Peptide Drug Conjugates and Their Role in Cancer Therapy

Abstract

Drug conjugates have become a significant focus of research in the field of targeted medicine for cancer treatments. Peptide-drug conjugates (PDCs), a subset of drug conjugates, are composed of carrier peptides ranging from 5 to 30 amino acid residues, toxic payloads, and linkers that connect the payload to the peptide. PDCs are further broken down into cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs), each having their own differences in the delivery of cytotoxic payloads. Generally, PDCs as compared to other drug conjugates-like antibody-drug conjugates (ADCs)-have advantages in tumor penetration, ease of synthesis and cost, and reduced off-target effects. Further, as compared to traditional cancer treatments (e.g., chemotherapy and radiation), PDCs have higher specificity for the target cancer with generally less toxic side effects in smaller doses. However, PDCs can have disadvantages such as poor stability and rapid renal clearance due to their smaller size and limited oral bioavailability due to digestion of its peptide structure. Some of these challenges can be overcome with modifications, and despite drawbacks, the intrinsic small size of PDCs with high target specificity still makes them an attractive area of research for cancer treatments.

Keywords: bioconjugates; carrier; linker; payload; peptide-drug conjugates.

Figure 1

Drug conjugates are composed of 3 parts, carrier, linker and payload. The carrier, also referred to as homing peptides, targets and delivers the drug to the respective tumor target. The payload is the cytotoxin that kills the cancer cells, while the linker region bridges the two PDC components together and induces drug release. This figure was created using BioRender online App and license.

Figure 2

Structure of ¹⁷⁷Lu-DOTA-TATE (Lutathera^® Novartis, Zaragoza Spain). Amino acid residues of the carrier peptide, the tyrosine-containing somatostatin analog Tyr3-octreotate (TATE), are labeled in blue. The payload (highlighted in yellow) is the macrocyclic chelating agent tetraazacyclododecane-tetraacetic acid (DOTA) bound to the beta-emitting radionuclide lutetium-177 (¹⁷⁷Lu). The linker region (highlighted in grey) consists of an amide bond formed by coupling a carboxyl group of DOTA with the N-terminal amino group of the carrier at D-Phe1.

Figure 3

Theoretical summary of the steps that lead to the internalization of the specific (overexpressed receptor) within cancer cells. Step 1 involves the recognition of the PDC by the receptor. Once the PDC is internalized, the drug is released (Step 2). Note: The red lightning bolt depicts the release of the drug. The receptors are separated from the ligand and can be recycled back to the cell membrane. Cleavage of the linker results in drug release and subsequent cancer cell death (Step 3). This figure was created using BioRender software and license.

Figure 4

Cleavable linkers. (A) A prototypical pH-sensitive linker contains a hydrazone moiety, which is cleaved in an acidic environment such as within an endosome or lysosome. (B) An example of an enzyme-sensitive linker is the lysosomal cathepsin-sensitive valine-citrulline-p-aminobenzyloxycarbonyl (PABC) function. Chemical rearrangement and release of the PABC moiety during the cleavage reaction enables free release of the payload. (C) A redox-sensitive linker is exemplified by a simple disulfide bond, which is reduced by intracellular reducing agents such as glutathione to release the payload.

Figure 5

(A) 3-dimensional structure of somatostatin-14 (ball-and-stick rendering) in complex with somatostatin receptor 2 (surface rendering) (PDB-ID: 7T10). Residues of the conserved tetrapeptide Phe-Trp-Lys-Thr (FWKT) receptor-binding motif are labeled. The chemical structure of somatostatin-14 is also shown. (B) 3-dimensional structure of octreotide (ball-and-stick rendering) in complex with somatostatin receptor 2 (surface rendering) (PDB-ID: 7T11). The chemical structure of ¹⁷⁷Lu-DOTA-TATE (Luthera^®), a somatostatin receptor-targeting radiopharmaceutical containing a Tyr3-octreotate carrier function, is also shown. 3-dimensional molecular graphics and analyses performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases [52].