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  • br Table Primers for Real

    2020-08-28


    Table 1. Primers for Real-Time RT-PCR
    Gene
    Assay Number
    Human CAMP
    Human KRT20
    Human TUBB1
    Human TUBB3
    Human FPR2
    Human P2RX7
    Mouse GAPDH
    Unisp6
    Inventoried primer list of RT-PCR reactions.
    www.moleculartherapy.org
    REFERENCES
    25. Rejniak, K.A. (2012). Investigating dynamical deformations of tumor SCH 772984 in circula-tion: predictions from a theoretical model. Front. Oncol. 2, 111.
    35. Sasportas, L.S., and Gambhir, S.S. (2014). Imaging circulating tumor cells in freely moving awake small animals using a miniaturized intravital microscope. PLoS ONE 9, e86759.
    Advanced Drug Delivery Reviews xxx (2019) xxx
    Contents lists available at ScienceDirect
    Advanced Drug Delivery Reviews
    Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases
    Divya Dheer a,b,c, Julien Nicolas a, , Ravi Shankar b,c,
    a Institut Galien Paris-Sud, Univ Paris-Sud, UMR CNRS 8612, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry Cedex, France
    b Bio-organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
    c Academy of Scientific and Innovative Research (AcSIR), CSIR-IIIM, Jammu Campus, Jammu 180001, India
    Article history:
    Available online xxxx
    Keywords:
    Cathepsins
    Enzymes
    Cancer
    Drug delivery
    Optical imaging 
    Cathepsins are an important category of enzymes that have attracted great attention for the delivery of drugs to improve the therapeutic outcome of a broad range of nanoscale drug delivery systems. These proteases can be utilized for instance through actuation of polymer-drug conjugates (e.g., triggering the drug release) to bypass limitations of many drug candidates. A substantial amount of work has been witnessed in the design and the evaluation of Cathepsin-sensitive drug delivery systems, especially based on the tetra-peptide sequence (Gly-Phe-Leu-Gly, GFLG) which has been extensively used as a SCH 772984 spacer that can be cleaved in the presence of Ca-thepsin B. This Review Article will give an in-depth overview of the design and the biological evaluation of Cathepsin-sensitive drug delivery systems and their application in different pathologies including cancer before discussing Cathepsin B-cleavable prodrugs under clinical trials.
    1. Introduction
    Cathepsins are widely known proteolytic enzymes whose main function is to degrade proteins or peptides [1]. Nevertheless, this per-ception has changed over the past many years as they are being consid-ered as important signaling molecules playing different crucial roles [2,3]. There are dozens of Cathepsins which are classified according to their structure, catalytic mechanism and substrate. Based on the human genome draft sequence, the main Cathepsin categories are ser-ine (Cathepsin A and G), aspartic (Cathepsin D and E) and lysosomal cysteine proteases (Cathepsin B,C,F,H,K,L1,L2/V,O,S,W,X/Z) [4,5]. They have multiple functions, as one finds digestive proteases (present in sa-liva, stomach and intestines) for food processing inside the gastrointes-tinal tract (GIT), lysosomal proteases for intracellular housekeeping or caspases for transduction of one-way signal in apoptosis [6–8]. Interest-ingly, lysosomal Cathepsins (i.e., intracellular enzymes) have been widely involved in drug targeting as they require a slightly acidic envi-ronment to exhibit optimal enzymatic activity [9–11]. Given the fea-tures of disease-associated proteolysis (i.e., cleavage of amide bond), different types of prodrugs, nanocarriers, biomaterials or probes, have been designed and synthesized to exert their activity in endosomal/
    Corresponding author.
    Corresponding author at: Bio-organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India E-mail addresses: [email protected] (J. Nicolas), [email protected] (R. Shankar).
    lysosomal compartments [12–14]. For instance, Cathepsins can induce the release of active ingredients from nanocarriers, chemically or phys-ically, leading to enhanced therapeutic activity or in situ imaging sensi-tivity [15]. Kopecek, Duncan and others have shown the importance of protease-cleavable linkers, especially those sensitive to Cathepsin B, in polymer-based, nanoscale drug delivery constructs for enhancing the in vivo delivery of drugs to tumor tissues [16–18].
    Cysteine cathepsins and their substrate interaction have been well-identified on the basis of papain (Carica papaya) used as a model of ly-sosomal proteases, as first introduced by Schechter and Berger [19]. In this model, the substrate residues (P) as well as the subsites (S) were given nomenclature based on their position bonded to the protease sur-face. Later, this model was revisited by Turk et al. [20] who showed that the subsites were positioned on the left-hand side (i.e., S2’, S1 and S3) along with right-hand side of the active site (i.e., S1’ and S2), and further composed of two L-domain loops consisting of Gln-19–Cys-25 as well as Arg-59–Tyr-67 residues and two R-domain loops consisting of Leu-134–His-159 as well as Asn-175–Ser-205 residues (Fig. 1) [5].