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  • br Protein based peptidic systems br Drug delivery systems b

    2020-08-28


    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 Anti-Human TNF-alpha 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 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
    to be biologically stable as assessed by fluorescence resonance energy transfer (FRET) (Fig. 15) and also inactive in the Anti-Human TNF-alpha blood circulation. NucA was conjugated to the hydroxyl group at position 2′ of the drug via a dipeptide bond sensitive to Cathepsin B, which then got cleaved once inside the cells by Cathepsin B, thus triggering the anticancer mechanism.
    The GFLG sequence was also embedded into a star-shaped peptidic prodrug structures that can be cleaved by Cathepsin B. This feature has been used to develop drug delivery vehicles for 2-methoxyestradiol (2ME) which is a natural metabolite of estradiol with antiproliferative and anti-angiogenic activities (Fig. 16) [140]. In the context of combination therapy, a dual-functionalized linker bearing Dox and Ptx, and comprising a maleimide moiety for its subse-quent coupling to albumin through its cysteine-34 position, was designed [141]. Each drug was linked by a self-immolative para-aminobenzyloxy carbonyl linker and a cleavable dipeptide (Phe-Lys) sensitive to Cathepsin B, leading to drug release at the tumor site (Fig. 17).A similar approach combining a polymer prodrug and a polymer-enzyme bioconjugate was used to selectively and rapidly deliver a cytotoxic drug to the target site [142].
    Fig. 15. Schematic illustration of the in vivo tracking of the degraded Cathepsin B-labile dipeptide bond linker exploiting FRET with fluorescein amidate (FAM) and dual-labeled rhodamine B (Rh) NucA-Ptx bioconjugate. Adapted with permission from Ref. [139].
    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. 16. Representation of the degradation of star-shaped peptidic prodrug structures that can be cleaved by Cathepsin B. Adapted with permission from Ref. [140].