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  • br Similarly PHPMA was functionalized with Cy acceptor

    2020-08-30


    Similarly, PHPMA was functionalized with Cy5 (acceptor fluorophore) and Cy3 (donor fluorophore) or epirubicin (EPI) through a GFLG linker
    Fig. 22. Schematic structure of PHPMA functionalized by Cy5 and EPI for further FRET-monitoring of the EPI release mediated by Cathepsin B. Adapted with permission from Ref. [172].
    Please cite this article as: D. Dheer, J. Nicolas and CCK-8 R. Shankar, Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases, Adv. Drug Deliv. Rev., https://doi.org/10.1016/j.addr.2019.01.010
    and evaluated by FRET during cell uptake and intracellular drug delivery experiments (Fig. 22) [172]. Thanks to the Cathepsin B-sensitive linker, the conjugates bearing EPI (2P-EPI) led to a fourfold terminal half-life compared to first generation (P-EPI) conjugate and complete tumor re-mission with ~100 days inhibition of tumorigenesis in mice.
    The specific presence of cysteine Cathepsins has also been exploited to perform radiolabeled drug delivery for nanoscale conjugates with the aim of inducing enhanced diagnostic and radiotherapeutic efficacy. For instance, PHPMA was radiolabeled with Lutetium-117 (117Lu) via a pep-tide sequence made of two consecutive metabolically active linkers (MALs) sensitive to Cathepsin B and S, that are overexpressed in the liver and the spleen [173]. The MALs were shown to be metabolized by CCK-8 into single metabolites. The 117Lu-peptide-PHPMA conju-gate showed a substantial retention decrease in the long run in the liver and the spleen, compared to non-cleavable counterparts on human pancreatic adenocarcinoma xenograft mouse model. In another study, the Garrison's group developed the synthesis of cathepsin S-susceptible 177Lu-labeled or FRET-capable multiblock PHPMA copoly-mers, which resulted into fast in vitro cleavage of both copolymers. Quicker clearance and lower non-target retention without reducing tumor targeting was also shown on pancreatic ductal adenocarcinoma
    mouse model [174]. This study therefore took benefit of the presence of Cathepsin S in MPS tissues to lower non-target accumulation.
    A targeted, theranostic prodrug relying on Cathepsin-B-sensitive Gem release and activation of a caspase-3 specific probe was designed (Fig. 23) [175]. The targeting relied on the RGD peptide for accumula-tion into pancreatic cancer cells with overexpressed αvβ3 integrin. The GFLG peptide was then hydrolyzed by Cathepsin B leading to Gem re-lease as well as the apoptotic probe. This system showed promising properties as a platform for both pancreatic cancer cell targeting and real-time, non-invasive imaging.
    In tumor imaging, many proteases can be used for the activation of
    fluorescent probes including near-infrared emitting dyes. Therefore, in vivo molecular profiling of protease activity can be performed with such probes in endoscopy or tomographic optical imaging [176]. For instance, it has been reported the design of quenched activity-based probe (qABP) mediated by Cathepsin S [177]. It showed high tumor-specific fluorescence in a syngeneic breast cancer model. Other activity-based probes targeting Cathepsin X have been designed [178]. Cathepsin X is involved in a many different biological mechanisms,
    such as aging, cancer, neurodegenerative disorders, inflammation, etc. [179–181]. These probes were successfully used for the selective
    Fig. 23. Schematic structure of consecutive enzymatic reaction using a gemcitabine-based prodrug along with apoptotic probe for the killing and monitoring of pancreatic cancer cells.
    Adapted with permission from Ref. [175].
    Please cite this article as: D. Dheer, J. Nicolas and R. Shankar, Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases, Adv. Drug Deliv. Rev., https://doi.org/10.1016/j.addr.2019.01.010
    Fig. 24. Chemical structure of NIR fluorescent probe sensitive to Cathepsin B [185].
    labeling and imaging of Cathepsin X in vitro and in vivo, thus making them a valuable tool for examining protease activity and functions.
    Malarial parasites are known to generate significant concentrations of mobile ferrous iron [182]. In this context, parasite-specific, FeII-sensitive delivery of a potent dipeptidyl aminopeptidase inhibitor through Cathepsin C was demonstrated by using activity-based probes [183]. Production of FeII was triggered in the presence of 1,2,4-trioxolone moiety leading to instant drug release prior to the fragmen-tation of the aforesaid moiety. Further in vivo evaluation was performed using Plasmodium berghei model of murine malaria which showed selective drug targeting in parasitic infections.