CPP-Assisted Intracellular Drug Delivery, What Is Next?

Abstract

For the past 20 years, we have witnessed an unprecedented and, indeed, rather miraculous event of how cell-penetrating peptides (CPPs), the naturally originated penetrating enhancers, help overcome the membrane barrier that has hindered the access of bio-macromolecular compounds such as genes and proteins into cells, thereby denying their clinical potential to become potent anti-cancer drugs. By taking the advantage of the unique cell-translocation property of these short peptides, various payloads of proteins, nucleic acids, or even nanoparticle-based carriers were delivered into all cell types with unparalleled efficiency. However, non-specific CPP-mediated cell penetration into normal tissues can lead to widespread organ distribution of the payloads, thereby reducing the therapeutic efficacy of the drug and at the same time increasing the drug-induced toxic effects. In view of these challenges, we present herein a review of the new designs of CPP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy in combating tumor oncology.

Keywords: CPPs; intracellular delivery; pH and enzyme triggered drug delivery system.

Figure 1

Cell penetrating peptide (CPP)-assisted strategies employed in achieving intracellular delivery of bio-macromolecular compounds and nano-carriers.

Figure 2

Mechanisms reported for the CPP-mediated intracellular drug delivery strategy.

Figure 3

Illustration of the: (a) antibody-guided; and (b) Magnetic iron oxide nanoparticles (MION)-involved targeted drug delivery system (Reproduced according to [98,102]).

Figure 4

Examples of the pH-sensitive nano-carriers equipped with an efficient CPP exposure: (a) polyHis-based micelles responded to acidic tumor microenvironments by an efficient CPP exposure; and (b) TAT-peptide-decorated liposomes comprising a hydrolyzable PEG shell allowing improved exposure of the TAT (redrawn according to [105,106]).

Figure 5

Illustration of the MMP2-triggered, CPP-mediated intracellular delivery strategy of drug-encapsulated liposome (Reproduced according to [114]).