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  • 2-NBDG br In the following we


    In the following, we have covered Cathepsin-sensitive drug delivery systems for anticancer therapy, by distinguishing five different types of systems: (i) polymeric; (ii) inorganic; (iii) dendritic/comb-like; (iv) lipidic and (v) protein-based/peptidic.
    Different types of polymeric systems have been utilized to develop drug-polymer conjugates for anticancer drug delivery [28,78–85]. Given Cathepsin B is a lysosomal cysteine protease overexpressed in the microenvironment of advanced tumors [86], this feature has been widely exploited in cancer therapy using polymer-based drug delivery systems bearing the Cathepsin B-sensitive GFLG sequence [87]. This
    area was pioneered by Kopeck who developed PHPMA-based drug con-jugates containing GFLG sequences on the polymer backbone as well as on the side-chains, giving enhanced therapeutic efficacy while still maintaining their biocompatibility. This system was further extended to a two-drug combination approach using gemcitabine (Gem, unstable in vivo) and paclitaxel (Ptx, poorly water soluble) linked to either diblock, tetrablock or hexablock PHPMA copolymers obtained by a com-bining RAFT polymerization and “click” chemistry (Fig. 3). The diblock copolymer (Mn~100 kDa) was found to be the most efficient one in vivo on A2780 human ovarian carcinoma xenografts in nude mice. It indeed showed a more pronounced synergistic antitumor effect com-pared to other structures, thus overcoming the limitations of the free drug.
    The strongest synergistic interactions in acute myeloid leukemia (AML) was also observed as assessed in HL-60 human AML 2-NBDG when cytarabine and GDC-0980 were linked to similar GFLG-bearing PHPMA copolymers, conversely to daunorubicin or JS-K [88]. Similarly, another study reported on the combination of GDC-0980 (P13K/mTOR inhibi-tor) and docetaxel against prostate cancer and showed promising results (Fig. 4) [89]. Several other combinations directed against cancer have also been explored from PHPMA copolymer bearing GFLG sequences [90–94].
    In a more mechanistic study, two PHPMA-based multiblock S-CMP (small copolymer block size) and L-CMP (long copolymer block size) have been synthesized [95]. Both the copolymer blocks and the peptide linkers were tagged with 125I and 177Lu, respectively (Fig. 5). S-CMP showed increased cleavage rates by Cathepsin S compared to L-CMP resulting from the lower steric hindrance as assessed by in vitro studies. The cleavage and clearance of the different blocks were both greater in-side the tumor and the liver, as observed from radioisotopic ratios.
    Dox has been conjugated to different polymeric architectures via Cathepsin-sensitive linkers. For instance, Dox was linked to an octa-guanidine-based peptide sequence (Phe-Lys) via 4-aminobenzyloxy carbonyl (PABC) as a self-immolative linker, resulting in a G8-PP1-FK-PABC-Doxprodrug. It was able to be cleaved by lysosomal Cathepsin B and inducing selective toxicity against HeLa cells without affecting healthy cells [96]. On the contrary, small-molecule (MW b 500 g. mol−1) self-assemblies have also been utilized to develop a generic cross-linked micellar drug delivery system based on gemcitabine (Gem) prodrugs (Fig. 6a). This system proved to be advantageous as compared to well-known polymeric micellar systems in terms of com-position, colloidal stability, drug payload (~58 wt%), biosafety, as well as ease of synthesis, functionalization and in vitro/in vivo anticancer ac-tivity [97–99]. Infact, nearly 60% of the drug was released from 2-NBDG the mi-celles by Cathepsin B in phosphate buffer saline (PBS) at pH 5.5 for 240 h conversely to b7% without Cathepsin B because of the amide bond in between the drug and the promoiety (Fig. 6b) [100].