Sejin Son

ROS-generating TiO2 nanoparticles for non-invasive sonodynamic therapy of cancer

The non-invasive photodynamic therapy has been limited to treat superficial tumours, primarily ascribed to poor tissue penetration of light as the energy source. Herein, we designed a long-circulating hydrophilized titanium dioxide nanoparticle (HTiO2 NP) that can be activated by ultrasound to generate reactive oxygen species (ROS). When administered systemically to mice, HTiO2 NPs effectively suppressed the growth of superficial tumours after ultrasound treatments. In tumour tissue, the levels of proinflammatory cytokines were elevated several fold and intense vascular damage was observed. Notably, ultrasound treatments with HTiO2 NPs also suppressed the growth of deeply located liver tumours at least 15-fold, compared to animals without ultrasound treatments. This study provides the first demonstration of the feasibility of using HTiO2 NPs as sensitizers for sonodynamic therapy in vivo.

Glycol chitosan nanoparticles as specialized cancer therapeutic vehicles: Sequential delivery of doxorubicin and Bcl-2 siRNA

Conventional chemotherapy is plagued with adverse side effects because cancer treatments are subject to numerous variations, most predominantly from drug resistance. Accordingly, multiple or multistage chemotherapeutic regimens are often performed, combining two or more drugs with orthogonal and possibly synergistic mechanisms. In this respect, glycol chitosan (GC)-based nanoparticles (CNPs) serve as an effective platform vehicle that can encapsulate both chemotherapeutics and siRNA to achieve maximal efficacy by overcoming resistance. Herein, DOX-encapsulated CNPs (DOX-CNPs) or Bcl-2 siRNA-encapsulated CNPs (siRNA-CNPs) exhibited similar physicochemical properties, including size, surface properties and pH sensitive behavior, regardless of the different physical features of DOX and Bcl-2 siRNA. We confirmed that the CNP platform applied to two different types of drugs results in similar in vivo biodistribution and pharmacokinetics, enhancing treatment in a dose-dependent fashion.

Structural modification of siRNA for efficient gene silencing

Small interfering RNA (siRNA) holds a great promise for the future of genomic medicine because of its highly sequence-specific gene silencing and universality in therapeutic target. The medical use of siRNA, however, has been severely hampered by the inherent physico-chemical properties of siRNA itself, such as low charge density, high structural stiffness and rapid enzymatic degradation; therefore, the establishment of efficient and safe siRNA delivery methodology is an essential prerequisite, particularly for systemic administration. For an efficient systemic siRNA delivery, it is a critical issue to obtain small and compact siRNA polyplexes with cationic condensing reagents including cationic polymers, because the size and surface properties of the polyplexes are major determinants for achieving desirable in vivo fate. Unfortunately, synthetic siRNA is not easily condensed with cationic polymers due to its intrinsic rigid structure and low spatial charge density. Accordingly, the loose siRNA polyplexes inevitably expose siRNA to the extracellular environment during systemic circulation, resulting in low therapeutic efficiency and poor biodistribution. In this review, we highlight the innovative approaches to increase the size of siRNA via structural modification of the siRNA itself. The attempts include several methodologies such as hybridization, chemical polymerization, and micro- and nano-structurization of siRNA. Due to its increased charge density and flexibility, the structured siRNA can produce highly condensed and homogenous polyplexes compared to the classical monomeric siRNA. As a result, stable and compact siRNA polyplexes can enhance serum stability and target delivery efficiency in vivo with desirable biodistribution. The review specifically aims to provide the recent progress of structural modification of siRNA. In addition, the article also briefly and concisely explains the improved physico-chemical properties of structured siRNA with respect to stability, condensation ability and gene silencing efficiency.

Echogenic Glycol Chitosan Nanoparticles for Ultrasound-Triggered Cancer Theranostics.

Theranostic nanoparticles hold great promise for simultaneous diagnosis of diseases, targeted drug delivery with minimal toxicity, and monitoring of therapeutic efficacy. However, one of the current challenges in developing theranostic nanoparticles is enhancing the tumor-specific targeting of both imaging probes and anticancer agents. Herein, we report the development of tumor-homing echogenic glycol chitosan-based nanoparticles (Echo-CNPs) that concurrently execute cancer-targeted ultrasound (US) imaging and US-triggered drug delivery. To construct this novel Echo-CNPs, an anticancer drug and bioinert perfluoropentane (PFP), a US gas precursor, were simultaneously encapsulated into glycol chitosan nanoparticles using the oil in water (O/W) emulsion method. The resulting Echo-CNPs had a nano-sized particle structure, composing of hydrophobic anticancer drug/PFP inner cores and a hydrophilic glycol chitosan polymer outer shell. The Echo-CNPs had a favorable hydrodynamic size of 432 nm, which is entirely different from the micro-sized core-empty conventional microbubbles (1-10 μm). Furthermore, Echo-CNPs showed the prolonged echogenicity via the sustained microbubble formation process of liquid-phase PFP at the body temperature and they also presented a US-triggered drug release profile through the external US irradiation. Interestingly, Echo-CNPs exhibited significantly increased tumor-homing ability with lower non-specific uptake by other tissues in tumor-bearing mice through the nanoparticles enhanced permeation and retention (EPR) effect. Conclusively, theranostic Echo-CNPs are highly useful for simultaneous cancer-targeting US imaging and US-triggered delivery in cancer theranostics.

Nanoparticle-Based Combination Therapy for Cancer Treatment.

In recent years, combination of different types of therapies using nanoparticles has emerged as an advanced strategy for cancer treatment. Most of all, combination of chemotherapeutic drug and siRNA in nanoformulation has shown a great potential, because siRNA-mediated specific gene silencing can compensate for the incomplete anti-cancer actions of chemotherapy. In this article, nanoparticle-based combination therapy for cancer treatment is introduced to be focused on the therapeutic chemical and siRNA combination. It is classified into 3 groups: 1) general chemotherapy combined with siRNA carrying nanoparticle, 2) co-delivery of chemical and siRNA therapeutics within a single nanoparticle, and 3) Use of multiple nanoparticles for chemical and siRNA therapeutics. The purpose of the combination and the mechanisms of anti-cancer action was described according to the categories. Examples of some recent developments of nanotechnology-based chemo- and siRNA- therapeutics combination therapy are summarized for better understanding of its practical application.

The EPR Effect in Cancer Therapy

The enhanced permeability and retention (EPR) effect is the property which small sized nanoparticles and macromolecular drugs can accumulate more in tumor than in normal tissues. The EPR effect is generally due to the larger pore size of neo-vasculatures and poor lymphatic clearance of tumors, and it is strongly influenced by the size of small molecules including nanoparticles. The EPR effect has been considered as an alternative method for delivery of conventional anticancer drugs, and favorable bio-distribution of cancer therapeutic nanoparticles in blood would be considered to achieve a high level of accumulation in solid tumors. Based on the EPR concept, a variety of drugs in nano-carrier systems have been developed for cancer therapy. In this chapter, current progress and good examples for EPR effect-utilized anticancer therapy are reviewed.

Reducible Polyethylenimine Nanoparticles for Efficient siRNA Delivery in Corneal Neovascularization Therapy

The aim of this study is to establish the safe and effective ocular delivery system of therapeutic small interfering RNA (siRNA) in corneal neovascularization therapy. The major hurdle present in siRNA-based corneal neovascularization (CNV) therapy is severe cytotoxicity caused by repetitive drug treatment. A reducible branched polyethylenimine (rBPEI)-based nanoparticle (NP) system is utilized as a new siRNA carrier as a hope for CNV therapy. The thiolated BPEI is readily self-crosslinked in mild conditions to make high molecular weight rBPEI thus allowing the creation of stable siRNA/rBPEI nanoparticles (siRNA-rBPEI-NPs). In the therapeutic region, the rBPEI polymeric matrix is effectively degraded into nontoxic LMW BPEI inside the reductive cytosol causing the rapid release of the encapsulated siRNA into the cytosol to carry out its function. The fluorescent-labeled siRNA-rBPEI-NPs can release siRNA into the entire corneal region after subconjuctival injection into the eye of Sprague Dawley rats thus confirming the proof of concept of this system.

Antitumor therapeutic application of self-assembled RNAi-AuNP nanoconstructs: Combination of VEGF-RNAi and photothermal ablation

Nucleic acid-directed self-assembly provides an attractive method to fabricate prerequisite nanoscale structures for a wide range of technological applications due to the remarkable programmability of DNA/RNA molecules. In this study, exquisite RNAi-AuNP nanoconstructs with various geometries were developed by utilizing anti-VEGF siRNA molecules as RNAi-based therapeutics in addition to their role as building blocks for programmed self-assembly. In particular, the anti-VEGF siRNA-functionalized AuNP nanoconstructs can take additional advantage of gold-nanoclusters for photothermal cancer therapeutic agent. A noticeable technical aspect of self-assembled RNAi-AuNP nanoconstructs in this study is the precise conjugation and separation of designated numbers of therapeutic siRNA onto AuNP to develop highly sophisticated RNA-based building blocks capable of creating various geometries of RNAi-AuNP nano-assemblies. The therapeutic potential of RNAi-AuNP nanoconstructs was validated in vivo as well as in vitro by combining heat generation capability of AuNP and anti-angiogenesis mechanism of siRNA. This strategy of combining anti-VEGF mechanism for depleting angiogenesis process at initial tumor progression and complete ablation of residual tumors with photothermal activity of AuNP at later tumor stage showed effective tumor growth inhibition and tumor ablation with PC-3 tumor bearing mice.