Small molecules as cancer targeting ligands: Shifting the paradigm

Conventional chemotherapeutics exploration is hampered due to their nonspecific distribution leading to unintended serious toxicity. Toxicity is so severe that deciding to go for chemotherapy becomes a question of concern for many terminally ill cancer patients. However, with evolving times nanotechnology assisted in reducing the haywire distribution and channelizing the movement of drug-enclosing drug delivery systems to cancer cells to a greater extent, yet toxicity issues still could not be obliterated. Thus, active targeting appeared as a refuge, where ligands actively or specifically deliver linked chemotherapeutics and carriers to cancer cells. For a very long time, large molecule weight/macromolecular ligands (peptides and big polymers) were considered the first choice for ligand-directed active cancer targeting, due to their specificity towards overexpressed native cancer receptors. However, complex characterization, instability, and the expensive nature demanded to reconnoitre better alternatives for macromolecule ligands. The concept of small molecules as ligands emerged from the idea that few chemical molecules including chemotherapeutics have a higher affinity for cancer receptors, which are overexpressed on cell membranes, and may have the ability to assist in drug cellular uptake through endocytosis. But now the question is, can they assist the conjugated macro cargos to enter the cell or not? This present review will provide a holistic overview of the small molecule ligands explored till now.