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Review
. 2023 Jun 29;15(7):1848.
doi: 10.3390/pharmaceutics15071848.

Smart Delivery Systems Responsive to Cathepsin B Activity for Cancer Treatment

Vera S Egorova  1 , Ekaterina P Kolesova  1 , Manu Lopus  2 , Neng Yan  3 , Alessandro Parodi  1   4 , Andrey A Zamyatnin Jr  1   4   5   6
Affiliations
Review

Smart Delivery Systems Responsive to Cathepsin B Activity for Cancer Treatment

Vera S Egorova et al. Pharmaceutics. .

Abstract

Cathepsin B is a lysosomal cysteine protease, contributing to vital cellular homeostatic processes including protein turnover, macroautophagy of damaged organelles, antigen presentation, and in the extracellular space, it takes part in tissue remodeling, prohormone processing, and activation. However, aberrant overexpression of cathepsin B and its enzymatic activity is associated with different pathological conditions, including cancer. Cathepsin B overexpression in tumor tissues makes this enzyme an important target for smart delivery systems, responsive to the activity of this enzyme. The generation of technologies which therapeutic effect is activated as a result of cathepsin B cleavage provides an opportunity for tumor-targeted therapy and controlled drug release. In this review, we summarized different technologies designed to improve current cancer treatments responsive to the activity of this enzyme that were shown to play a key role in disease progression and response to the treatment.

Keywords: cathepsin B; enzyme-induced cleavage; peptide linkers; proteolytic activity; responsive nanocarrier.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of cathepsin B maturation. Preprocathepsin B is synthesized into the rough endoplasmic reticulum. The cleavage of the signal peptide (SP) results in the formation of procathepsin B, which is transferred to the Golgi apparatus and finally to lysosomes (see the detailed description of the maturation process in the text). The star indicates Cys29 in the active site. The figure was generated using www.biorender.com, accessed on 17 March 2023.
Figure 2
Figure 2
Structure of human cathepsin B. (A) Ribbon diagram of the enzyme. The heavy chain is shown in blue and the light chain is shown in green. The yellow mark indicates Cys29 residue in the active site (PDB ID: 1CSB, https://doi.org/10.2210/pdb1CSB/pdb) [29]. (B) Occluding loop of human cathepsin. (B) During the interaction with the substrate, Cys29 and His199 act as the catalytic nucleophile and general base. Gln23 stabilizes the oxyanion tetrahedral intermediate, whereas Trp221 and Trp225 form a hydrophobic pocket around the active site. Residues mediating the peptidyldipeptidase activity are indicated in bold. Ion pairs are formed between Asp22 and His110, and between Arg116 and Asp224, whereas His111 is unpaired. Figure reprinted from Krupa et al [26].
Figure 3
Figure 3
Schematic representation of ADC mechanism of action: targeted drug delivery and release. Figure reprinted from Ponziani et al. [83].
Figure 4
Figure 4
Schematic diagram of CtsB-sensitive M13 phage-SPION system: (A) Schematic diagram of the system. (B) Mechanism of payload delivery and release. Figure reprinted from the International Journal of Nanomedicine 2021 16 7091–7102 [113]. Originally published by and used with permission from Dove Medical Press Ltd.
Figure 5
Figure 5
Schematic illustration of the CtsB-sensitive nuclear-targeted QD@mSiO2 nanoparticles. Figure reprinted from Li et al. [130]. Originally published by and used with permission from John Wiley & Sons, Inc.
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