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In vivo imaging techniques
Published in Raquel Seruca, Jasjit S. Suri, João M. Sanches, Fluorescence Imaging and Biological Quantification, 2017
Patrícia Carvalho, André Roma, Sérgia Velho
Radioligands used in PET and SPECT imaging are designed with the same rationale: target and take advantage of specific aspects of tumor biology, including molecular biomarkers, such as overexpression of growth factor receptors and protein kinases or biological events like angiogenesis, apoptosis, hypoxia, and tumor proliferation. These two imaging techniques can have outstanding value in many aspects of the drug development process, providing useful information that can improve the efficiency and cost-effectiveness of clinical trials [53]. PET with the radiotracer 2-deoxy-2-(18F) fluoro-d-glucose (18F-FDG), a glucose analog, are the most commonly used in human and mice cancer imaging. This method exploits the increased expression of glucose transporters and the activation of the glycolytic pathway in cancer cells to preferentially metabolize and retain 18F-FDG. Besides being used to tumor detection purposes, PET–FDG has been used in various cancer models, for instance, in lung cancer [54], glioblastoma, and lymphoma [55] to assess tumor metabolism and evaluate the effects of anticancer drugs, demonstrating its value in pharmacodynamics studies. Recently, in a prostate xenograft model, caged FDG glycosylamines were used to explore the characteristic acidic pH of tumor microenvironments to develop a prodrug strategy that targets this characteristic, with potential clinical translation [56]. Several other probes, designed to target different cancer cell markers [57–60], that can even be functionalized with antibodies [61] or antibody mimetics [62], have been developed and are available for cancer and metastasis imaging in various models. SPECT has, in the same line of PET, been successfully used in tumor and metastasis detection and therapy response evaluation, using probes that target, for example, human epidermal growth factor receptor 1, 2, and 3 [63–65], urokinase-type plasminogen activator receptor [66], carcinoembryonic antigen [67] and α5β1 integrin [68]. Most importantly, SPECT imaging of a radiolabeled probed targeting claudin-4 (a protein that is overexpressed in several premalignant precursor lesions) allowed the detection of precancerous aplastic lesions in mouse models of breast cancer, establishing a new early detection tool [69].
Nanoamorphous Drug Delivery Technology and an Exploration of Nanofabrication
Published in Vineet Kumar, Praveen Guleria, Nandita Dasgupta, Shivendu Ranjan, Functionalized Nanomaterials II, 2021
Wen Chin Foo, Keat Theng Chow, Yuet Mei Khong, Rajeev Gokhale
Proteins exist in the nanoscale, hence naturally befit the field of nanotherapeutics (Erickson 2009). The first therapeutic protein, insulin was commercialized in 1922; however, it was the development of therapeutic monoclonal antibodies (mAb) which catalyzed the rapid rise of protein therapeutics and biologics in the 21st century (Watier and Reichert 2017). Human antibodies are one of the most robust and versatile protein structures capable of binding to a large range of biological targets with varying shapes, sizes, and properties. Their basic structure comprises two identical pairs of light and heavy chains linked together by disulfide bonds, which constitute two fragment antigen-binding (Fab) regions and one fragment crystallizing (Fc) region. The two Fab regions selectively bind targets (antigens), a property conferred by the complementarity-determining regions (CDR) of its variable domains, while the Fc region interacts with fragment crystallizable receptors (FcR) and complement component C1q to affect biological activity (Prabakaran and Dimitrov 2017). Although antibodies can be customized to bind diverse targets with high affinity, their large molecular size (~150 kDa) is associated with poor tumor penetration and renal clearance. These limitations, coupled with increasing knowledge of antibody structure-function relationships, availability of antibody sequence and structural data repositories, bioinformatics and in silico modeling have led to the advent of antibody mimetics. Antibody mimetics are alternative protein scaffolds engineered to afford antibody-like binding activity but with molecular weights smaller by an order of magnitude and typically better thermal, chemical, and proteolytic stability attributed to their homogeneous secondary structure. A successful example of antibody mimetics are monobodies which are derived from the 10th human fibronectin type III (FN3) domain. Amino acid diversification of the β-sheet and surface loop regions form a concave surface which binds to the convex surface of the target with maximal interface area (Koide et al. 2012). Monobodies are commercialized under the name AdnectinsTM by Adnexus, now part of Bristol Myers Squibb, and its flagship drug pegdinetanib (Angiocept®) which functions as an antagonist of the vascular endothelial growth factor receptor-2 (VEGFR-2) has entered phase II clinical trials for glioblastoma treatment (Lipovšek 2010, Vazquez-Lombardi et al. 2015).
Selection, purification, and characterization of a HER2-targeting soluble designed ankyrin repeat protein by E. coli surface display using HER2-positive melanoma cells
Published in Preparative Biochemistry & Biotechnology, 2018
Xiaofei Chen, Xiaoxiao Yu, Xiaoda Song, Li Liu, Yuting Yi, Wenbing Yao, Xiangdong Gao
Here, we provided a simple method for the generation of HER2-targeting DARPin. A DARPin library was built from mimivirus, a kind of giant virus. The library was displayed on E. coli to conduct the live cell sorting on HER2-positive/negative cells.[15,16] After three rounds of screening, a DARPin was selected and purified. The production yield of selected DARPin was about 70 mg/L in a soluble form. The affinity of selected DARPin with HER2 subdomain I was evaluated by flow cytometry and microscale thermophoresis (MST). The kd value between selected DARPin and HER2 was 1.05 ± 0.47 µM. The in vitro experiment showed the capacity of selected DARPin to inhibit tumor cell growth. At a concentration of 640 nM, the selected DARPin could inhibit the growth of SK-BR-3 at a rate of 46.34% in 72 hr by MTT assay. Therefore, we demonstrated that E. coli display combining with selection on live cells was a dependable method for the selection of antibody mimetic DARPin and provided a drug candidate for cancer therapy.