Curb challenges of the “Trojan Horse” approach: Smart strategies in achieving effective yet safe cell-penetrating peptide-based drug delivery

Abstract

Cell-penetrating peptide (CPP)-mediated intracellular drug delivery system, often specifically termed as “the Trojan horse approach”, has become the “holy grail” in achieving effective delivery of macromolecular compounds such as proteins, DNA, siRNAs, and drug carriers. It is characterized by the unique cell- (or receptor-), temperature-, and payload-independent mechanisms, therefore offering potent means to improve poor cellular uptake of a variety of macromolecular drugs. Nevertheless, this “Trojan horse” approach also acts like a double-edged sword, causing serious safety and toxicity concerns to normal tissues or organs for in vivo application, due to lack of target selectivity of the powerful cell penetrating activity. To overcome this problem of potent yet non-selective penetration vs. targeting delivery, a number of “smart” strategies have been developed in recent years, including controllable CPP-based drug delivery systems based on various stimuli-responsive mechanisms. This review article provides a fundamental understanding of these smart systems, as well as a discussion of their real-time in vivo applicability.

Diving through Membranes: Molecular Cunning to Enforce the Endosomal Escape of Antibody-Targeted Anti-Tumor Toxins

“…Thus, small molecule drugs used to rupture the endosomal limiting membrane as described in physicochemical methods and for leakage-inducing molecules are in one respect more favorable than molecular ferries based on viral proteins and non-human cell penetrating peptides that possess an inherent immunogenicity when presented to the human immune system. In their favor, viral systems are highly specific for their target cell whereas cell penetrating peptides and other small molecules lack target selectivity [132]. To overcome this problem, a number of strategies have been developed in recent years.…”

“…To overcome this problem, a number of strategies have been developed in recent years. For CPP-based drug delivery systems, specificity can be gained through various tumordependent stimuli-responsive mechanisms [132] or direct fusion of the CPP to the targeted toxin together with the inclusion of cleavable peptides to ensure endosomal activation and cytosolic trapping once internalized by the target cancer cell [46]. For leakage inducing systems, other solutions have been sought and found.…”

Peptide-mediated vectorization of metal complexes: conjugation strategies and biomedical applications

“…[24][25][26] In the similar vein, other peptide sequences such as mitochondriapenetrating sequences (MPPs) 27 or more specific targeting sequences for nuclear (NLS) 5 and mitochondrial delivery (MLS) allow a broad range of possibilities to gain effective intracellular trafficking. 28 On the other hand, targeted drug delivery approaches are required to obtain selectivity against diseased tissues.…”

A BODIPY-embedding miltefosine analog linked to cell-penetrating Tat(48-60) peptide favors intracellular delivery and visualization of the antiparasitic drug

“…The nature of CPP-cargo linkage, a crucial issue in CPP delivery strategies (Huang et al, 2013;Nasrolahi Shirazi et al, 2013), can be roughly divided into covalent and non-covalent. The latter is preferred for large payloads such as proteins or, especially, nucleic acids (Crombez et al, 2011;Deshayes et al, 2010;Henriques et al, 2005;Lindberg et al, 2013), whose charge complementarity with cationic CPPs is thus usefully exploited.…”