Elsevier

Journal of Controlled Release

Volume 244, Part B, 28 December 2016, Pages 194-204
Journal of Controlled Release

Development of a multifunctional envelope-type nano device and its application to nanomedicine

https://doi.org/10.1016/j.jconrel.2016.06.042Get rights and content

Abstract

Successful nanomedicines should be based on sound drug delivery systems (DDS) the permit intracellular trafficking as well as the biodistribution of cargos to be controlled. We have been developing new types of DDS that are multifunctional envelope-type nano devices referred to as MENDs. First, we will focus the in vivo delivery of siRNA to hepatocytes using a YSK-MEND which is composed of pH-responsive cationic lipids. The YSK-MEND is capable of inducing efficient silencing activity in hepatocytes and can be used to cure mice that are infected with hepatitis C or B. The YSK-MEND can also be applied to cancer immunotherapy through the activation of immune cells by delivering different compounds such as cyclic-di-GMP, siRNA or alpha-galactosylceramide as a lipid antigen. The findings indicate that, as predicted, these compounds, when encapsulated in the YSK-MEND, can be delivered to the site of action and induced immune activation through different mechanisms. Finally, a MITO-Porter, a membrane fusion-based delivery system to mitochondria, is introduced as an organelle targeting DDS and a new strategy for cancer therapy is proposed by delivering gentamicin to mitochondria of cancer cells. These new technologies are expected to extend the therapeutic area of Nanomedicine by increasing the power of DDS, especially from the view point of controlled intracellular trafficking.

Introduction

The concept of drug delivery systems (DDS) was born in the 20th century and Doxil is now recognized as one of the most successful achievements in the history of DDS for delivering anticancer agents to tumor tissue with its distribution to normal tissue such as the heart, kidney, etc. decreased. This targeting strategy relies on the EPR-effect (enhanced permeability and retention effect) and is classified as passive targeting. In the case of doxorubicin (DOX), there is no need to control the cellular uptake and intracellular trafficking of DOX, since DOX efficiently enters cancer cells and reaches the nucleus where its pharmacological action is exerted. To expand the therapeutic scope of DDS from low molecular compounds such as DOX to peptides, proteins and nucleic acids, more sophisticated types of DDS are required to enhance their cellular uptake and intracellular trafficking. Nucleic acids are expected to be the next generation medicine, since their action is very selective due to very specific recognition of sequences of nucleic acid base pairs as well as the direct action against the causes of diseases at the DNA/RNA level.

We have been developing a multifunctional envelope-type nano device (MEND) for use as an intelligent DDS that will permit, not only the biodistribution but also the intracellular trafficking of cargos (nucleic acids, proteins, peptides, etc.) to be controlled [1]. An octaarginine peptide known as a cell penetrating peptide can be incorporated in the MEND for surface modification in the form of stearylated octaarginine (R8). The R8-MEND has the ability to enhance the cellular uptake and transfection activity of pDNA/short interfering RNA (siRNA) in most dividing cells, but its application was limited to cellular conditions, since cationically charged nanoparticles are taken up by the liver and spleen once they are introduced into the blood circulation. YSK lipids are new types of pH-responsive cationic lipids in which the cationic charge is eliminated at normal pH, but develops a cationic charge in the acidic conditions in endosomes after cellular internalization. Such types of environmentally responsive materials have the ability to efficiently escape from endosomes as well as being rapidly taken up by hepatocytes in in vivo conditions [2]. This family of YSK lipids has been used to stimulate immune action by delivering a variety of compounds such as a low molecular compound, siRNA or lipid antigens through different mechanisms.

We are also in the process of developing a MITO-Porter, a membrane fusion-type DDS that targets mitochondria. Mitochondrial dysfunction is known to be associated with many kinds of diseases, including diabetes, obesity, neurodegenerative diseases, cardiac infarction and cancer. In spite of this, developing a DDS that can reach the matrix of mitochondria where transcription/translation of the mitochondria genome occurs remains a formidable task. A MITO-Porter for achieving this was developed based on lipid compositions that were screened based on in vitro fusion assays using isolated mitochondria, and have been shown to fuse efficiently with mitochondrial membranes [3]. The MITO-Porter was shown to be capable of delivering peptides, proteins and nucleic acids to mitochondria via membrane fusion. A new strategy for cancer therapy is therefore now possible by using the MITO-Porter as an organelle targeting DDS.

Section snippets

Short interference RNA as a potential treatment of liver diseases

It is estimated that > 4000 diseases are the result of genetic disorders in liver tissue [4]. Moreover, it is estimated that > 200 million persons are infected with hepatotropic viruses, including the hepatitis B virus (HBV) and the hepatitis C virus (HCV) [5]. Short interfering RNA (siRNA) can induce the sequence-dependent specific silencing of gene expression through RNA interference (RNAi) [6]. siRNA theoretically can target all endogenous mRNAs and exogenous RNAs as well, including viral

MEND system meets to cancer immunotherapy

Cancer immunotherapy has been received with skepticism for a long time, because of the insufficient therapeutic effects reported in clinical trials. However, in the past decade, this has drastically changed, because of the appearance of immune checkpoint inhibitors [38] and adoptive T-cell therapy [39]. It can now be said that cancer immunotherapy is now established as 4th most effective cancer therapy following surgical therapy, chemotherapy and radiation therapy. However, the immunomodulatory

Mitochondria, a candidate for a target organelle in cancer therapy

Mitochondria have been implicated in cancer cell proliferation, invasion, metastasis and even drug resistance mechanisms [83], [84], [85], making them a potential target organelle for cancer therapy. We summarized the current status of mitochondrial drug delivery systems (DDS) directed to cancer therapy (Table 1). In addition, our recent efforts regarding the validation of cancer therapeutic strategy using our original mitochondrial DDS, MITO-Porter, are described.

Acknowledgements

This work was supported in part of a Grant-in-Aid for Young Scientist (A) [Grant No. 26713002], a Grant-in-Aid for Young Scientist (B) [Grant No. 15K20831] and a Grant-in-Aid for Scientific Research (B) [Grant No. 26282131] from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government (MEXT). We appreciate Dr. Milton S. Feather for this helpful advice in writing the English manuscript. No potential conflicts of interest were disclosed.

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