Cancer-Targeting Applications of Cell-Penetrating Peptides

Abstract

Cell-penetrating peptides (CPPs) offer a unique and efficient mechanism for delivering therapeutic agents directly into cancer cells. These peptides can traverse cellular membranes, overcoming one of the critical barriers in drug delivery systems. In this review, we explore recent advancements in the application of CPPs for cancer treatment, focusing on mechanisms, delivery strategies, and clinical potential. The review highlights the use of CPP-drug conjugates, CPP-based vaccines, and their role in targeting and inhibiting tumor growth.

Keywords: apoptosis inductors; cancer; cancer immunotherapy; cell-penetrating peptides; fluorescent peptide dye; multi resistance; peptide receptor radionuclide therapy; selective membrane disruption; targeted cancer therapeutic peptides; targeted drug delivery.

Figure 1

CPPs with Intrinsic Anticancer Activity. This figure presents CPPs that exert therapeutic effects through intrinsic biological functions, independent of cargo. Highlighted CPPs include ATX-101, which disrupts PCNA interactions; PEP-010, which induces caspase-9-mediated apoptosis; SAHBD, which inhibits MCL-1 to promote apoptosis; p28, stabilizing p53 for cell-cycle arrest; P1pal-7, which targets PAR1 to reduce tumor angiogenesis; EN1-iPEP, a transcription factor inhibitor triggering selective apoptosis; and Bac1-24, enhancing nuclear localization of therapeutic peptides. Only selected examples of the CPPs discussed in this communication are shown. [Created in BioRender. Moreno-Vargas, L. (2024) BioRender.com/c08a709 | CC-BY 4.0].

Figure 2

CPPs as Cargo Carriers for Targeted Delivery. This figure highlights the role of CPPs as efficient drug delivery vehicles, enabling targeted transportation of therapeutic agents into cancer cells. Included CPPs are AVB-620, pVEC, PEGA, Z12, Pep-1, MAP, and SAP(E), which exhibit diverse cargo-loading mechanisms: AVB-620 for real-time imaging, pVEC for direct cell translocation, PEGA for selective tumor targeting, Z12 and Pep-1 for immune modulation and selective cell penetration, MAP for membrane disruption, and SAP(E) as a complex-forming agent to enhance cellular uptake and cytotoxicity of its payloads in target cells, minimizing off-target toxicity. Only selected examples of the CPPs discussed in this communication are shown. [Created in BioRender. Moreno-Vargas, L. (2024) BioRender.com/u64r118 | CC-BY 4.0].

Figure 3

Internalization Mechanisms of CPPs Across Cell Membranes. CPPs employ diverse mechanisms to cross cell membranes, including direct translocation, endocytosis, and interactions with receptors overexpressed in membranes. Despite shared characteristics, CPPs exhibit distinct internalization routes that vary across peptide families and depend on experimental conditions. Factors such as charge, length, structure, and peptide concentration play critical roles in determining the internalization route. The CPPs listed in this communication are highlighted, noting that individual CPPs can often engage multiple internalization pathways. [Created in BioRender. Moreno-Vargas, L. (2024) BioRender.com/j68n394 | CC-BY 4.0].