C-Terminal Residue of Ultrashort Peptides Impacts on Molecular Self-Assembly, Hydrogelation, and Interaction with Small-Molecule Drugs

Abstract

Single molecular changes on a tripeptide can have dramatic effects on their self-assembly and hydrogelation. Herein, we explore C-terminal residue variation on two consistent ultrashort peptide backbones, i.e. acetylated-Leu-Ile-Val-Ala-Gly-Xaa and acetylated-Ile-Val-Xaa (Xaa = His, Arg, Asn). The objective of this study is to identify candidates that can form hydrogels for small-molecule drug (SMD) delivery. Haemolysis and cytotoxicity (with human adipose-derived mesenchymal stem cells) assays showed that the new soluble peptides (Xaa = His, Arg) are cytocompatible. Gelation studies showed that all but acetylated-Ile-Val-Arg could gel under physiological conditions. Longer peptidic backbones drive self-assembly more effectively as reflected in field emission scanning electron microscopy (FESEM) and circular dichroism spectroscopy studies. Rheological studies revealed that the resultant hydrogels have varying stiffness and yield stress, depending on the backbone and C-terminal residue. Visible spectroscopy-based elution studies with SMDs (naltrexone, methotrexate, doxorubicin) showed that besides the C-terminal residue, the shape of the SMD also determines the rate and extent of SMD elution. Based on the elution assays, infrared spectroscopy, and FESEM, we propose models for the peptide fibril-SMD interaction. Our findings highlight the importance of matching the molecular properties of the self-assembling peptide and SMD in order to achieve the desired SMD release profile.

<p>Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy</p>

“…reduce the dosage and side effects of alendronate drugs. For instance, peptide-based nanoparticles 31 and hydrogels 32 are currently being used for drug delivery due to their ease of tunability. In this study, we used a similar method to generate Ale-EVs nanoparticle systems.…”

A Global Review on Short Peptides: Frontiers and Perspectives

“…Modified peptides with aromatic amino acids or functionalized side chains (e.g., Fmoc) promote additional stacking interactions ( Figure 4 ), which are helpful in the self-assembly process. Peptide-based bio-functional supramolecular materials (nanomedicines, hydrogels, drug delivery vehicles, gene or drug carriers, biomimetic-cell culture scaffolds, tissue-engineering systems, biosensors, emulsifiers, peptidomimetic antibiotics, bioimaging nanoprobes, three-dimensional (3D) bioprinting inks, vaccine adjuvants) have low toxicity and high biocompatibility and are useful in various applications, like drug delivery, tissue engineering, immunology, cancer therapy, and stem cell culture [ 38 , 95 , 101 , 131 , 132 , 133 , 134 , 135 , 136 ]. Supramolecular nanotherapeutics have better stability and efficacy, which helps to overcome problems related to peptide poor biostability and short plasma half-life.…”

<p>Enhanced Anti-Brain Metastasis from Non-Small Cell Lung Cancer of Osimertinib and Doxorubicin Co-Delivery Targeted Nanocarrier</p>

“…25 Furthermore, the T7 peptide was modified on the surface of the nanoparticles due to electrostatic adsorption, or it was engaged in NH-π stacking with doxorubicin, in which the amide NH of T7 interacts with π cloud of doxorubicin. 34 The properties of various nanoparticles including ζ potential, particle size, and drug loading content are shown in Supporting information , Table S1. The drug loading content of AZD9291 and DOX reached 28.62% and 34.34%, respectively.…”