Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application

Abstract

Cell-penetrating peptides (CPPs) are short peptides (fewer than 30 amino acids) that have been predominantly used in basic and preclinical research during the last 30 years. Since they are not only capable of translocating themselves into cells but also facilitate drug or CPP/cargo complexes to translocate across the plasma membrane, they have potential applications in the disease diagnosis and therapy, including cancer, inflammation, central nervous system disorders, otologic and ocular disorders, and diabetes. However, no CPPs or CPP/cargo complexes have been approved by the US Food and Drug Administration (FDA). Many issues should be addressed before translating CPPs into clinics. In this review, we summarize recent developments and innovations in preclinical studies and clinical trials based on using CPP for improved delivery, which have revealed that CPPs or CPP-based delivery systems present outstanding diagnostic therapeutic delivery potential.

Keywords: cell-penetrating peptides; cellular uptake; diagnosis; targeting; translocate.

Figure 1

A schematic diagram illustrating the types of CPPs.

Figure 2

The schematic of cellular uptake mechanisms of CPP or CPP/cargo. Two types of pathways were presented: direct translocation and endocytosis. Direct translocation is divided into three models: “Barrel-Stave” model, “Carpet-like” model, and the Inverted-micelle model. Endocytosis is composed of macropinocytosis, caveolin-mediated endocytosis, clathrin-mediated endocytosis, and clathrin- and caveolin-independent endocytosis.

Figure 3

(A) Schematic illustration for the design of siRNA loaded TMV-TAT. (B) Gene silencing process of TMV-TAT within the cells (Tian et al., 2018b) (with reproduction permission).

Figure 4

DLNPs deliver APTstat3 for Psoriasis treatment via transcutaneous administration (Kim et al., 2018) (with reproduction permission).

Figure 5

(A) The schematic of synthetic R8-Pdots as imaging agents for whole-body cell tracking in deep organs. (B) The TEM image of Pdots, the scale bar is 100 nm. (C) Fluorescence imaging of MCF-7 cells labeled with R8-Pdots (red) and the cell nucleus was stained by Hoechst 33258. Scale bar: 20 μm. (D) Fluorescence imaging of the mouse in vivo (Zhang et al., 2018b) (with reproduction permission).

Figure 6

Illustration of CPP-modified ATTEMPTS system (Shin et al., 2014) (with reproduction permission).

Figure 7

MMP2-responsive multifunctional liposomal nanocarrier and its drug delivery strategy (Zhu et al., 2012) (with reproduction permission).