Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

Abstract

Cathepsins are an important category of enzymes that have attracted great attention for the delivery of drugs to improve the therapeutic outcome of a broad range of nanoscale drug delivery systems. These proteases can be utilized for instance through actuation of polymer-drug conjugates (e.g., triggering the drug release) to bypass limitations of many drug candidates. A substantial amount of work has been witnessed in the design and the evaluation of Cathepsinsensitive drug delivery systems, especially based on the tetra-peptide sequence (Gly-Phe-Leu-Gly, GFLG) which has been extensively used as a spacer that can be cleaved in the presence of Cathepsin B. This Review Article will give an in-depth overview of the design and the biological evaluation of Cathepsin-sensitive drug delivery systems and their application in different pathologies including cancer before discussing Cathepsin B-cleavable prodrugs under clinical trials.

Harnessing Endogenous Stimuli for Responsive Materials in Theranostics

“…Cysteine cathepsins (B, C, F, H, K, L1, L2/V, O, S, W, X/Z) are located in the endosome/lysosome intracellular compartment, making them useful in the design of enzyme-degradable nanomaterials, conjugates, biomaterials, and probes for intracellular release or activation. 94 − 98 In particular, cathepsin B has been well studied for cancer applications, including breast, lung, prostate, and colorectal cancers, due to its overexpression in tumor tissue cells. 94 , 99 Kopeček and Duncan, among others, have had success with cathepsin-cleavable linkers between drug molecules and polymers, research which started in the 1980s and progressed to phase II clinical trials for anti-cancer therapy.…”

Current Status and Perspectives of Protease Inhibitors and Their Combination with Nanosized Drug Delivery Systems for Targeted Cancer Therapy

“…In recent years, novel nanoparticle (NP) formulations such as non-traditional drug distribution platforms have been studied extensively for selective targeting and neutralizing proteases. [81][82][83][84][85]…”

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

“…So far, intracellular proteases (e.g. cathepsins, legumain) and glycosidases (β‐glucuronidase, β‐galactosidase) have been investigated more extensively, and the cathepsin B‐sensitive Val‐Cit dipeptide ( 1 , Scheme ) can be considered a milestone, being included in the marketed conjugates Adcetris™ and Polivy™, as well as in other ADCs undergoing clinical evaluation . The success of these linkers has stimulated intense research activity, especially at the industrial level, aimed not only at increasing the serum stability and cleavage selectivity of linker substrates in the presence of a specific effector, but also in the validation of new tumor‐associated enzymes as potential drug release mediators.…”