Integrin-Targeting Peptides for the Design of Functional Cell-Responsive Biomaterials

Abstract

Integrins are a family of cell surface receptors crucial to fundamental cellular functions such as adhesion, signaling, and viability, deeply involved in a variety of diseases, including the initiation and progression of cancer, of coronary, inflammatory, or autoimmune diseases. The natural ligands of integrins are glycoproteins expressed on the cell surface or proteins of the extracellular matrix. For this reason, short peptides or peptidomimetic sequences that reproduce the integrin-binding motives have attracted much attention as potential drugs. When challenged in clinical trials, these peptides/peptidomimetics let to contrasting and disappointing results. In the search for alternative utilizations, the integrin peptide ligands have been conjugated onto nanoparticles, materials, or drugs and drug carrier systems, for specific recognition or delivery of drugs to cells overexpressing the targeted integrins. Recent research in peptidic integrin ligands is exploring new opportunities, in particular for the design of nanostructured, micro-fabricated, cell-responsive, stimuli-responsive, smart materials.

Design of α/β-Hybrid Peptide Ligands of α4β1 Integrin Equipped with a Linkable Side Chain for Chemoselective Biofunctionalization of Microstructured Materials

“…As a proof of concept, herein we describe the preparation of monolayers of zeolites coated with novel ligands inspired from the potent α4β1 integrin antagonist BIO1211 [ 32 ], stably bonded to the crystals via urea linkages. Generally, the practicability of peptide–material conjugates is questioned mainly because the peptides grafted onto biomaterial surfaces might be rapidly hydrolyzed by serum proteins in vivo, thus nullifying the functionalization [ 9 , 10 , 54 , 55 ]. In point of fact, BIO1211 was found to have poor stability under physiological conditions [ 33 , 34 ].…”

“…Unfortunately, most RGD antagonists gave contrasting results and repeatedly failed to demonstrate therapeutic benefits in cancer patients [ 5 ]. In search for alternative utilizations [ 6 ], the RGD ligands have been conjugated to drugs, drug carrier systems, fluorescent tags, nanoparticles (NPs), materials, etc., for cancer therapy or imaging [ 7 , 8 ], and more recently for innovative applications, such as smart and responsive materials [ 9 , 10 ]. To the purpose, several RGD peptides equipped with suitable linkable side chains have been designed.…”

Peptide-Conjugated Nano Delivery Systems for Therapy and Diagnosis of Cancer

“…Therefore, short peptide sequences that produce integrin-binding motives have gathered huge attention as a potential therapy; however, it was not found to pass the clinical trial successfully. Therefore, the integrin peptide ligand was alternatively used in conjugation with NDS for the specific delivery of drug to the cell, which is overexpressing the integrin receptor [87].…”

Peptide-Assisted Nucleic Acid Delivery Systems on the Rise

“…Tumor-targeting peptides, usually comprising less than 50 amino acids, are synthesized naturally or artificially [27,28]. For example, peptide sequences containing an arginine-glycine-aspartic acid (RGD) motif are among the most prominent targeting moieties for non-viral delivery systems [29]. The strong affinity of the RGD motif for integrin receptors expressed on vascular endothelial cells and overexpressed on many cancer cells [30] facilitates cell attachment and uptake of nanocarriers by receptor-mediated endocytosis (Figure 2) [31].…”