ReviewMultifunctional envelope-type nano device for controlled intracellular trafficking and selective targeting in vivo
Graphical abstract
Introduction
In the last decade of the 20th century, long circulation liposomes encapsulating Doxorubicin appeared in clinics as an innovative drug delivery system (DDS). This DDS relied on the enhanced permeability and retention (EPR) effect [1] and this strategy is classified as passive targeting [2]. While this represented a breakthrough in history of DDS, a paradigm-shift occurred in the field of drug discovery and development in the 21st century, where antibody-drugs emerged as blockbusters and occupied top marketing drugs. Therefore, it is recognized that a new strategy is required to produce new drugs which address unmet medical needs such as cancer, central nervous disorders, immunodeficiencies, etc., and Nanomedicine is expected to be a breakthrough technology in the development of new medicines, since the functional compounds should be delivered to the site of action via an intelligent delivery system which can control intracellular trafficking as well as biodistribution using molecular mechanisms identified so far [3].
We have been in the process of developing a multifunctional envelope-type nano device (MEND) which has been inspired by viral vectors which evolved in nature. MEND is designed so as to control intracellular trafficking of nano carriers as well as to control tissue distribution [4]. Octaarginine (R8) was introduced into MEND to enhance cellular uptake, since R8 was found as a cell penetrating peptide [5]. Surface modification of MEND with R8 in the form of stearyl-R8 not only enhanced cellular uptake but also endosomal escape after taken up via macropinocytosis, when modified with high density R8 [6]. In case of low density R8 modification, R8-MEND was assigned to degradation pathway after taken up via clathrin-mediated endocytosis [6]. As a result, high density R8-MEND could induce as high transfection activities as adenovirus in dividing cell lines [7]. In parallel, we have challenged to overcome PEG-dilemma when we deliver nano particles to tumor tissues based on EPR-effect [8]. PEGylation is so effective for nano particles in long blood circulation, however, it remarkably inhibit the escape from endosomes in tumor cells. We proposed a few strategies to overcome this dilemma by introducing cleavable PEG into PEG-lipid. Cleavable PEG successfully degraded in tumor tissue and PEG free MEND could induce transfection activities or silencing effect in tumor cells [9], however, the efficacy was not enough to move into clinics.
In this review, we provide a summary of our recent progress controlling the intracellular trafficking of peptide antigens as well as lipid antigen in immune cells for efficient vaccination by focusing on endosomal escape. MITO-Porter was introduced as an organelle targeting system, which is an envelope-type fusion-based mitochondrial delivery system, intended to deliver not only small molecular compounds but also proteins/nucleic acids for functional regulation of mitochondria [10]. It is also important to control in vivo biodistribution for a view point of efficacy as well as toxicity. In vivo siRNA delivery would be one of the most expected technologies for successful application of nucleic acids into clinics. Recently, we succeeded in designing a pH-responsive cationic lipid for siRNA delivery to the liver and optimized the system to induce efficient silencing in liver. Finally, we will focus on a powerful active targeting system to the vasculature in adipose tissue where, we thought, the passive targeting strategy does not work [11]. Tissue selective targeting systems promise to expand a new field of therapy via Nanomedicine.
Section snippets
Delivery of a nucleic acid adjuvant
Cellular immunity is indispensable for the efficient elimination of tumors. Cytotoxic T lymphocytes (CTL) mainly function as terminators against tumor cells in cellular immunity. CTL is activated by cytokines and antigen presentation via the major histocompatibility complex I (MHC-I) on antigen presenting cells (APCs). APCs degrade cytosolic antigens via proteasomes and present antigen derived peptides on MHC-I molecules. It is necessary to deliver tumor associated antigens to the cytosol in
Drug delivery systems targeted to mitochondria
Mitochondria carry out various essential functions including ATP production and apoptosis regulation, and possess their own genome, mitochondrial DNA (mtDNA). It has recently become evident that a variety of human diseases are associated with mitochondrial dysfunction [39], [40]. Therefore, mitochondria represent promising organelles for various fields including life sciences, drug discovery and gene therapy. To achieve success, it will be necessary to deliver functional agents into
In vivo delivery of siRNA to the liver
Despite attempts to improve the efficacy of drug delivery systems, systems for the efficient delivery of therapeutic nucleic acids, including siRNAs and DNAs, are still under development. As these systems enter the targeted cells via endocytosis, it is important to avoid compartmentalization in endolysosomal vesicles and to localize the therapeutic molecules at the sites of action such as cytoplasm and nucleus [72]. It thus appears that the endosomal escape process is a common obstacle to
Adipose vasculature as an attractive target for the control of obesity
Obesity is one of the biggest health problems worldwide and is defined as an excessive and/or abnormal fat accumulation that leads to increased risks for numerous chronic disorders including cardiovascular disease, diabetes and cancer. Therefore, a promising strategy for the effective and safe treatment of obesity is highly required. It is known that adipose tissue has high angiogenic properties [111], [112] and its growth is dependent on angiogenesis [113], [114]. Thus, the microvasculature in
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