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  • Pifithrin-α br A great amount of work is also currently

    2022-08-18


    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 Pifithrin-α 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.
    2.1.5. Protein-based/peptidic systems
    Drug delivery systems based on proteins or peptides represent an appealing class of materials especially because of their biocompatibility [131–135]. For instance, proteinticles, which are proteins that can self-assemble inside cells into nanoscale particles, can be employed in many different biomedical applications owing to their enhanced bio-compatibility, conversely to synthetic nanomaterials [136]. Conferring cathepsin-sensitivity to such systems have also been reported, espe-cially for small interfering RNA (siRNA) delivery where it showed great potential against various cancers. For instance, proteinticles based on human ferritin were genetically engineered to display Pifithrin-α at their surface different functional peptides in a simultaneous manner, such as cationic peptides for self-assembling siRNA, cancer
    Fig. 13. Schematic representation and proposed action mechanism of a sorbitol scaffold functionalized by octa-guanidine moieties and conjugated to Dox. Adapted with permission from Ref. [124].
    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. 14. Schematic representation showing conjugation of the lipidated Cathepsin B inhibitor (NS-629) at the surface of a liposome to target extracellular (EC) Cathepsin B. Adapted with permission from Ref. [127].
    cell-targeting or cell penetrating peptide [137]. They led to enhanced siRNA capture, cancer cell targeting together with enhanced penetra-tion into the cytoplasm of tumor cells. They were eventually cleaved by Cathepsin B for intracellular release of siRNA inside tumor cells, lead-ing to efficient gene silencing. One of the greatest advantages of proteinticles is that such functional peptides of different nature can be evenly placed on their surface, depending on the tumor cell type through a simple genetic modification, thus making it a very versatile system for targeted siRNA delivery. Another study revealed the devel-opment of a polyglutamate amine (APA) nanocarriers containing miRNA and siRNA polyplexes which showed great accumulation into pancreatic tumor cells [138]. It was also shown that the release of miRNA occurred from APA-containing polyplex in the presence of Ca-thepsin B.
    Given the poor water-solubility of many anticancer drugs, a consid-erable amount of research has been done to improve their hydrophilic-ity by conjugation to hydrophilic moieties via Cathepsin-sensitive linkers. For instance, Ptx has been conjugated to a highly water-soluble nucleolin aptamer (NucA) for the targeting of ovarian cancer with reduced off-site toxicity [139]. The resulting bioconjugate proved