Browsing by Author "Chen, Fang-Ming"

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Bispecific antibody (HER2 x mPEG) enhances anti-cancer effects by precise targeting and accumulation of mPEGylated liposomes
(2020-07-15)
Chen, I-Ju
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Cheng, Yi-An
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Ho, Kai-Wen
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Lin, Wen-Wei
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Cheng, Kai-Wen
Targeted antibodies and methoxy-PEGylated nanocarriers have gradually become a mainstream of cancer therapy. To increase the anti-cancer effects of targeted antibodies combined with mPEGylated liposomes (mPEG-liposomes), we describe a bispecific antibody in which an anti-methoxy-polyethylene glycol scFv (alpha mPEG scFv) was fused to the C-terminus of an anti-HER2 (alpha HER2) antibody to generate a HER2 x mPEG BsAb that retained the original efficacy of a targeted antibody while actively attracting mPEG-liposomes to accumulate at tumor sites. HER2 xmPEG BsAb can simultaneously bind to HER2high expressing MCF7/HER2 tumor cells and mPEG molecules on mPEG-liposomal doxorubicin (Lipo-Dox). Pre-incubation of HER2 x mPEG BsAb with cells increased the endocytosis of Lipo-DiD and enhanced the cytotoxicity of Lipo-Dox to MCF7/HER2 tumor cells. Furthermore, pre-treatment of HER2 x mPEG BsAb enhanced the tumor accumulation and retention of Lipo-DiR 2.2-fold in HER2-high expressing MCF7/HER2 tumors as compared to HER2-low expressing MCF7/neol tumors. Importantly, HER2 x mPEG BsAb plus Lipo-Dox significantly suppressed tumor growth as compared to control BsAb plus Lipo-Dox in MCF7/HER2 tumor-bearing mice. These results indicate that HER2 x mPEG BsAb can enhance tumor accumulation of mPEG-liposomes to improve the therapeutic efficacy of combination treatment. Anti-mPEG scFv can be fused to any kind of targeted antibody to generate BsAbs to actively attract mPEG-drugs and improve anti-cancer efficacy. Statement of Significance Antibody targeted therapy and PEGylated drugs have gradually become the mainstream of cancer therapy. To enhance the anti-cancer effects of targeted antibodies combined with PEGylated drugs is very important. To this aim, we fused an anti-PEG scFv to the C-terminal of HER2 targeted antibodies to generate a HER2xmPEG bispecific antibody (BsAb) to retain the original efficacy of targeted antibody whilst actively attract mPEG-liposomal drugs to accumulate at tumor sites. The present study demonstrates pretreatment of HER2xmPEG BsAb can enhance tumor accumulation of mPEG-liposomal drugs to improve the therapeutic efficacy of combination treatment. Anti-mPEG scFv can be fused to any kind of targeted antibody to generate BsAbs to actively attract mPEG-drugs and improve anti-cancer efficacy. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
Enhanced drug internalization and therapeutic efficacy of PEGylated nanoparticles by one-step formulation with anti-mPEG bispecific antibody in intrinsic drug-resistant breast cancer
(2019-08-01)
Cheng, Yi-An
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Chen, I-Ju
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Su, Yu-Cheng
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Cheng, Kai-Wen
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Lu, Yun-Chi
For those patients with HER2-overexpressing breast cancer, treatment with PEGylated liposomal doxorubicin (PLD) is inefficacious due to the intrinsic low sensitivity to doxorubicin. A very large increase in drug accumulation by active targeting may enhance the therapeutic efficacy of PLD. We established a humanized bispecific antibody (BsAb; mPEG x HER2) which has dual specificity for methoxy-polyethylene glycol (mPEG) and human epidermal growth factor receptor 2 (HER2) to enhance the specificity, internalization and anticancer activity of PLD for cancer cells that overexpress HER2. One-step formulation of PLD with mPEG x HER2 converted the PLD into HER2 targeted liposomes that were stable at 4 degrees C in PBS as well as at 37 degrees C in the presence of serum. alpha HER2/PLD induced receptor-mediated endocytosis and enhanced doxorubicin accumulation in MCF7/HER2 (HER2-amplified) breast cancer cells. alpha HER2/PLD also displayed more than 200-fold increased cytotoxicity to MCF7/HER2 cells and 28-fold increased cytotoxicity to drug-resistant MDA-MB-361 cells with a physical deletion of the TOP2A gene. alpha HER2/PLD specifically accumulated doxorubicin in the nucleus of cancer cells in tumor-bearing mice and produced significantly greater antitumor activity against MCF7/HER2 (P < 0.0001) and MDA-MB-361 (P < 0.05) tumors as compared to untargeted PLD. Furthermore, the cardiotoxicity of alpha HER2/PLD was similar to that of PLD in human cardiomyocytes and in mice. Our results indicate that the one-step formulation of PLD by mPEG x HER2 is a simple method to confer tumor specificity, increase drug internalization and enhance the anticancer activity of PLD against HER2-overexpressing and doxorubicin-resistant breast cancer.
Fabrication and characterization of back-side illuminated InGaN/GaN solar cells with periodic via-holes etching and Bragg mirror processes
(2014-08-25)
Chang, Yi-An
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Chen, Fang-Ming
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Tsai, Yu-Lin
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Chang, Ching-Wen
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Chen, Kuo-Ju
In this study, the design and fabrication schemes of back-side illuminated InGaN/GaN solar cells with periodic via-holes etching and Bragg mirror processes are presented. Compared to typical front-side illuminated solar cells, the improvements of open-circuit voltage (V-oc) from 1.88 to 1.94 V and short-circuit current density (J(sc)) from 0.84 to 1.02 mA/cm(2) are observed. Most significantly, the back-side illuminated InGaN/GaN solar cells exhibit an extremely high fill factor up to 85.5%, leading to a conversion efficiency of 1.69% from 0.66% of typical front-side illuminated solar cells under air mass 1.5 global illuminations. Moreover, the effects of bottom Bragg mirrors on the photovoltaic characteristics of back-side illuminated solar cells are studied by an advanced simulation program. The results show that the J(sc) could further be improved with a factor of 10% from the original back-side illuminated solar cell by the structure optimization of bottom Bragg mirrors. (C) 2014 Optical Society of America
Humanized bispecific antibody (mPEG x HER2) rapidly confers PEGylated nanoparticles tumor specificity for multimodality imaging in breast cancer
(2020-08-27)
Cheng, Yi-An
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Wu, Tung-Ho
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Wang, Yun-Ming
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Cheng, Tian-Lu
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Chen, I-Ju
Background: Developing a universal strategy to improve the specificity and sensitivity of PEGylated nanoaparticles (PEG-NPs) for assisting in the diagnosis of tumors is important in multimodality imaging. Here, we developed the anti-methoxypolyethylene glycol (mPEG) bispecific antibody (BsAb; mPEG x HER2), which has dual specificity for mPEG and human epidermal growth factor receptor 2 (HER2), with a diverse array of PEG-NPs to confer nanoparticles with HER2 specificity and stronger intensity. Result: We used a one-step formulation to rapidly modify the nanoprobes with mPEG x HER2 and optimized the modified ratio of BsAbs on several PEG-NPs (Lipo-DiR, SPIO, Qdot and AuNP). The alpha HER2/PEG-NPs could specifically target MCF7/HER2 cells (HER2(++)) but not MCF7/neo1 cells (HER2(+/-)). The alpha HER2/Lipo-DiR and alpha HER2/SPIO could enhance the sensitivity of untargeted PEG-NPs on MCF7/HER2 (HER2(++)). In in vivo imaging, alpha HER2/Lipo-DiR and alpha HER2/SPIO increased the specific targeting and enhanced PEG-NPs accumulation at 175% and 187% on 24 h, respectively, in HER2-overexpressing tumors. Conclusion: mPEG x HER2, therefore, provided a simple one-step formulation to confer HER2-specific targeting and enhanced sensitivity and contrast intensity on HER2 positive tumors for multimodality imaging.
Numerical analysis on the effect of electron blocking layer in 365-nm ultraviolet light-emitting diodes
(2015-01-01)
Chen, Fang-Ming
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Chang, Jih-Yuan
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Kuo, Yen-Kuang
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Lin, Bing-Cheng
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Kuo, Hao-Chung
For 365-nm ultraviolet light-emitting diodes (UV LEDs), an electron blocking layer (EBL) is usually utilized to mitigate electron overflow. However, using EBL might obstruct holes from injecting into the active region. Moreover, the large polarization field in conventional EBL might also pull down the effective barrier height for electrons, and thus the electrons could easily overflow to the p-side region. To solve the above drawbacks, in this study, the Al content and p-doping concentration of the EBL in typical 365-nm UV LEDs are investigated systematically. Specifically, designs of AlGaN/GaN superlattice EBL and Al-content-graded EBL are explored in detail.
Numerical Study of (0001) Face GaN/InGaN p-i-n Solar Cell With Compositional Grading Configuration
(2012-06-15)
Kuo, Yen-Kuang
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Lin, Bing-Cheng
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Chang, Jih-Yuan
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Chen, Fang-Ming
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Kuo, Hao-Chung
The advantages of a (0001) face GaN/InGaN p-i-n solar cell with compositional grading configuration between i-InGaN/p-GaN layers are studied numerically. With the use of the grading layer, the conversion efficiency is markedly promoted due to the reduction of potential barrier height for holes and due to the decrease of polarization. Optimized conversion efficiency is obtained when the thickness of the grading layer increases to a critical value. This critical thickness is strongly influenced by the polarization charges and doping concentration of the grading layer. When the density of the polarization charges is high or the doping concentration is low, a thick grading layer is required to achieve high efficiency.
Selective antibody activation through protease-activated pro-antibodies that mask binding sites with inhibitory domains
(2017-09-14)
Chen, I-Ju
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Chuang, Chih-Hung
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Hsieh, Yuan-Chin
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Lu, Yun-Chi
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Lin, Wen-Wei
Systemic injection of therapeutic antibodies may cause serious adverse effects due to on-target toxicity to the antigens expressed in normal tissues. To improve the targeting selectivity to the region of disease sites, we developed protease-activated pro-antibodies by masking the binding sites of antibodies with inhibitory domains that can be removed by proteases that are highly expressed at the disease sites. The latency-associated peptide (LAP), C2b or CBa of complement factor 2/B were linked, through a substrate peptide of matrix metalloproteinase-2 (MMP-2), to an anti-epidermal growth factor receptor (EGFR) antibody and an anti-tumor necrosis factor-alpha (TNF-alpha) antibody. Results showed that all the inhibitory domains could be removed by MMP-2 to restore the binding activities of the antibodies. LAP substantially reduced (53.8%) the binding activity of the anti-EGFR antibody on EGFR-expressing cells, whereas C2b and CBa were ineffective (21% and 9.3% reduction, respectively). Similarly, LAP also blocked 53.9% of the binding activity of the anti-TNF-alpha antibody. Finally, molecular dynamic simulation showed that the masking efficiency of LAP, C2b and CBa was 33.7%, 10.3% and -5.4%, respectively, over the binding sites of the antibodies. This strategy may aid in designing new protease-activated pro-antibodies that attain high therapeutic potency yet reduced systemic on-target toxicity.
Simulation and Experimental Study on Barrier Thickness of Superlattice Electron Blocking Layer in Near-Ultraviolet Light-Emitting Diodes
(2016-08-01)
Kuo, Yen-Kuang
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Chen, Fang-Ming
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Lin, Bing-Cheng
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Chang, Jih-Yuan
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Shih, Ya-Hsuan
The optical performance and relevant physical properties of near-ultraviolet (NUV) GaN-based light-emitting diodes (LEDs) are investigated. Specifically, the influence of traditional AlGaN bulk electron blocking layer (EBL) and AlGaN/GaN superlattice (SL) EBL with various thicknesses of AlGaN layers on NUV LEDs is explored. It is indicated from the band diagrams, electrostatic field profile, electron reflecting and hole transmitting spectra, and carrier concentrations profile that the use of a thin AlGaN layer of AlGaN/GaN SL EBL is beneficial to the electron confinement and hole injection in the active region, which results in the high internal quantum efficiency and low efficiency droop at high injection current. Moreover, the experimental results show that replacing the traditional AlGaN bulk EBL with the AlGaN/GaN SL EBL can markedly improve the optical performance. When compared with the NUV LED with traditional AlGaN bulk EBL, the output power of the NUV LED with the proposed AlGaN/GaN SL EBL increases from 13.5 to 48.7 mW at 100 mA.