Peptide
Linker

Pharmacokinetics
Mechanism of action

Drug

Peptide

In PDCs, the peptides that specifically bind to targets can be categorized into homing peptides and cell-penetrating peptides based on their functions.

The homing peptide will direct the whole PDC construct to the targeted cell and limit off-target delivery. These homing peptides often have precedent in the literature for having a strong binding affinity to the target site within the nanomole magnitude (Chem Soc Rev. 50(3): 1480-1494, 2021). In addition to their targeting properties, some peptides also act as cell-penetrating peptides (CPPs). These peptides exhibit some properties such as hydrophobicity, amphiphilicity, and a negative charge that facilitates across cell membranes. The cell-penetrating peptide not only transmits drugs to the targeted tissue but also allows cell internalization (Chem Soc Rev. 7: 1613-1621, 2012).

Based on their shape, peptides can further be classified into linear peptides and cyclic peptides, with the latter often exhibiting superior stability in vivo (Chem Soc Rev. 44(1): 91-102, 2015).Beyond cyclization, various strategies can be employed to enhance peptide stability, including amino acid modification, conjugation with large chemical molecules, and formulation adjustments (J Food Biochem. 43(1): e12571, 2018).

The choice of peptide affects the efficiency of drug endocytosis in PDCs, once the target has been selected, the selection of a suitable peptide for the PDC is also important and has a significant impact on efficacy, pharmacokinetic/pharmacodynamic profile, and therapeutic indices. The ideal peptide for PDCs should have a strong target binding affinity, high stability, low immunogenicity, efficient internalization, and a long plasma half-life.

Pharmacokinetics

Compared to biologics, peptides have a much shorter circulatory half-life (days vs. weeks) resulting in the need for sub-optimal frequent drug administrations, result in a slow progression of PDCs (Lancet. 394(10200): 793-804, 2019; Pharmacol Ther. 200: 110-125, 2019). Meanwhile, short half-lives are also experienced due to rapid renal clearance, resulting in many hampered peptide in vivo studies and ultimately the pursuit of the peptide as a drug (Nat Rev Drug Discov. 19(4): 277-289, 2020). Several ways can be used to try and improve the ADME properties of peptides such as the improvement of the cell permeability, enhancement of chemical and proteolysis stability and reduction of renal clearance overall resulting in the extension of the circulatory half-life (J Food Biochem. 43(1): e12571, 2019).

Drug

There are a range of cytotoxic drugs available for cancer treatment, the cytotoxic drugs chosen usually have a low IC50, typically within the nanomolar range. However, these drugs can only target the desired cells in a non-specific manner. The use of a peptide allows for specific targeted therapy, consequently resulting in the enhancement of several properties (FEBS J. 287(10): 1936-1969, 2020).

Examples of payloads used within PDCs include chemotherapeutic agents such as Doxorubicin, Taxol, as well as radiolabeled nucleotides. PDCs are not limited to only the use as therapeutics but are widely used as imaging agents (Front Chem. 8: 571, 2020).

Linker

The choice of the linker is one of the key factors in the design of a PDC and needs to take into account the microenvironment in which the PDC is located so as not to interfere with the binding affinity and drug efficacy of the peptide to its receptor. Linkers used in PDCs must exhibit stability to prevent premature and nonspecific drug release (J Med Chem. 64(1): 216-232, 2021). There are different types of linkers used in PDCs depending on their length, stability, release mechanism, functional groups, hydrophilicity/hydrophobicity, and other characteristics. Linkers can be categorized into non-cleavable linkers and cleavable linkers. Among the cleavable linkers, there are pH-sensitive linkers, GSH concentration-sensitive linkers, and enzyme-sensitive linkers.

Mechanism of action

The mechanism of action for a PDC varies depending on several factors including the linker and peptide. A cleavable linker can be cleaved in the presence of stimuli at a specific pH or enzymes..

The location of the stimuli will determine the mechanism of action. One scenario is where a PDC will follow a similar process to that of an ADC, first internalization and then intracellular cleavage to release the cytotoxin. An alternative scenario occurs when cleavage occurs outside the cell followed by internalization of the cytotoxin (Drug Deliv. 25(1): 448-460, 2018).