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Enzyme-Responsive Nanomedicine
Published in Lin Zhu, Stimuli-Responsive Nanomedicine, 2021
Hong Wu, SongYan Guo, Tie Hong Yang
Cathepsin is a kind of cysteine aspartic acid-specific protease and, as popular targets for early drug design, significantly influences the drug efficacy against cancer [35]. The natural milieu of these enzymes is the lysosomal compartment, where a low pH ensures optimal catalytic activity of the acid protease [36]. Cathepsin B, a cysteine protease, is recognized as a promising biomarker for cancer diagnosis and prognosis [37–40]. Malignant tumors are usually characterized by large amount and/or high activity of CTB, indicating that CTB may be the ideal target for the design of anticancer drugs [41]. Boc-Val-Cit- and Cbz-Val-Cit-, two CTB substrates, are the popularly used CTB-sensitive linkers in the nanomedicine. Table 3.2 summarizes the recent research on cathepsin B-responsive nanomedicine.
Lipase-Mediated Biocatalysis as a Greener and Sustainable Choice for Pharmaceutical Processes
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Monika Sharma, Tanya Bajaj, Rohit Sharma
Cathepsin K inhibitors are an important class of antiresorptive agents that help prevent bone loss, while allowing the bone formation process to continue. Odanacatib (Fig. 1.24) is an orally bioavailable, potent, and selective cathepsin K inhibitor currently being used to treat osteoporosis. Synthesis of odanacatib relies on an enzyme resolution-mediated dynamic kinetic for the production of a key chiral fluoroleucine intermediate of odanacatib. The ring-opening ethanolysis of azlactone to form fSJ-y-fluoroleucine ethyl ester is the basic step commercially mediated by the Novozyme 435. Immobilized Candida antarctica lipase-B on an acrylic resin were also tested. In another study, CAL-B enzyme immobilized on polymethacrylate resin (CAL-B EXE120) was found to possess better stability and increased ethanolysis (Truppo and Hughes, 2011).
Recent Progress in Polymer Therapeutics as Nanomedicines
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Sahar Israeli Dangoor, Shani Koshrovski Michael, Hemda Baabur-Cohen, Liora Omer, Ronit Satchi-Fainaro
A common example is the oligopeptide spacers, which is terminated with a drug and susceptible to enzymatically catalyzed hydrolysis in the lysosomes, specifically by cathepsins B and K. The cathepsin B-cleavable tetrapeptide Gly-Phe-Leu-Gly was extensively used in HPMA copolymer for delivery of several anti-cancer drugs, since cathepsin B is overexpressed in many tumor cells and tumor endothelial cells [56]. This spacer is cleaved intracellularly in the lysosome, and therefore is used for drug release in the cytosol. Recently, cathepsins were also used to activate Turn-ON nano-probes. The probes were composed of non-degradable HPMA copolymer backbone conjugated to self-quenched (homo-FRET) near-infrared Cy5 dyes through the cleavable linker Gly-Phe-Leu-Gly. Upon accumulation in the tumor, overexpressed cathepsins at the tumor site cleave the dyes from the polymeric backbone and generate a fluorescence signal that will assist surgeons’ decision, in real time during surgery, regarding the tumor margins needed to be removed [57]. Another common enzymatically cleavable tetrapeptide is the Gly-Gly-Pro-Nle spacer, which is cleaved by cathepsin K. Cathepsin K is involved in bone resorption (osteoporosis, osteoarthritis and bone neoplasms), and overexpressed in bone metastases. It is localized and active in the tumor microenvironment. Cathepsin K-cleavable peptide has been used in polymer–drug conjugates to deliver drugs to bone tissues for the treatment of calcified diseases and bone metastases [25, 58, 59]. It should be noted that there are further peptide sequences, which are known to be cleaved by cathepsins, such as Phe-Lys or Val-Arg by cathepsin B [60] and Phe-Arg by cathepsins B and L [61].
Microstructured titanium functionalized by naringin inserted multilayers for promoting osteogenesis and inhibiting osteoclastogenesis
Published in Journal of Biomaterials Science, Polymer Edition, 2021
Ke Shen, Xiaojing Zhang, Qiang Tang, Xingtang Fang, Chunlei Zhang, Zhaojing Zhu, Yanhua Hou, Min Lai
In order to better prove the inhibitory effect of LBL (NA) coated-Ti substrates on osteoclast formation, osteoclastic genes were measured using qRT-PCR after 7 days of culture and these results are shown in Figure 7. Cathepsin K (CTSK) encodes a member of the cysteine protease cathepsin family, which is highly expressed in osteoclasts and is involved in the degradation of collagen and other bone matrix proteins [42]. Nuclear factor of activated T cells (NFAT) is mainly expressed in immune cells and plays a key role in immune response [43]. Overexpression of TRAP is one of the main causes of osteoporosis and it is abundant in osteoclasts [41]. V-ATPase (VATP) is a specific site in the plasma membrane that is involved in the reabsorption of osteoclast attachment sites [44]. As can be seen from the Figure 7, the expression of these osteoclastic genes on LBL (NA) coated-Ti substrate decreased compared to Ti substrates. Osteoclastic genes on LBL coated-Ti substrates also decreased compared with Micro-Ti substrates to a certain extent. These results indicate that LBL (NA) coated-Ti substrates can inhibit osteoclast generation, which was inseparable from the role of NA. NA may abrogate osteoclastogenesis and bone resorption via the inhibition of RANKL-induced NF-κB and ERK activation [39].
Diagnosis and management of implant debris-associated inflammation
Published in Expert Review of Medical Devices, 2020
Stuart B. Goodman, Jiri Gallo, Emmanuel Gibon, Michiaki Takagi
Increased expression of proteinases is another important molecular consequence of the reaction. Neutral proteinases are produced for export into the extracellular space. It is thought that under physiological conditions ‘physiological’ pH close to 7.4 prevails. Indeed, it has been described that mononuclear phagocytes and foreign body giant cells produce excessive amounts of neutral proteinase, collagenases and other matrix metalloproteinases (MMPs). In concert, these substances are able to degrade all components of the extracellular matrix. It is well known that MMP-1 (collagenase-1, fibroblast collagenase), MMP-14 (membrane-type MMP; MT1-MMP) and MMP-2/-9 (gelatinase) and other MMPs with collagenolytic and/or gelatinolytic potential are produced [44,59]. Inflammatory cytokines, such as IL-1, TNF-alpha, and platelet-derived growth factor (PDGF) can induce MMP production. Excessive activation of the secreted proteinases leads to weakening of the extracellular matrix components at the implant-host interface [60]. As the pH in the peri-implant tissues is quite low, acidic cysteine proteinase, cathepsin K, could become autoactivated [61]. Cathepsin K was first found to be the major proteinase of osteoclasts. Cathepsin K is generally considered to be responsible for bone collagen degradation in the acidic Howship’s lacunae after HCl-mediated dissolution of the bone hydroxyapatite mineral. Later cathepsin K has been found in other cells, including macrophages, osteoblasts, and fibroblasts. Auto-activated cathepsin K in the acidic peri-implant milieu has been found in high concentrations in peri-implant fluid and tissues [61,62]. Thus, extracellular matrix-degrading enzymes could be responsible for the weakening of the implant-host interface.