Peptide-based delivery of therapeutics in cancer treatment

Abstract

Current delivery strategies for cancer therapeutics commonly cause significant systemic side effects due to required high doses of therapeutic, inefficient cellular uptake of drug, and poor cell selectivity. Peptide-based delivery systems have shown the ability to alleviate these issues and can significantly enhance therapeutic loading, delivery, and cancer targetability. Peptide systems can be tailor-made for specific cancer applications. This review describes three peptide classes, targeting, cell penetrating, and fusogenic peptides, as stand-alone nanoparticle systems, conjugations to nanoparticle systems, or as the therapeutic modality. Peptide nanoparticle design, characteristics, and applications are discussed as well as peptide applications in the clinical space.

Keywords: Cancer; Drug therapy; Gene therapy; Nanoparticle conjugation; Peptide delivery.

Graphical abstract

Fig. 1

Targeting peptides bind to overexpressed cell receptors commonly seen in cancer cells. This binding can induce receptor-mediated endocytosis, enhancing peptide-cargo cell uptake. Created with Biorender.com.

Fig. 2

Cell penetrating peptides can be utilized to deliver siRNA and other cargo through electrostatic interactions with the positively charged amino acid residues. Cell penetrating peptides are primarily internalized via endocytotic mechanisms, including micropinocytosis, clathrin-mediated, and caveolae-mediated endocytosis. Under acidic conditions in the endosome, some cell penetrating peptides are protonated and can induce an influx of water and chloride ions into the endosome, resulting in increased internal pressure and eventual endocytotic rupture and release chemotherapeutics, allowing for subsequent RNAi activity. Created with BioRender.com.

Fig. 3

Depiction of fusogenic peptide-based nanoparticles delivering bioactive siRNAs through pH-sensitive endosomal escape. Taken up through endocytosis, fusogenic peptides undergo a conformational change to adopt a helical secondary structure under acidic conditions within the endosome, resulting in fusion and disruption of the membrane to allow the release of complexed cargo into the cytosol for subsequent incorporation with RNAi machinery. Adapted from “siRNA Nanoparticle Delivery System,” by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.

Fig. 4

Fusogenic peptides can undergo three different conformational changes to cause endosomal membrane interactions. α-helices (A–D) [166] are the main structure formation upon protonation in an acidic environment and can exhibit time and pH-dependent fusion depth, as demonstrated through molecular simulations with dodecylphosphocholine (DPC) micelles. Internal loop (E–H) [164,165] and β-sheet (I–K) [167] structures have also been noted as major players in fusogenicity, dependent on the internal amino acid sequence, and have been described in viruses including Ebola, sarcoma, and the gp41 fusion domain of HIV (HFP). Panels A–D used with permission from Brice and Lazaridis [166], panels E–H with permission from Gregory et al. [165], and panels I–K with permission from Sackett and Shai [167]. Permission related to panel A–D should be directed to ACS and can be accessed at https://pubs.acs.org/doi/10.1021/jp409412g.