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  • br D Endocytosis E Drug

    2020-08-28


    (D) Endocytosis. (E) Drug release mediated by Cathepsin B. (F) Tumor cell death. Adapted with permission from Ref. [112].
    Fig. 9. Synthesis of gatekeeper-supported functionalization with 3-(azidopropyl)triethoxysilane capped with peptide sequence and further delivery of Doxby action of Cathepsin B.
    Adapted with permission from Ref. [113].
    mPEG-PAMAM dendrimers of different chain lengths for the formation of Dox-loaded magnetite nanoparticles have also been reported [121]. In this system, Cathepsin B was used to selectively degrade the dendritic
    shell to trigger sustained Dox release near the tumor cells. The concept of enzymatic breakdown of the nanocarrier may represent a new approach for controlled drug delivery systems. Also, Cathepsin
    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. 10. Synthesis of Dox-peptide-coated, magnetic Cicaprost nanoparticles cleaved by Cathepsin B for Dox release inside cancer cells. Adapted with permission from Ref. [115].
    B-responsive and amphiphilic PEGylated dendritic polymer-drug conju-gates (PEGylated dendron-GFLG-Dox) were obtained by “click” chemis-try and led to enhanced antitumor efficacy (Fig. 12).
    Another study reported on the combination of undecapeptide KKLFKKILKKL-NH2 with the GFLG sequence for the delivery of chlorambucil (CLB) [122]. The free drug was inactive (IC50 = 73.7 to N100 μM) conversely to its prodrug (IC50 = 3.6–16.2 μM) on various can-cer cell lines including MCF-7, PC-3, CAPAN-1, 1BR3G and SKMEL-28. CLB-Gly-OH was indeed released when Cathepsin B was present as evi-denced by Cathepsin B enzymatic assays. Also, these studies supported the fact that CLB would be released in the lysosomal compartment.
    A comparative study was reported between dendrimers based on mPEG conjugated to Dox via a Cathepsin B-cleavable Gly-Phe-Leu-Gly sequence and GFLG-free dendrimers [123]. The GFLG sequence-bearing nanoconstructs were formulated into nanoparticles exhibiting Cathepsin B-sensitive drug delivery properties. The enhanced anticancer activity compared to that of free Dox Cicaprost was validated in vivo in a CT26 tumor xeno-graft mouse model.
    Asorbitol scaffold functionalized by octa-guanidine moieties and conjugated to Dox via a GLPG sequence, another peptidic substrate of Cathepsin B, was produced (Fig. 13) [124]. This conjugate was efficiently taken up by the cells via electrostatic interaction between guanidine
    Fig. 11. Synthesis of Gem-loaded, decorated QDs and their dual enzymatic behavior. Adapted with permission from Ref. [116].
    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. 12. Synthesis of amphiphilic PEGylated dendron-GFLG-Dox conjugate followed by its self-assembly into NPs. Adapted with permission from Ref. [121].
    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
    moieties and negatively-charged phospholipids/sulphates exposed at the surface of the cells. Dox was then released into lysosomes via selec-tive cleavage by Cathepsin B. Enhanced cytotoxicity compared to that of free Dox was obtained on HeLa cells that are known to express Cathepsin B.
    A great amount of work is also currently been carried out to design lipid-based drug delivery systems either as drug-loaded lipidic nanocarriers or lipidic prodrug nanocarriers [125,126]. However, exam-ples of Cathepsin-sensitive lipidic drug delivery systems are rather scarce. For instance, when a lipidated Cathepsin B inhibitor (NS-629) was anchored into a liposome bilayer (Fig. 14), its selective targeting and internalization into tumors and stromal cells was shown ex vivo and in vivo, confirming that using Cathepsin B as an efficient leverage for cancer diagnosis and treatment [127].
    Combination therapy, that relies on the simultaneous administration of at least two different drugs, is increasingly used to treat various diseases, including cancer [128,129]. Combination therapy from cathepsin-sensitive lipidic systems was illustrated by the conception of
    methotrexate-methoxypoly(ethylene glycol)-1,2-distearoyl-snglycero-3-phosphoethanolamine (Mtx-MePEG-DSPE) prodrug micelles loaded with mitomycin C-soybean phosphatidylcholine (SPC-MMC) prodrugs [130]. This micellar system exhibited synergistic anticancer activity in presence of Cathepsin B because of the amide linker in between the poly-mer and the drugs, as opposed to the action of individual drugs.