Dually Cross-Linked Core-Shell Structure Nanohydrogel with Redox-Responsive Degradability for Intracellular Delivery.

Siyuan Deng,Marco Minicucci,Barbara Campisi,Maria Gigliobianco,Sara Salucci,Piera Di Martino,Giorgia Zambito,Giulio Lupidi,Emin Mijit,Pietro Gobbi,Laura Mezzanotte,Michela Battistelli,Manuela Cortese,Roberta Censi,Dario Voinovich

doi:10.3390/pharmaceutics13122048

Abstract

A redox-responsive nanocarrier is a promising strategy for the intracellular drug release because it protects the payload, prevents its undesirable leakage during extracellular transport, and favors site-specific drug delivery. In this study, we developed a novel redox responsive core-shell structure nanohydrogel prepared by a water in oil nanoemulsion method using two biocompatible synthetic polymers: vinyl sulfonated poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate)-polyethylene glycol-poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate) triblock copolymer, and thiolated hyaluronic acid. The influence on the nanohydrogel particle size and distribution of formulation parameters was investigated by a three-level full factorial design to optimize the preparation conditions. The surface and core-shell morphology of the nanohydrogel were observed by scanning electron microscope, transmission electron microscopy, and further confirmed by Fourier transform infrared spectroscopy and Raman spectroscopy from the standpoint of chemical composition. The redox-responsive biodegradability of the nanohydrogel in reducing environments was determined using glutathione as reducing agent. A nanohydrogel with particle size around 250 nm and polydispersity index around 0.1 is characterized by a thermosensitive shell which jellifies at body temperature and crosslinks at the interface of a redox-responsive hyaluronic acid core via the Michael addition reaction. The nanohydrogel showed good encapsulation efficiency for model macromolecules of different molecular weight (93% for cytochrome C, 47% for horseradish peroxidase, and 90% for bovine serum albumin), capacity to retain the peroxidase-like enzymatic activity (around 90%) of cytochrome C and horseradish peroxidase, and specific redox-responsive release behavior. Additionally, the nanohydrogel exhibited excellent cytocompatibility and internalization efficiency into macrophages. Therefore, the developed core-shell structure nanohydrogel can be considered a promising tool for the potential intracellular delivery of different pharmaceutical applications, including for cancer therapy.

Highlights

IntroductionThe development of novel drug delivery systems has been attracting increasing interest to promote the progress of medical diagnosis and treatment.Enormous polymeric nanoscale particles have been studied as drug carriers, including manganic inorganic nanoparticles [1], noisome [2,3], nanomotor [4], micelle [5], solid nanoparticles [6,7], and nanohydrogels [8], among others
In the past decades, the development of novel drug delivery systems has been attracting increasing interest to promote the progress of medical diagnosis and treatment.Enormous polymeric nanoscale particles have been studied as drug carriers, including manganic inorganic nanoparticles [1], noisome [2,3], nanomotor [4], micelle [5], solid nanoparticles [6,7], and nanohydrogels [8], among others
The chemical structure of Trib-sulf was determined by proton nuclear magnetic resonance (1 H-NMR)

Summary

Introduction

The development of novel drug delivery systems has been attracting increasing interest to promote the progress of medical diagnosis and treatment.Enormous polymeric nanoscale particles have been studied as drug carriers, including manganic inorganic nanoparticles [1], noisome [2,3], nanomotor [4], micelle [5], solid nanoparticles [6,7], and nanohydrogels [8], among others. Different from the most commonly studied solid polymeric nanoparticles, nanohydrogels composed of water-swollen and cross-linked biopolymers, exhibit inherent biocompatibility, hydrophilicity, tissue-like mechanical properties, and high porosity. These characteristics make them suitable for the encapsulation of macromolecular biotherapeutics, for example cytokine IL-2 [10] and peptide epitopes [11], to contribute to cancer immunotherapy. Their nanoscale dimensions coupled with their hydrophilicity make them suitable for systemic administration and prolonged circulation time in the blood stream [12]

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