical imaging-guided cancer therapy should have capabilities of both accurate tumor diagnosis and high therapeutic efficacy for the personalized treatment. Various biomedical imaging-guided cancer therapies are currently being investigated to overcome current limitations that include low sensitivity of diagnosis and poor drug delivery to the tumor site. Here, we report the development of a multifunctional theranostic contrast agent demonstrating high sensitive photoacoustic and ultrasound imaging and effective local delivery of anticancer drug to a tumor site. A microbubble (porphyrin-MB) was developed using phospholipid-porphyrin conjugates to enhance ultrasound and photoacoustic signal intensities simultaneously. Paclitaxel-loaded human serum albumin nanoparticles (PTX-HSA-NPs) were then conjugated onto the surface of the microbubble. The developed PTX-HSA-NPs conjugated porphyrin-MB (porphyrin-MB-NPs) provided sensitive, dual modal images of a tumor at 700 nm optimal laser wavelength for photoacoustic imaging and 5-14 MHz operating frequency for the ultrasound imaging. In addition, porphyrin-MB-NPs efficiently suppressed tumor growth by ultrasound exposure. Exposure to the focused ultrasound triggered the collapse of porphyrin-MB-NPs, resulting in the local release of PTX-HSA-NPs and enhanced penetration into the tumor site. The increased preferential accumulation and penetration of PTX-HSA-NPs suppressed tumor growth 10-fold more than without exposure to ultrasound. In conclusion, the developed porphyrin-MB-NPs establish a new paradigm in simultaneous bi-functional ultrasound/photoacoustic imaging diagnosis and locally triggered release of nanomedicine and enhanced chemotherapy efficiency.

Photoacoustic-based nanomedicine for cancer diagnosis and therapy.

Photoacoustic imaging is the latest promising diagnostic modality that has various advantages such as high spatial resolution, deep penetration depth, and use of non-ionizing radiation. It also employs a non-invasive imaging technique and optically functionalized imaging. The goal of this study was to develop a nanomedicine for simultaneous cancer therapy and diagnosis based on photoacoustic imaging. Human serum albumin nanoparticles loaded with melanin and paclitaxel (HMP-NPs) were developed using the desolvation technique. The photoacoustic-based diagnostic and chemotherapeutic properties of HMP-NPs were evaluated through in vitro and in vivo experiments. The size and zeta potential of the HMP-NPs were found to be 192.8±21.11nm and -22.2±4.39mV, respectively. In in vitro experiments, HMP-NPs produced increased photoacoustic signal intensity because of the loaded melanin and decreased cellular viability because of the encapsulated paclitaxel, compared to the free human serum albumin nanoparticles (the control). In vivo experiments showed that the HMP-NPs efficiently accumulated inside the tumor, resulting in the enhanced photoacoustic signal intensity in the tumor site, compared to the normal tissues. The in vivo chemotherapy study demonstrated that HMP-NPs had the capability to treat cancer for an extended period. In conclusion, HMP-NPs were simultaneously capable of photoacoustic diagnostic and chemotherapy against cancer.

Entrapped doxorubicin nanoparticles for the treatment of metastatic anoikis-resistant cancer cells

Metastasized and chemoresistant secondary breast cancer treatment commonly shows very low efficacy. A new efficient treatment method is required to overcome the limitation against the secondary breast cancer. In this study, anoikis-resistant breast cancer cells, MDA-MB-231 and MCF-7 were developed as models of chemoresistant and metastatic breast cancer. Doxorubicin encapsulating human serum albumin nanoparticles (HSA+DOX NPs) were fabricated to confirm the benefits of nanoparticles at the treatment of anoikis-resistant breast cancer cells. The side population (SP) fraction in the anoikis-resistant cancer cells was higher than the parental cells. HSA+DOX NPs were more cytotoxic to anoikis-resistant cancer cells than free doxorubicin. The confocal microscope images demonstrated HSA+DOX NPs to deliver more doxorubicin into cells compared to the free doxorubicin by bypassing the drug efflux pump systems of anoikis-resistant cancer cells. In this study, a nanomedicine-based drug delivery carrier shows a potential in treating a metastasized and chemoresistant breast cancer.

Microbubbles used for contrast enhanced ultrasound and theragnosis: a review of principles to applications

Abstract Ultrasound was developed several decades ago as a useful imaging modality, and it became the second most popular diagnostic tool due to its non-invasiveness, real-time capabilities, and safety. Additionally, ultrasound has been used as a therapeutic tool with several therapeutic agents and in nanomedicine. Ultrasound imaging is often used to diagnose many types of cancers, including breast, stomach, and thyroid cancers. In addition, ultrasound-mediated therapy is used in cases of joint inflammation, rheumatoid arthritis, and osteoarthritis. Microbubbles, when used as ultrasound contrast agents, can act as echo-enhancers and therapeutic agents, and they can play an essential role in ultrasound imaging and ultrasound-mediated therapy. Recently, various types of ultrasound contrast agents made of lipid, polymer, and protein shells have been used. Air, nitrogen, and perfluorocarbon are usually included in the core of the microbubbles to enhance ultrasound imaging, and therapeutic drugs are conjugated and loaded onto the surface or into the core of the microbubbles, depending on the purpose and properties of the substance. Many research groups have utilized ultrasound contrast agents to enhance the imaging signal in blood vessels or tissues and to overcome the blood–brain barrier or blood-retina barrier. These agents are also used to help treat diseases in various regions or systems of the body, such as the cardiovascular system, or as a cancer treatment. In addition, with the introduction of targeted moiety and multiple functional groups, ultrasound contrast agents are expected to have a potential future in ultrasound imaging and therapy. In this paper, we briefly review the principles of ultrasound and introduce the underlying theory, applications, limitations, and future perspectives of ultrasound contrast agents.

Reducible Polyethylenimine Nanoparticles for Efficient siRNA Delivery in Corneal Neovascularization Therapy

The aim of this study is to establish the safe and effective ocular delivery system of therapeutic small interfering RNA (siRNA) in corneal neovascularization therapy. The major hurdle present in siRNA-based corneal neovascularization (CNV) therapy is severe cytotoxicity caused by repetitive drug treatment. A reducible branched polyethylenimine (rBPEI)-based nanoparticle (NP) system is utilized as a new siRNA carrier as a hope for CNV therapy. The thiolated BPEI is readily self-crosslinked in mild conditions to make high molecular weight rBPEI thus allowing the creation of stable siRNA/rBPEI nanoparticles (siRNA-rBPEI-NPs). In the therapeutic region, the rBPEI polymeric matrix is effectively degraded into nontoxic LMW BPEI inside the reductive cytosol causing the rapid release of the encapsulated siRNA into the cytosol to carry out its function. The fluorescent-labeled siRNA-rBPEI-NPs can release siRNA into the entire corneal region after subconjuctival injection into the eye of Sprague Dawley rats thus confirming the proof of concept of this system.

Near-Infrared Plasmonic Assemblies of Gold Nanoparticles with Multimodal Function for Targeted Cancer Theragnosis

Here we report a novel assembly structure of near-infrared plasmonic gold nanoparticles (AuNPs), possessing both photoacoustic (PA) and photothermal (PT) properties. The template for the plasmonic AuNP assembly is a bioconjugate between short double-strand DNA (sh-dsDNA) and human methyl binding domain protein 1 (MBD1). MBD1 binds to methylated cytosine-guanine dinucleotides (mCGs) within the sequence of sh-dsDNA. Hexahistidine peptides on the engineered MBD1 function as a nucleation site for AuNP synthesis, allowing the construction of hybrid conjugates, sh-dsDNA-MBD1-AuNPs (named DMAs). By varying the length of sh-dsDNA backbone and the spacer between two adjacent mCGs, we synthesized three different DMAs (DMA_5mCG, DMA_9mCG, and DMA_21mCG), among which DMA_21mCG exhibited a comparable photothermal and surprisingly a higher photoacoustic signals, compared to a plasmonic gold nanorod. Further, epidermal growth factor receptor I (EGFR)-binding peptides are genetically attached to the MBD1 of DMA_21mCG, enabling its efficient endocytosis into EGFR-overexpressing cancer cells. Notably, the denaturation of MBD1 disassembled the DMA and accordingly released the individual small AuNPs (<5 nm) that can be easily cleared from the body through renal excretion without causing accumulation/toxicity problems. This DMA-based novel approach offers a promising platform for targeted cancer theragnosis based on simultaneous PA imaging and PT therapy.

Combination of chemotherapy and photodynamic therapy for cancer treatment with sonoporation effects

&NA; To overcome the limitations of single therapy, chemotherapy has been studied to be combined with photodynamic therapy. However, nanomedicine combining anticancer drug and photosensitizer still cannot address the insufficiency of drug delivery and the off‐targeting effect. To address drug delivery issue, we have developed a doxorubicin encapsulating human serum albumin nanoparticles/chlorin e6 encapsulating microbubbles (DOX‐NPs/Ce6‐MBs) complex system. Microbubbles enable ultrasound‐triggered local delivery via sonoporation for maximizing the drug delivery to a target site. In both in vitro and in vivo experiments, the developed DOX‐NPs/Ce6‐MBs drug delivery complex could be confirmed to transfer drugs deeply and effectively into cancerous tumors through the following three steps; (1) the local release of nanoparticles due to the cavitation of DOX‐NPs/Ce6‐MBs; (2) the enhanced extravasation of DOX‐NPs and Ce6‐liposome/micelle due to the sonoporation phenomenon; (3) the improved penetration of extravasated nanomedicines into the deep tumor region due to the mechanical energy of ultrasound. As a result, the developed DOX‐NPs/Ce6‐MBs complex with ultrasound irradiation showed increased therapeutic effects compared to the case where no ultrasound irradiation was applied. The DOX‐NPs/Ce6‐MBs was concluded from this study to be the optimal drug delivery system for external‐stimuli local combination (chemotherapy + PDT) therapy. Graphical abstract Figure. No Caption available. HighlightsNanoparticle/Microbubble complex can be an excellent carrier for multiple drugs.Microbubble in the complex can be used for both drug carrier and sonoporation.Sonoporation effects can improve local delivery efficiency of multiple drugs.Combination therapy can be improved by increasing tissue penetration of drugs.

Development and evaluation of a CEACAM6-targeting theranostic nanomedicine for photoacoustic-based diagnosis and chemotherapy of metastatic cancer

Metastasis is the leading cause of cancer-related deaths. A number of chemotherapeutic and early diagnosis strategies, including nanomedicine, have been developed to target metastatic tumor cells. However, simultaneous inhibition and imaging of metastasis is yet to be fully achieved. Methods: To overcome this limitation, we have developed human serum albumin-based nanoparticles (tHSA-NPs) with photoacoustic imaging capability, which target carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6). CEACAM6 is highly expressed in metastatic anoikis-resistant tumor cells. Results: In vitro, the CEACAM6-targeting tHSA-NPs efficiently targeted CEACAM6-overexpressing metastatic anoikis-resistant tumor cells. In vivo, CEACAM6-targeting tHSA-NPs administered intravenously to BALB/c nude mice efficiently inhibited lung metastasis in circulating anoikis-resistant tumor cells compared to the controls. In addition, anoikis-resistant tumor cells can be successfully detected by photoacoustic imaging, both in vitro and in vivo, using the intrinsic indocyanine green-binding affinity of albumin. Conclusion: In summary, the CEACAM6-targeting albumin-based nanoparticles allowed the delivery of drugs and photoacoustic imaging to metastatic anoikis-resistant tumor cells in vitro and in vivo. Based on the expression of CEACAM6 in a variety of tumors, CEACAM6-targeting nanomedicine might be used to target various types of metastatic tumor cells.

Semitransparent Ni/Ag/Ni electrode for use as anode in flexible red phosphorescent organic light-emitting diodes.

We suggested that Ni/Ag/Ni semitransparent electrodes for the exchange of indium-tin-oxide (ITO) electrode, which is the most commonly used as a transparent electrode in spite of the structural defects, limited supply of indium, and toxic, could be apply on flexible Organic Light-Emitting Diodes (OLEDs). Red phosphorescent OLEDs (PHOLEDs) using different types of electrodes as ITO and various conditions of Ni/Ag/Ni electrode were fabricated and analyzed. The electrical and optical properties of device using Ni/Ag/Ni electrode were improved than that of devices on ITO glass substrate at the 10,000 cd/m2 criterion due to the micro-cavity effect even though their transmittance has lower than ITO glass. In addition, we also fabricated red PHOLEDs of same structure on Ni/Ag/Ni flexible substrate of various conditions. As a result, flexible red PHOLED showed competitive characteristics compared to the device on a glass substrate. Therefore, this study could be suggested to additional research on flexible OLEDs display and light applications for ITO-free fabrication.