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  • Cortistatin-14 TFA br Fig Structure of Cathepsin B sensitive


    Fig. 17. Structure of Cathepsin B-sensitive, dual-functionalized linker bearing Dox and Ptx, and comprising a maleimide moiety for its coupling to albumin. Adapted with permission from Ref. [141].
    Pep42, which is a cyclic 13-mer oligopeptide, specifically binds to glucose-regulated protein 78 and translocates into the lysosomal compartment [143,144]. In this context, Pep42 was advantageously used to efficiently deliver Ptx and Dox into cancer cells for enhanced
    cytotoxicity [145]. More specifically, Pep42-prodrug bioconjugates containing a Cathepsin B-sensitive linker were synthesized and facilitated the uptake of both cytotoxic agents for their delivery into cancer cells.
    Fig. 18. Genetically engineered Cathepsin B-modulated bacteriophage conjugated to Dox. Adapted with permission from Ref. [148].
    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.,
    Nanoconstructs with methotrexate (Mtx) linked to a tuftsin-like peptide carrier via a GFLG spacer and several copies of a chemotactic targeting agent were designed [146]. These conjugates led to greater cy-totoxic effect than free Mtx and represented potential candidates for the
    specific targeting of cancer cells. Similarly, Dox-based dipeptide conju-gates were designed and tethered to monoclonal antibodies (mAbs) recognizing tumor associated antigens on renal cell carcinoma and ana-plastic large cell lymphoma [147]. The dipeptides were substrates for
    Fig. 19. Illustration of Dox-loaded, hollow mesoporous silica nanoparticles for in situ imaging of Cathepsin B and protease-mediated Dox release. (a) Nanoparticle synthesis.
    (b) Nanoparticle disassembly mediated by Cortistatin-14 TFA enzyme cascade reactions with Cortistatin-14 TFA hyaluronidase (HAase) and Cathepsin B (Cat B). (c) Specific delivery, controlled Dox release and intracellular imaging: (i) specific uptake via receptor-mediated endocytosis; (ii) accumulation in endosomes; (iii) endosomal escape and intracellular imaging of Cat B; (iv) Dox release triggered by enzymes. Adapted with permission from Ref. [169].
    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 antibodies 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.