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

Abstract

In cancer treatments, many natural and synthetic products have been examined; among them, protease inhibitors are promising candidates for anti-cancer agents. Since dysregulated proteolytic activities can contribute to tumor development and metastasis, antagonization of proteases with tailored inhibitors is an encouraging approach. Although adverse effects of early designs of these inhibitors disappeared after the introduction of next-generation agents, most of the proposed inhibitors did not pass the early stages of clinical trials due to their nonspecific toxicity and lack of pharmacological effects. Therefore, new applications that modulate proteases more specifically and serve their programmed way of administration are highly appreciated. In this context, nanosized drug delivery systems have attracted much attention because preliminary studies have demonstrated that the therapeutic capacity of inhibitors has been improved significantly with encapsulated formulation as compared to their free forms. Here, we address this issue and discuss the current application and future clinical prospects of this potential combination towards targeted protease-based cancer therapy.

Keywords:

• proteases
• inhibitors
• nanoscale drug-delivery system
• combination therapy
• cancer treatment

Acknowledgments

We thank Alexandr V. Bazhin for fruitful discussions in relation to this paper.

Abbreviations

HIV, human immunodeficiency virus; MMP, matrix metalloprotease; uPA, urokinase-type plasminogen activator; Cts, cathepsin; Ki, inhibitory constant; TIMP, tissue inhibitors of metalloproteinase; FDA, Food and Drug Administration; NP, nanoparticle; GNC, gold nanocluster; LTSL, lysolipid-containing thermosensitive liposome; PEG, polyethylene glycol; As, arsenic; U11, 11-amino-acid sequence; ATF, amino-terminal fragment; CPP, cell-penetrating peptide; PLGA, poly(lactic-co-glycolic acid).

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This research was funded by the Russian Science Foundation (grant # 16-15-10410).