Redox/pH-Responsive 2-in-1 Chimeric Nanoparticles for the Co-Delivery of Doxorubicin and siRNA.

Wei-Ting Kuo,Hsi-Chin Wu

doi:10.3390/polym13244362

Abstract

The co-delivery of chemotherapy drugs and gene-suppressing small interfering RNA (siRNA) show promise for cancer therapy. The key to the clinical realization of this treatment model will be the development of a carrier system enabling the simultaneous delivery (“co-delivery” instead of combinatorial delivery) of chemotherapy and siRNA agents to cancer. In this study, a co-delivery system was developed from two individual components to form one integrated nanovehicle through a redox-sensitive thiol–disulfide bond for the synergistic delivery of chemotherapy and RNA silencing: doxorubicin (Dox)-loaded N,O-carboxymethyl chitosan (NOCC) complex with a thiolated hyaluronic acid (HA-SH) nanocarrier and dopamine (Dopa)-conjugated thiolated hyaluronic acid (SH-HA-Dopa)-coated calcium phosphate (CaP)-siRNA nanocarrier. The 2-in-1 chimeric nanoparticles (NPs) were structurally stable together in the storage environment and in the circulation. This smart system selectively releases Dox and siRNA into the cytosol. Furthermore, equipped with the tumor-targeting component HA, the co-delivery system shows specific targeting and high cellular uptake efficiency by receptor-mediated endocytosis. In summary, these dual-responsive (redox and pH), tumor-targeting smart 2-in-1 chimeric NPs show promise to be employed in functional co-delivery and tumor therapy.

Highlights

The co-delivery of small interfering RNA with chemotherapeutic drugs has attracted considerable attention because of improved anti-tumor efficacy over singleregimen administration [1,2]
The structure of hyaluronic acid (HA)-SH was verified by the characteristic peaks between 2.5 ppm and 3.0 ppm (-NH-CH2-CH2), which represented the successful conjugation of thiol to HA (Figure 1d)
SH-HA-Dopa analysis demonstrated that the characteristic peaks of HA-SH were retained and that protons in the catechol ring were newly presented at 6.0–7.0 ppm [26]

Summary

Introduction

The co-delivery of small interfering RNA (siRNA) with chemotherapeutic drugs has attracted considerable attention because of improved anti-tumor efficacy over singleregimen administration [1,2]. The intracellular release of drugs can be responded to by the different concentrations of GSH in tumor tissues compared with healthy ones [4,6]. The slight differences in pH changes in tumor tissue (pH 6.5–6.8), endosomes (pH 5.5–6.5), lysosomes (pH 4.5–5.5) and blood and normal tissue (pH 7.4) have been extensively used to trigger the disassembly of pH-responsive delivery systems and cargo drugs into the cytosol via endolysosomal acidification and escape. Combination of oxidative environment and pH gradient in certain pathological conditions can promote the efficacy of drug delivery, resulting in an improvement of the therapeutic effect [7,8]

Methods

Results

Conclusion