On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

Abstract

Cancer is the second leading cause of death affecting nearly one in two people, and the appearance of new cases is projected to rise by >70% by 2030. To effectively combat the menace of cancer, a variety of strategies have been exploited. Among them, the development of peptide–drug conjugates (PDCs) is considered as an inextricable part of this armamentarium and is continuously explored as a viable approach to target malignant tumors. The general architecture of PDCs consists of three building blocks: the tumor-homing peptide, the cytotoxic agent and the biodegradable connecting linker. The aim of the current review is to provide a spherical perspective on the basic principles governing PDCs, as also the methodology to construct them. We aim to offer basic and integral knowledge on the rational design towards the construction of PDCs through analyzing each building block, as also to highlight the overall progress of this rapidly growing field. Therefore, we focus on several intriguing examples from the recent literature, including important PDCs that have progressed to phase III clinical trials. Last, we address possible difficulties that may emerge during the synthesis of PDCs, as also report ways to overcome them.

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

“…Many peptide‐binding receptors possess these features and accordingly, their activating peptide ligands (agonists) are promising tumor‐selective carriers for use in drug conjugates. [ 13,14 ] Additionally, targeting of peptide‐binding receptors can be also achieved with chemically designed small molecule binders or antibodies. [ 15,16 ] A directed drug delivery is then possible by engineering a modular conjugate system, consisting of the drug compound covalently attached to the receptor‐binding molecule (Figure 1).…”

CuII and AuIII Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy

“…Within this lively field of research, a wide range of metal‐based compounds have been designed and tested in the last decades to achieve the highest antiblastic activity along with a good toxicological profile . To enhance drug selectivity, researchers exploit specific target proteins on the cell′s phospholipid bilayer, which are overexpressed in neoplastic cells, by conjugating the drug to the corresponding antibody or small biomolecule . In particular, this paper discloses the synthesis and preliminary biological studies of coordination compounds functionalized with monosaccharides to obtain selective delivery of the cytotoxic metal payload into the tumor tissue.…”

“…[3] To enhanced rug selectivity,r esearchers exploit specific target proteins on the cell'sphospholipid bilayer,w hich are overexpressed in neoplastic cells, by conjugating the drug to the corresponding antibody or small biomolecule. [4][5][6][7][8] In particular, this paper discloses the synthesis and preliminaryb iological studies of coordination compounds functionalized with monosaccharides to obtain selective delivery of the cytotoxic metal payload into the tumor tissue. Discoveredb yW arburg in 1924, cancer cells require al arger supply of nutrients, in particular carbohydrates, than healthy cells, due to as eries of metabolic mutations.…”

The role of high‐density lipoproteins in antitumor drug delivery

“…The size, shape, and surface charge of particles condition the potential removal of them by kidney. Considering the pore diameter of 6–8 nm and negative charge of glomerular basement membrane, cationic particles with size less than 10 nm can be eliminated from circulation (Figure a) …”

“…Considering the pore diameter of 6-8 nm and negative charge of glomerular basement membrane, cationic particles with size less than 10 nm can be eliminated from circulation (Figure 2a). [10][11][12] High-density lipoproteins (HDLs) are the smallest lipoproteins with a diameter of 8-14 nm and highest ratio of protein to lipid resulting in the high density. With a density of 1.063-1.210 kg/L, HDLs are generally composed of lipids (e.g., phospholipids [PLs], cholesteryl esters [CEs], triglycerides [TGs], free cholesterol [FC], and sphingolipids), apolipoproteins (apo) (e.g., apoA-I, apoA-II, apoC, apoE, apoD, apoM and apoA-IV, and apoA-V), proteins related to lipid transfer (e.g., cholesterol ester transfer proteins [CEPT] and phospholipid transfer proteins [PLTP]), lipolytic enzymes (e.g., lecithin cholesterol acyltransferase [LCAT] and paraoxonase1 [PON1]), and inflammatory phase response proteins (e.g., serum amyloid A [SAA] and apoJ).…”