Functional ligands for improving anticancer drug therapy: current status and applications to drug delivery systems

Abstract

Conventional chemotherapy lacking target selectivity often leads to severe side effects, limiting the effectiveness of chemotherapy. Therefore, drug delivery systems ensuring both selective drug release and efficient intracellular uptake at the target sites are highly demanded in chemotherapy to improve the quality of life of patients with low toxicity. One of the effective approaches for tumor-selective drug delivery is the adoption of functional ligands that can interact with specific receptors overexpressed in malignant cancer cells. Various functional ligands including folic acid, hyaluronic acid, transferrin, peptides, and antibodies, have been extensively explored to develop tumor-selective drug delivery systems. Furthermore, cell-penetrating peptides or ligands for tight junction opening are also actively pursued to improve the intracellular trafficking of anticancer drugs. Sometimes, multiple ligands with different roles are used in combination to enhance the cellular uptake as well as target selectivity of anticancer drugs. In this review, the current status of various functional ligands applicable to improve the effectiveness of cancer chemotherapy is overviewed with a focus on their roles, characteristics, and preclinical/clinical applications.

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“…Synthetic agents include polymer and ligand agents. Ligands are usually attached to the surface of nanoparticles to increase drug deposition within the targeted organ and reduce systemic toxicity (Bajracharya et al 2022 ). Against this background, Yang et al prepared nanoparticles decorated with hyaluronic acid to increase drug deposition within LDD.…”

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“…Actively targeted drug delivery systems mainly use some specific or highly expressed biomarkers at the tumor site to deliver drugs to specific cells in a targeted manner. The surface of the drug delivery system is modified with specific ligands, such as proteins, antibodies, polypeptides or small chemical molecules, which can specifically bind to highly expressed receptors or antigens on the surface of the cell membrane, triggering endocytosis, thereby achieving drug delivery [ 109 ]. Based on some antigens or receptors that are highly expressed on the surface of tumor cells, such as CD19, carbonic anhydrase IX (CA IX), glycyrrhetinic acid (GA) receptors, asialoglycoprotein receptor (ASGPR), integrin α5 (ITGA5) receptor and folate acid (FA) receptor, some researchers have designed and constructed a variety of NCTD-loaded actively targeted nano-drug delivery systems to increase the concentration of NCTD in target cells, thereby enhancing its efficacy and reducing its toxicity and side effects (Table 3 ).…”

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“…Surface modifications (single or multiple) with various functional ligands such as transferrin, peptides, monoclonal antibodies, folic acid, hyaluronic acid, aptamers, anisamide, and biotin can be used to improve drug target selectivity. Furthermore, cell-penetrating peptides (CPPs), cholesterol, and ligands for tight junction opening in tumors are being actively pursued to improve the intracellular delivery of anticancer drugs [ 16 ]. These ligands can interact with specific receptors overexpressed in cancer cells, increasing drug uptake and ultimately making the therapy more effective and less toxic [ 16 , 17 ].…”

“…Furthermore, cell-penetrating peptides (CPPs), cholesterol, and ligands for tight junction opening in tumors are being actively pursued to improve the intracellular delivery of anticancer drugs [ 16 ]. These ligands can interact with specific receptors overexpressed in cancer cells, increasing drug uptake and ultimately making the therapy more effective and less toxic [ 16 , 17 ].…”