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Chih-Kuang Chen,1 Ping-Kuan Huang,2 Wing-Cheung Law,3 Chia-Hui Chu,4 Nai-Tzu Chen,5 Leu-Wei Lo4 1Department of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; 2Department of Fiber and Composite Materials, Feng Chia University, Taichung 40724, Taiwan; 3Department of Industrial and Systems Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, People’s Republic of China; 4Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan; 5Institute of New Drug Development, China Medical University, Taichung 40402, TaiwanCorrespondence: Chih-Kuang ChenDepartment of Materials and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung 80424, TaiwanTel +886-7-5252000 ext. 4060Fax +886-7-5254099Email chihkuan@mail.nsysu.edu.twLeu-Wei LoInstitute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, TaiwanTel +886-37-246166 ext. 37115Email lwlo@nhri.org.twAbstract: Gene-based therapies have emerged as a new modality for combating a myriad of currently incurable diseases. However, the fragile nature of gene therapeutics has significantly hampered their biomedical applications. Correspondingly, the development of gene-delivery vectors is of critical importance for gene-based therapies. To date, a variety of gene-delivery vectors have been created and utilized for gene delivery. In general, they can be categorized into viral- and non-viral vectors. Due to safety issues associated with viral vectors, non-viral vectors have recently attracted much more research focus. Of these non-viral vectors, polymeric vectors, which have been preferred due to their low immunogenicity, ease of production, controlled chemical composition and high chemical versatility, have constituted an ideal alternative to viral vectors. In particular, biodegradable polymers, which possess advantageous biocompatibility and biosafety, have been considered to have great potential in clinical applications. In this context, the aim of this review is to introduce the recent development and progress of biodegradable polymers for gene delivery applications, especially for their chemical structure design, gene delivery capacity and additional biological functions. Accordingly, we first define and categorize biodegradable polymers, followed by describing their corresponding degradation mechanisms. Various types of biodegradable polymers resulting from natural and synthetic polymers will be introduced and their applications in gene delivery will be examined. Finally, a future perspective regarding the development of biodegradable polymer vectors will be given.Keywords: gene therapy, gene delivery, non-viral vectors, polymeric vectors, biodegradable polymers

Nai-Tzu Chen,1 Eugene D Barth,2,3 Tsung-Hsi Lee,4 Chin-Tu Chen,5 Boris Epel,2,3 Howard J Halpern,2,3 Leu-Wei Lo5,61Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan; 2Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; 3Center for EPR Imaging In Vivo Physiology, University of Chicago, Chicago, IL 60637, USA; 4Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan; 5Department of Radiology, University of Chicago, Chicago, IL 60637 USA; 6Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, TaiwanPurpose: Tumor oxygenation is a critical parameter influencing the efficacy of cancer therapy. Low levels of oxygen in solid tumor have been recognized as an indicator of malignant progression and metastasis, as well as poor response to chemo- and radiation therapy. Being able to measure oxygenation for an individual’s tumor would provide doctors with a valuable way of identifying optimal treatments for patients.Methods: Electron paramagnetic resonance imaging (EPRI) in combination with an oxygen-measuring paramagnetic probe was performed to measure tumor oxygenation in vivo. Triarylmethyl (trityl) radical exhibits high specificity, sensitivity, and resolution for quantitative measurement of O2 concentration. However, its in vivo applications in previous studies have been limited by the required high dosage, its short half-life, and poor intracellular permeability. To address these limitations, we developed high-capacity nanoformulated radicals that employed fluorescein isothiocyanate-labeled mesoporous silica nanoparticles (FMSNs) as trityl radical carriers. The high surface area nanostructure and easy surface modification of physiochemical properties of FMSNs enable efficient targeted delivery of highly concentrated, nonself-quenched trityl radicals, protected from environmental degradation and dilution.Results: We successfully designed and synthesized a tumor-targeted nanoplatform as a carrier for trityl. In addition, the nanoformulated trityl does not affect oxygen-sensing capacity by a self-relaxation or broadening effect. The FMSN-trityl exhibited high sensitivity/response to oxygen in the partial oxygen pressure range from 0 to 155 mmHg. Furthermore, MSN-trityl displayed outstanding intracellular oxygen mapping in both in vitro and in vivo animal studies.Conclusion: The highly sensitive nanoformulated trityl spin probe can profile intracellular oxygen distributions of tumor in a real-time and quantitative manner using in vivo EPRI.Keywords: tumor oxygenation, electron paramagnetic resonance imaging (EPRI), mesoporous silica nanoparticles (MSNs), triarylmethyl (trityl) spin probe