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  • br Please cite this article as D


    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.,
    Fig. 20. (a) Sentization of endo-lysosomal membrane in the presence of dye released by enzymatic digestion of the nanoparticles. (b) Endo-lysosomal disruption by NIR laser leading to saporinrelease. Adapted with permission from Ref. [170].
    Cathepsin B and got cleaved with comparable kinetics. Importantly, both prodrugs were 70-fold more potent than free Dox.
    In another study, cytotoxic drug-carrying filamentous bacteriophages were chemically modified to tunedifferent key parameters (e.g., pharma-cokinetics, biodistribution, immunogenicity)and compared to bare phages [148]. Anti-ErbB2 and anti-ERGR Pimozide were used as targeting entities, whereas Dox was tethered to phages through an amide linkage and also to genetically-engineered Cathepsin-B (Fig. 18). In vitro studies explained the good penetration into tumors cells by their needle-like structure. This conjugate can be seen as a novel drug-delivery platform which might solve many issues related to the hydro-phobicity of drugs at the target specific sites.
    2.2. Bone-targeting drug delivery systems
    The most common skeleton disorders are arthritis, osteoporosis, oste-omyelitis, osteosarcoma as well as metastatic bone cancer [37,149]. Bone metastasis is one of the most devastating stages of cancer [150]. In addi-tion, there are several limitations associated with the systemic adminis-tration of drugs for bone treatment and bone-related diseases such as poor drug uptake at the target site, potential systemic toxicity as well
    as suboptimal efficacy [149]. Interestingly, there are examples in the lit-erature describing Cathepsin-sensitive polymer conjugates for bone targeting purposes [151–154]. Therefore, drug delivery systems targeted towards bones can be adapted to bone diseases where the drug can be selectively delivered with minimal side effects [155].
    In a similar fashion to what has been reported for anticancer therapy, HPMA was conjugated to prostaglandin E1 (PGE1) via a spacer sensitive to Cathepsin K, which is an enzyme overexpressed in osteoclasts [156]. The Cathepsin K-sensitive spacer comprised Gly-Gly-Pro-Nle as the tetrapeptide sequence and a self-eliminating 4-aminobenzyl alcoholmoiety. Copolymerization of the resulting PGE1-containing HPMA macromonomer with HPMA yielded the desired PHPMA-PGE1conjugates,that released unmodified PGE1 after incubation with Cathepsin K. PHPMA was also post-functionalized by a D-aspartic acid octapeptide targeting ligand. Therefore, this new drug delivery system might be a solution to treat osteoporosis and other bone-related pathologies.
    Targeting inflammatory joints in rheumatoid arthritis (RA) was achieved by AWO54, a new prodrug that binds to endogenous albumin and was composed of Mtx, a spacer based on lysine and an enzyme-sensitive peptide linker linked to a maleimide moiety for further linkage
    Fig. 21. Structure of dual-functionalized PHPMA nanocarriers with Cy5 and Cy7 dyes for further Cathepsin B-mediated release of Cy7. Adapted with permission from Ref. [171].
    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.,
    to albumin [157]. The prodrug was cleaved by two enzymes, Cathepsin B and plasmin, that exist in high concentrations in synovial effusion under RA condition, thus releasing Mtx lysine derivatives. The in situ coupling of endogenous albumin, AWO54 was found to be better in terms of dosage and efficacy than administration of the parent drug for treating collagen-induced arthritis.