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  • br In a more mechanistic study two

    2020-08-28


    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 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].
    Another report focused on the construction of PEGylated, enzyme-sensitive,macrocyclic pillar[5]arene amphiphiles which self-assembled in water into micelles with high Dox loading capacity [101]. The micelles had enzyme-cleavable amide bonds that were cleaved by L-asparaginase (L-ASP) used here as a mimic of intracellular Cathepsin B because it can catalyze the hydrolysis of asparagine to aspartic NVP-2 (Fig. 7). The Dox-loaded micelles led to significant cytotoxicity on MCF-7 and multidrug-resistant MCF-7/ADR cells, comparatively to drug-free micelles.
    Folic acid (FA) surface-functionalized, biodegradable poly(ethylene oxide)-b-poly(L-glutamic acid) (FA-PEG-b-PLG) block copolymer vesi-cles loaded with cisplatin were also reported [102]. The drug was re-leased intracellularly from the rigid block due to overexpressed Cathepsin B which cleaved the nanostructure because of the increased activity of this proteolytic enzyme in metabolizing PLG acid residues. The enzyme was also responsible for the higher activity in metabolizing polyglutamate (PGA) residues. The nanovesicles exhibited surface-positioned FA moieties for active targeting via selective cell binding and led to enhanced cytotoxicity towards HeLa cells.
    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. 2. Structure of different cathepsin-sensitive drug-linker bioconjugates along with their indicated cleavable sites.
    PGA was also used as a polymer scaffold to link both Ptxand an integrin-targeted ligand (E-[c(RGDfK)2]) on the side chains, to give PGA-Ptx-E-[c(RGDfK)2]). The resulting conjugate gave significant enhancement in anticancer activity compared to free Ptx [103]. As assessed by the in vitro drug release profile, Ptx was released in the pres-ence of Cathepsin B but PGA-Ptx-E-[c(RGDfK)2] was found to be stable in plasma. Interestingly, incorporation of a targeting ligand towards
    integrin expressing cells led to anti-angiogenic mechanism to overcome multi-drug resistance.
    Another targeted drug delivery system was reported and consisted in a heterobifunctional oligomeric PEG chains embedding octreotide as a ligand for the targeting of somatostatin receptors and either an an-ticancer drug (Dox) tethered via a dipeptidic substrate for Cathepsin B, or a fluorescent dye [104]. This oligomeric prodrug system was suitable
    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
    Table 1
    List of Cathepsin overexpressing cancer types.
    Family Cathepsin Location Tumor site Reference
    Cysteine Proteases General Intracellular, lysosomes Most [42–44]
    Cathepsin K Extracellular Breast, bone [45–49]
    Cathepsin B Extracellular and pericellular under Breast, cervix, colon, colorectal, gastric, head and neck, liver, [50–61]
    pathological conditions lung, melanoma, ovarian, pancreatic, prostate, thyroid
    Cathepsin L