Abstract
Since their identification over twenty-five years ago, the plethora of cell-penetrating peptides (CPP) and their applications has skyrocketed. These 5 to 30 amino acid in length peptides have the unique property of breaching the cell membrane barrier while carrying cargoes larger than themselves into cells in an intact, functional form. CPPs can be conjugated to fluorophores, activatable probes, radioisotopes or contrast agents for imaging tissues, such as tumors. There is no singular mechanism for translocation of CPPs into a cell, and therefore, many CPPs are taken up by a multitude of cell types, creating the challenge of tumor-specific translocation and hindering clinical effectiveness. Varying strategies have been developed to combat this issue and enhance their diagnostic potential by derivatizing CPPs for better targeting by constructing specific cell-activated forms. These methods are currently being used to image integrin-expressing tumors, breast cancer cells, human histiocytic lymphoma and protease-secreting fibrosarcoma cells, to name a few. Additionally, identifying safe, effective therapeutics for malignant tumors has long been an active area of research. CPPs can circumvent many of the complications found in treating cancer with conventional therapeutics by targeted delivery of drugs into tumors, thereby decreasing off-target side effects, a feat not achievable by currently employed conventional chemotherapeutics. Myriad types of chemotherapeutics such as tyrosine kinase inhibitors, antitumor antibodies and nanoparticles can be functionally attached to these peptides, leading to the possibility of delivering established and novel cancer therapeutics directly to tumor tissue. While much research is needed to overcome potential issues with these peptides, they offer a significant advancement over current mechanisms to treat cancer. In this review, we present a brief overview of the research, leading to identification of CPPs with a comprehensive state-of-the-art review on the role of these novel peptides in both cancer diagnostics as well as therapeutics.
Highlights
Introduction published maps and institutional affilAs so often happens in science, the discovery of cell-penetrating peptides (CPP) was a serendipitous one
Two independent groups of researchers working on the human immunodeficiency virus (HIV) viral coat Trans-activator of Transcription (Tat) protein observed the protein’s ability to cross cell membrane barriers without any transfection reagents [1,2]
This study highlights a promising CPP (F3) and CPP-NP combination for tumor imaging, demonstrating that there are multiple variations of CPPs and combinations that can be used to advance tumor imaging [41]. Another strategy to enhance tumor imaging is via use of activatable CPPs (ACPPs)
Summary
CPPs are a promising tool for tumor imaging due to their high binding affinity, small size, specific uptake, high stability, rapid clearance from non-specific targets, and retention in specific targets [17,18,19,20,21]. Tat cannot target tumors, its stability in vivo and rapid translocation across cell membranes show promising abilities as peptide chelates and fluorophore conjugates to serve as imaging agents (Figure 1). Another study used the CPP dual targeting combination to target tumor cells, but with the addition of another i imaging (Figure 1) (photoacoustic (PA) and MRI imaging). Another strategy to enhance tumor imaging is via use of activatable CPPs (ACPPs) In this method, the CPP contains a region which can penetrate cells and carry cargo (polycation), a region which can target metalloproteases-2 (MMP-2) and MMP-9 (proteasecleavable linker), and a region which quenches the function of the cell-penetrating region (polyanion). Using Cy5 and Gd chelates allowed for dual labeling of the ACPP dendrimer combination for fluorescent and MRI imaging in tumor-bearing mice. The results showed better uptake and tumor specificity than previously reported results, once again illustrating the myriad ways in which CPPs can be altered and combined to improve tumor imaging [43]
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