Strontium Sulfite: A New pH-Responsive Inorganic Nanocarrier to Deliver Therapeutic siRNAs to Cancer Cells.

Md Karim,Ahsanul Kaiser,Athirah Bakhtiar,Jayalaxmi Shetty,Rowshan Islam,Ezharul Chowdhury

doi:10.3390/pharmaceutics11020089

Md Karim, Ahsanul Kaiser + Show 4 more

Open Access

https://doi.org/10.3390/pharmaceutics11020089

Copy DOI

Journal: Pharmaceutics	Publication Date: Feb 20, 2019
Citations: 12	License type: CC BY 4.0

Affiliation: Monash University Malaysia, Mahsa University

Abstract

Inorganic nanoparticles hold great potential in the area of precision medicine, particularly for treating cancer owing to their unique physicochemical properties, biocompatibility and improved pharmacokinetics properties compared to their organic counterparts. Here we introduce strontium sulfite nanoparticles as new pH-responsive inorganic nanocarriers for efficient transport of siRNAs into breast cancer cells. We employed the simplest nanoprecipitation method to generate the strontium sulfite nanoparticles (SSNs) and demonstrated the dramatic roles of NaCl and d-glucose in particle growth stabilization in order to produce even smaller nanosize particles (Na-Glc-SSN) with high affinity towards negatively charged siRNA, enabling it to efficiently enter the cancer cells. Moreover, the nanoparticles were found to be degraded with a small drop in pH, suggesting their potential capability to undergo rapid dissolution at endosomal pH so as to release the payload. While these particles were found to be nontoxic to the cells, they showed higher potency in facilitating cancer cell death through intracellular delivery and release of oncogene-specific siRNAs targeting ros1 and egfr1 mRNA transcripts, than the strontium sulfite particles prepared in absence of NaCl and d-glucose, as confirmed by growth inhibition assay. The mouse plasma binding analysis by Q-TOF LC-MS/MS demonstrated less protein binding to smaller particles of Na-Glc-SSNs. The biodistribution studies of the particles after 4 h of treatment showed Na-Glc-SSNs had less off-target distribution than SSNs, and after 24 h, all siRNAs were cleared from all major organs except the tumors. ROS1 siRNA with its potential therapeutic role in treating 4T1-induced breast tumor was selected for subsequent in vivo tumor regression study, revealing that ROS1 siRNA-loaded SSNs exerted more significant anti-tumor effects than Na-Glc-SSNs carrying the same siRNA following intravenous administration, without any systemic toxicity. Thus, strontium sulfite emerged as a powerful siRNA delivery tool with potential applications in cancer gene therapy.

Highlights

Nanotechnology has contributed immensely to cancer gene therapy via introducing multiple nanocarriers to carry plasmid DNA, mRNA, siRNA, miRNA and anti-sense oligonucleotides (AONs) to the cytoplasm of targeted cancer cells [1]
SiRNA copes with the abnormal tumor microenvironment (TME) including the dense extracellular matrix (ECM), and leaky and heterogeneous vessels which contribute to increased interstitial fluid pressure (IFP) [5,6,7,8]
strontium sulfite nanoparticles (SSNs) and Na-Glc-SSNs synthesized via a simple precipitation method emerge as pH-sensitive smart carriers for effectively delivering therapeutic siRNAs to the tumor

Summary

Introduction

Nanotechnology has contributed immensely to cancer gene therapy via introducing multiple nanocarriers to carry plasmid DNA, mRNA, siRNA, miRNA and anti-sense oligonucleotides (AONs) to the cytoplasm of targeted cancer cells [1]. SiRNA copes with the abnormal tumor microenvironment (TME) including the dense extracellular matrix (ECM), and leaky and heterogeneous vessels which contribute to increased interstitial fluid pressure (IFP) [5,6,7,8] To overcome this hurdle, naked siRNA potentially requires a vehicle to be successfully delivered into the target cancer cells. Inorganic NPs of gold, carbonate apatite, quantum dots, iron oxide, mesoporous silica, and so on, represent a highly sophisticated platform for delivering siRNAs into the target cancer cells and provide greater advantages depending on the type of cancers These include unique physic-chemical properties, high biocompatibility, improved pharmacokinetics and pharmacodynamics properties and active intracellular delivery in contrast to organic ones [12,13,14,15]. Inorganic pH-sensitive carbonate apatite NPs were shown to significantly and carry both small molecular anticancer drugs and nucleic acids to cancer cells [29,30,31,32,33]

Methods

Results

Conclusion