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  • Breast colorectal Aspartic Proteases Cathepsin E Endosomal s

    2020-08-28

    Breast, colorectal [62–65] Aspartic Proteases Cathepsin E Endosomal structures, ER, Golgi bodies Cervical, gastric, lung, pancreas adenocarcinomas [61,66–70]
    Cathepsin D Lysosomes Breast, colorectal, ovarian [71–77]
    Fig. 3. Illustration of GFLG-containing PHPMA prodrugs. Adapted with permission from Ref. [87].
    Fig. 4. GFLG-containing PHPMA prodrugs for combination therapy (GDC-0980 and docetaxel) for prostate cancer exhibiting effective anti-Cancer Stem Cell (CSC) effect and in vitro increased anti-bulk tumor effect. Adapted with permission from Ref. [89].
    Fig. 5. Chemical structure of PHPMA-based, dual-labeled small copolymer block size (S-CMP) and long copolymer block size (L-CMP) showing cleavage sites for Cathepsin S [95].
    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. 6. Chemical structure of the gemcitabine prodrug (a) and in vitro drug release profile from the gemcitabine prodrug micellar system (b). Adapted with permission from Ref. [100].
    for tumor cell imaging expressing both Cathepsin B and somatostatin receptors and led to selective cytotoxicity towards cancer cells.
    Inorganic materials (e.g., silica, gold, iron oxide, quantum dots, etc.) is also an attractive family of materials that have been extensively inves-tigated for anticancer drug delivery [105–111]. In this area, a Cathepsin B-induced tumor targeted drug delivery system loaded with Dox was developed by immobilizing cleavable rotaxanes onto mesoporous silica nanoparticles (MSNs) [112]. Nano-constructs comprising a rotaxane moiety and a GFLG sequence linked to the RGDS peptide were used as Cathepsin B-cleavable stoppers for the cyclodextrin valves by means of “click” chemistry (Fig. 8). Thanks to the targeting ligand displayed at its surface, such system demonstrated efficient receptor-mediated tumor cell uptake and selective enzymatic 1438492-26-2 of GFLG peptide.
    MSNs were also coated with Cathepsin B-sensitive peptide se-quences (alkynyl-GIVRAKEAEGIVRAK-OH) through triazole rings and led to efficient Dox release (Fig. 9). The study also proved that this peptide sequence was selectively cleaved by Cathepsin B as assessed by in vitro experiments [113].
    This peptide sequence was also anchored onto silica supports to de-velop nanoparticles with prevented release the loaded [Ru(bipy)3]2+ dye unless specific proteases are present [114]. In another study, an enzyme-cleavable peptide precursor conjugated to Dox was further
    linked onto the surface of silica-coated magnetic nanoparticles by using “click” chemistry (Fig. 10) [115]. The nanocarriers exhibited effi-cient Dox release and selective intracellular Dox delivery into tumors with high Cathepsin B expression together with imaging of cancer cells.
    A dual enzymatic responsive nanoconstruct for pancreatic cancer therapy was engineered and relied on surface functionalization of CdSe/ZnS quantum dots (QDs) by an amphiphilic PEG-GGPLGVRGK-NH2 polymer sensitive to matrix metalloproteinases (MMP-9), and by Gem via a GELG Cathepsin B substrate sequence [116]. Some of the PEG chains were also functionalized by cycloRGD as a tumor-homing li-gand. The nanocarrier exhibited long circulating features and increased drug accumulation at tumor sites, resulting in successful delivery of Gem in BxPD-3 cells because of their inherently elevated concentrations of Cathepsin B (Fig. 11).
    2.1.3. Dendrimeric/comb-like systems
    Dendrimers, which are perfectly monodisperse and highly branched
    3D macromolecules, have been the topic of great attention especially as drug carriers [117–119]. For example, peptide dendrimers surface-functionalized by methoxy polyethylene glycol (mPEG) and Dox through the GFLG sequence have been designed [120]. The resulting enzyme-responsive dendrimer-GFLG-Dox nanocarrier gave greater ac-cumulation and retention in ovarian tumor cells(SKOV-3), leading to improved anticancer effect and no obvious systemic toxicity. Similarly,
    Fig. 7. Structure of Dox-loaded, PEGylated, enzyme-sensitive, macrocyclic pillar[5]arene amphiphiles and their self-assembly into micelles. Adapted with permission from Ref. [101].
    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. 8. (A)Mesoporous silica nanoparticle (MSN) functionalization. (B) Cathepsin-sensitive Dox-loaded MSNs. (C) Cell integrin receptor-mediated targeting by RGDS (Arg-Gly-Asp-Ser).