Trends in Molecular Medicine
ReviewCell-penetrating peptides: breaking through to the other side
Section snippets
Moving across cell membranes
The inability of therapeutics to reach their designated cellular and intracellular target sites is one of the main obstacles for administering active molecules, particularly where cell membranes prevent proteins, peptides, and nanoparticulate drug carriers from entering cells in the absence of active transport. Targeting to specific intracellular organelles such as nuclei, mitochondria, and lysosomes could further expand the possibilities for drug delivery systems and the development of
Classes of CPPs
The proof-of-concept of protein transduction into cells was first described in 1988 in parallel by Frankel and Pabo [5] and Green and Loewenstein [6] who discovered that the transactivator of transcription (TAT) protein of HIV can cross cell membranes and be efficiently internalized by cells in vitro, resulting in transactivation of the viral promoter. In 1997, Vives et al. [7] used the same approach to study truncated versions of TAT and identified a minimal sequence that enabled cell entry. A
Cellular uptake mechanisms of CPPs
Although the mechanism of CPP accumulation in the cytoplasm is not fully understood, it seems clear that two types of intracellular uptake coexist, but differ dramatically in terms of the efficiency of accumulation, and therefore, in possible applications. In addition to the CPP electrostatic interactions and hydrogen bonding that are responsible for the direct transduction of small molecules through the lipid bilayer 20, 21, energy-dependent macropinocytosis is a primary endocytotic pathway
CPP-modified nanocarriers for intracellular delivery
Although the mechanisms underlying the cellular uptake of CPPs and their conjugates remain highly debated, these peptides have been successfully used to mediate the intracellular delivery of a variety of molecules of pharmacological interest in different cell types and have the potential to improve intracellular delivery of a large arsenal of biologically active agents 32, 33, 34. The major advantage of CPPs is their ability to transport cargo to intracellular compartments of the cell (e.g.,
CPP-modified stimulus-responsive and ‘smart’ nanocarriers
Although of considerable clinical potential, CPPs also have a few important drawbacks and limitations. First, they have the undesirable characteristic of nonspecificity and can enter any cell they come in contact with. This lack of selectivity affects the risk of drug-induced toxic effect on normal tissues. Secondly, the stability in vivo of these peptides is at risk until they reach their target. These peptides can be enzymatically cleaved by plasma enzymes and thus need to be sterically
Concluding remarks and future perspectives
CPPs have been shown to assist intracellular delivery of a variety of biomolecules both in vitro and in vivo. The absence of cell specificity of CPPs along with their susceptibility to proteolytic cleavage under physiological conditions has lead to the design of so-called ‘smart’ delivery platforms, based on the physiological or microenvironmental features peculiar to the targeted tissue or cell type. An external local trigger can also be used to enhance a carrier's cargo release. CPP-modified
Acknowledgments
This work was supported by National Institutes of Health grants RO1 CA121838 and RO1 CA128486 to V.P. Torchilin. W.C. Hartner is gratefully acknowledged for his help during preparation of this manuscript.
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