br Among the different pathologies Cathepsins
Among the different pathologies, Cathepsins have been largely employed as leverage to treat cancer from various Cathepsin-sensitive drug delivery systems because of its overexpression at the tumor sites. For instance, cysteine proteases have increased activity as well as aberrant localization within the tumor microenvironment, which contributes to cancer progression, proliferation and SCH772984 . Such findings led to the development of the glycyl-penylalanyl-leucyl-glycine (GFLG) sequence that is hydrolyzed by Cathepsin B. In this area, poly(N-(2-hydroxypropyl)methacrylamide-doxorubicin
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. 1. Schematic representation of the revised papain model showing different subsites based on substrate-mimicking inhibitors bonded to the active-site cleft. Reproduced with permission from Ref. .
(PHPMA-Dox, also called PK1) were the first clinically investigated conjugates for anticancer therapy that comprised Cathepsin-sensitive degradable GFLG sequences . Since PK1, several PHPMA-drug conju-gates have entered clinical trials [23,24], which confirmed the great po-tential of these systems. Some of the structures of the different drug delivery conjugates are gathered in Fig. 2 along with their cathepsin cleavable sites for better understanding [25–27].
Whereas several reviews have already been published on targeted polymer-based drug delivery systems [28–31], cysteine Cathepsins as imaging probes [32–35], aging and neurodegeneration , disease management  and other protease functions [38,39], the dynamic in-volvement of Cathepsins in targeted drug delivery systems including their role in various diseased states and their clinical prospects have never been covered in a single Review Article.
2. Cathepsin-sensitive drug delivery systems
2.1. Anticancer drug delivery systems
In the past few decades, anticancer drug delivery has attracted extensive interest from both academia and industry. A considerable effort is being spent on the design of nanoscale systems having suitable properties for drug delivery purposes such as stealthiness, non-immunogenicity, biocompatibility as well as biodegradability. The fate of stealth nanoscale systems is governed, at least in part, by the enhanced permeability and retention (EPR) effect (also called passive targeting). It allows for their preferential accumulation at the tumor site because of leaky vasculatures and lack of lymphatic drainage [40,41]. Interestingly, a variety of different Cathepsins have been reported to be overexpressed in many types of cancers; mostly found in cancer cells but also in cancer-associated leukocytes, fibroblasts, osteoclasts, myoepithelial cells as well as endothelial cells . The list of cancer overexpressing Cathepsins is given below (Table 1). Hence, the intimate relationships between Cathepsins and cancer stimulated the conception of (macro)molecules sensitive to the presence of Cathepsins for enhanced therapeutic effect.
In the following, we have covered Cathepsin-sensitive drug delivery systems for anticancer therapy, by distinguishing five different types of systems: (i) polymeric; (ii) inorganic; (iii) dendritic/comb-like; (iv) lipidic and (v) protein-based/peptidic.
Different types of polymeric systems have been utilized to develop drug-polymer conjugates for anticancer drug delivery [28,78–85]. Given Cathepsin B is a lysosomal cysteine protease overexpressed in the microenvironment of advanced tumors , this feature has been widely exploited in cancer therapy using polymer-based drug delivery systems bearing the Cathepsin B-sensitive GFLG sequence . This
area was pioneered by Kopeck who developed PHPMA-based drug con-jugates containing GFLG sequences on the polymer backbone as well as on the side-chains, giving enhanced therapeutic efficacy while still maintaining their biocompatibility. This system was further extended to a two-drug combination approach using gemcitabine (Gem, unstable in vivo) and paclitaxel (Ptx, poorly water soluble) linked to either diblock, tetrablock or hexablock PHPMA copolymers obtained by a com-bining RAFT polymerization and “click” chemistry (Fig. 3). The diblock copolymer (Mn~100 kDa) was found to be the most efficient one in vivo on A2780 human ovarian carcinoma xenografts in nude mice. It indeed showed a more pronounced synergistic antitumor effect com-pared to other structures, thus overcoming the limitations of the free drug.
The strongest synergistic interactions in acute myeloid leukemia (AML) was also observed as assessed in HL-60 human AML cells when cytarabine and GDC-0980 were linked to similar GFLG-bearing PHPMA copolymers, conversely to daunorubicin or JS-K . Similarly, another study reported on the combination of GDC-0980 (P13K/mTOR inhibi-tor) and docetaxel against prostate cancer and showed promising results (Fig. 4) . Several other combinations directed against cancer have also been explored from PHPMA copolymer bearing GFLG sequences [90–94].