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Current Pharmaceutical Design, 2019, 25, 1536-1553 REVIEW ARTICLE 1536 Send Orders for Reprints to [email protected] Current Pharmaceutical Design, 2019, 25, 1536-1553 REVIEW ARTICLE ISSN: 1381-6128 eISSN: 1873-4286 Recent Technological Advances in the Mass Spectrometry-Based Nanomedicine no. Studies: An Insight from Nanoproteomics Impact Factor: 2.412 BENTHAM SCIENCE Jing Tanga,b,†, Yunxia Wanga,†, Yi Lia, Yang Zhanga,b, Runyuan Zhanga, Ziyu Xiaoa, Yongchao Luoa, Xueying Guoa, Lin Taoc, Yan Loud, Weiwei Xueb and Feng Zhu*,a,b aCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou 401331, China; bSchool of Pharmaceutical Sciences and Collaborative Innovation Center for Brain Science, Chongqing University, Chongqing 401331, China; cKey Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Province, School of Medicine, Hangzhou Normal University, Hangzhou 310036, China; dZhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People’s Republic of China Abstract: Nanoscience becomes one of the most cutting-edge research directions in recent years since it is gradu- A R T I C L E H I S T O R Y ally matured from basic to applied science. Nanoparticles (NPs) and nanomaterials (NMs) play important roles in various aspects of biomedicine science, and their influences on the environment have caused a whole range of Received: April 9, 2019 uncertainties which require extensive attention. Due to the quantitative and dynamic information provided for Accepted: June 11, 2019 human proteome, mass spectrometry (MS)-based quantitative proteomic technique has been a powerful tool for DOI: nanomedicine study. In this article, recent trends of progress and development in the nanomedicine of proteomics 10.2174/1381612825666190618123306 were discussed from quantification techniques and publicly available resources or tools. First, a variety of popular protein quantification techniques including labeling and label-free strategies applied to nanomedicine studies are overviewed and systematically discussed. Then, numerous protein profiling tools for data processing and post- biological statistical analysis and publicly available data repositories for providing enrichment MS raw data in- formation sources are also discussed. Keywords: Nanoproteomics, nanomaterials, nanomedicine, protein quantification, mass spectrometry, biomedicine science. 1. INTRODUCTION and gel electrophoresis [18] could be applied to the nanomedicine Compared with the bulk phase, nanoparticles (NPs) and nano- field. Among these techniques, MS is powerful to provide chemical materials (NMs), which are of ultrafine particle size between one and structural information that is difficult to obtain through other nanometer to one hundred nanometers [1, 2], have unique charac- approaches. As reported, MS has become a current major tool due teristics of electrical, chemical and physical properties (e.g. semi- to the desirable throughput, sensitivity, and identification as well as conducting-, metallic-, magnetic-, and polymeric-nanosystems) [3], quantitation capability. In particular, it can interpret the encoded and large specific surface area for guaranteeing their high biological information in the genomes, analyze the orientation and conforma- activity [4, 5]. These unique characteristics make NPs play an im- tion of the proteins and prefractionate protein mixtures [19] and portant role in nanomedicine [6, 7]. Nanomedicine, defined as an small sets of proteins isolated in specific functional contexts. Inte- application of nanotechnology into the medicine [8], is a newly grating MS with protein microarrays could provide the novel in- emerging field and aims at drug delivery and the diagnosis, treat- sight into protein analysis for nanomedicine study. ment, and prevention of disease using NPs and NMs [8-10]. Due to Owing to offering quantitative and dynamic information on the advantages of improving effectiveness by biological targeting of proteins by directly profiling protein expression [20, 21], MS-based drugs, NPs are widely applied therapeutic and diagnostic ap- proteomics analysis plays an essential role in the realm of biomark- proaches in disease [11]. In the field of drug delivery, nanoparticles ers-identification and characterization [22]. Most diseases’ diagno- can reduce the toxicity of the drug and overcome the potential side sis, treatment, and prognosis can benefit a lot from it [23]. How- effects of conventional server therapies. As reported, NP-mediated ever, its application may be limited due to such low abundance of drug delivery could be used to directly target and deliver the NPs to most diseases’ biomarkers [24]. Thus, in order to rapidly detect low the given tissue, enhance the bioavailability and maintain the drugs abundance biomarkers, a high-throughput technological platform effect in the tissue. For example, gold nanoparticles were observed with the characteristics (ultra-sensitive and robust) is in urgent to be good candidates for improving anticancer targeted drug deliv- need. Despite the recent technological progresses in MS, low con- ery and drug release [12, 13]. It can carry and selectively release centration of biomarkers hinders the discovery of candidate bio- drugs in the desirable tissue, aiming at reducing side effects of marker [24]. Fortunately, the emergence of nanotechnology can drugs on normal cell and simultaneously elevating drug dose in make up for this deficiency. For example, some nanoparticles can diseased cell [14]. entrap and concentrate the biomarkers to make them easier for MS A variety of techniques such as immunoassays [15], mass spec- to detect [24, 25]. The superiority of integrating nanotechnology trometry (MS) [16], chromatography [16], protein-microarrays [17] into proteomics, including ultralow detection, high-throughput ca- pability, real-time detection, and low sample consumption, can achieve rapid detection on low abundance biomarkers. In sum, *Address correspondence to this author at the College of Pharmaceutical nano-assisted MS remarkably enhanced detection efficiency of Sciences, Zhejiang University, Hangzhou, China; proteins or peptides and contributed to the precision diagnostics E-mail: [email protected] † [17]. Till now, in MS-based nanoproteomics studies, diverse quanti- These authors contributed equally to this work. tative techniques (e.g., labeling, and label-free strategies) have been 1873-4286/19 $58.00+.00 © 2019 Bentham Science Publishers Current Pharmaceutical Design Recent Technological Advances in the Mass Spectrometry-Based Nanomedicine Studies Current Pharmaceutical Design, 2019, Vol. 25, No. 13 1537 widely applied. Detailed application of liquid chromatography tages and disadvantages of available proteome quantification meth- (LC)-MS/MS-based proteome quantification to various aspects of ods for nanoproteomics studies are provided in Table 1. current nanoproteomics is systematically illustrated in Fig. (1). In addition, a number of feature selection methods and available pub- 2.1. Labeling Quantification Technique lic resources have been developed and applied for accelerating Labeling quantification involves the addition of certain stable nanomedicine science process, especially the nanoparticle-based isotope, heavy amino acids or isobaric tags for labeling the sam- targeted drug delivery system [26, 27] and nanomaterials-related ple/cells to detect differences in protein abundance among different toxicity [28-30]. samples [31, 32]. A number of labeling approaches were employed Herein, a well-rounded review of current MS-based techniques for identifying certain changes in protein expression level when for nanomedicine was provided. Moreover, the sources of data in studied samples were exposed to NPs [32]. These labeling ap- nano-based targeted drug delivery and various nanomedicine- proaches based on stable isotope labeling mainly include three related toxicity studies from nanoproteomics perspective have been categories (metabolic labeling, enzymatic labeling, and chemical systematically discussed. First, through the assessments of both labeling) for relative and absolute quantitation. As reported, meta- challenges and potentials, a variety of quantification techniques and bolic labeling (e.g., stable-isotope labeling by amino acids in cell state-of-the-art feature selection methods are overviewed. Second, culture (SILAC) and N-terminal labeling) could change protein numerous powerful computational nanoproteomics tools and pub- abundances from different samples to the same level, which made licly available data repositories are also discussed. Finally, the pro- the microbial communities not appropriate for this labeling method spective orientation for MS-based quantification technique for [33], while chemical and enzymatic labeling based on different nanomedicine applications is also proposed. isotopic tags could address this issue. In addition, proteome cover- age, accuracy, precision and reproducibility of protein quantifica- 2. MS-BASED QUANTIFICATION TECHNIQUES FOR tion were also reported to offer certain differences among the three NANOPROTEOMIC STUDY types of labeling methods. For example, the chemical labeling has Label-free and labeling MS-based proteomics methods have unique advantages in both reproducibility and precision compared been widely applied to the various nanomaterials-associated studies with the metabolic labeling [34]. [31, 32]. The quantification workflows applied in the proteomic
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