Enzyme-Responsive Amphiphilic Peptide Nanoparticles for Biocompatible and Efficient Drug Delivery.

Su Jeong Song,Joon Sig Choi

doi:10.3390/pharmaceutics14010143

Su Jeong Song, Joon Sig Choi

Open Access

https://doi.org/10.3390/pharmaceutics14010143

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Abstract

Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides exhibit specific sensitivity towards the enzyme cathepsin B that helps effective controlled release of cargo molecules in the cytoplasm. Arginine can induce cell penetration, and histidine facilitates lysosomal escape by its buffering capacity. Herein, we propose an enzyme-responsive amphiphilic peptide delivery system (Arg-His-(Gly-Phe-Lue-Gly)3, RH-(GFLG)3). The self-assembled RH-(GFLG)3 globular nanoparticle structure exhibited a positive charge and formulation stability for 35 days. Nile Red-tagged RH-(GFLG)3 nanoparticles showed good cellular uptake compared to the non-enzyme-responsive control groups with d-form peptides (LD (LRH-D(GFLG)3), DL (DRH-L(GFLG)3), and DD (DRH-D(GFLG)3). The RH-(GFLG)3 nanoparticles showed negligible cytotoxicity in HeLa cells and human RBCs. To determine the drug delivery efficacy, we introduced the anticancer drug doxorubicin (Dox) in the RH-(GFLG)3 nanoparticle system. LL-Dox exhibited formulation stability, maintaining the physical properties of the nanostructure, as well as a robust anticancer effect in HeLa cells compared to DD-Dox. These results indicate that the enzyme-sensitive RH-(GFLG)3 peptide nanoparticles are promising candidates as drug delivery carriers for biomedical applications.

Highlights

Received: 7 December 2021Peptides are currently being investigated as carriers in delivery systems due to their excellent biocompatibility and biodegradability [1,2,3]
The peptides were synthesized by solid-phase peptide synthesis, purified using high performance liquid chromatography (HPLC), and characterized and confirmed by matrix assisted laser mass spectroscopy (MALDI-MS) (Figure S1)
These results prove that the peptides were successfully synthesized

Summary

Introduction

Peptides are currently being investigated as carriers in delivery systems due to their excellent biocompatibility and biodegradability [1,2,3]. Peptides are involved in important biological mechanisms, which can impart strategic and efficient roles in peptidebased systems [4,5]. Cell-penetrating peptides (CPPs) are applied to enhance cellular uptake [6,7]. The nuclear localization sequence (NLS) can be used to import proteins into the cell nucleus by nuclear transport, to the gene delivery system that requires penetration into the nuclear membrane for effective gene expression [8,9]. NLS has been used as a good strategy for gene delivery. Mitochondrial targeting peptides have been reported as useful tools for strategic delivery systems [10,11]. Peptides have been researched as valuable biomaterials for novel delivery systems

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