Sangmin Jeon

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.

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.

Inorganic Nanoparticles for Image-Guided Therapy

Recently, nanotechnology has provided significant advances in biomedical applications including diagnosis and therapy. In particular, nanoparticles have emerged as valuable outcomes of nanotechnology due to their unique physicochemical properties based on size, shape, and surface properties. Among them, a large amount of research has reported imaging and therapeutic applications using inorganic nanoparticles with special properties. Inorganic nanoparticles developed for imaging and therapy contain metal (Au), metal oxide (Fe3O4, WO3, WO2.9), semiconductor nanocrystal (quantum dots (QDs)), and lanthanide-doped upconversion nanoparticles (UCNPs). Based on their intrinsic properties, they can generate heat, reactive oxygen species (ROS), or energy transfer, so that they can be used for both imaging and therapy. In this review, we introduce biocompatible inorganic nanoparticles for image-guided thermal and photodynamic therapy, and discuss their promising results from in vitro and in vivo studies for biomedical applications.

A versatile gold cross-linked nanoparticle based on triblock copolymer as the carrier of doxorubicin

In an attempt to develop biostable nanoparticles (NPs) as potential carriers of anticancer drugs, we prepared a triblock copolymer that can self-assemble into NPs and be gold cross-linked in aqueous conditions. The triblock copolymer, composed of poly(e-caprolactone)-block-poly(2-(dimethylamino) ethyl methacrylate)-block-poly(ethylene glycol) (PCL-b-PDMAEMA-b-PEG), was synthesized by a combination of ring-opening polymerization, atom transfer radical polymerization and click chemistry. The chemical structures and compositions of the triblock copolymer and its intermediates were characterized by FT-IR and 1H NMR. The triblock copolymer formed spherical NPs (195 nm in diameter) in PBS (pH 7.4). The anticancer drug, doxorubicin (DOX), was loaded into the NPs using a dialysis method. Tertiary amine groups, present in the PDMAEMA block of the triblock polymer, were used for in situ gold cross-linking, which was confirmed using transmission electron microscopy and UV/VIS spectroscopy. Bare NPs released 80% of DOX over 6 days, whereas only 40% of the DOX was released from gold cross-linked NPs (GNPs), implying that the gold cross-links act as a diffusion barrier of DOX. Owing to the slow release of DOX, the cytotoxicity of DOX-GNPs was much lower than that of DOX-loaded bare NPs. The blood concentrations of DOX were also monitored after intravenous injection of free DOX and DOX-loaded NPs into the tail veins of rats. The results indicated that the blood circulation time of DOX was longest for DOX-GNP, followed by DOX-NP, and free DOX. Overall, DOX-GNPs may be a promising carrier for hydrophobic anticancer drugs.

Gold-stabilized carboxymethyl dextran nanoparticles for image-guided photodynamic therapy of cancer

Photodynamic therapy (PDT) has been extensively investigated to treat cancer since it induces cell death through the activation of photosensitizers by light. However, its success has been hampered by the insufficient selectivity of photosensitizers to tumor tissues. In an attempt to increase the therapeutic efficacy of PDT by targeting the photosensitizer specifically to the tumor site, we prepared chlorin e6 (Ce6)-loaded gold-stabilized carboxymethyl dextran nanoparticles (Ce6-GS-CNPs). Ce6-GS-CNPs possessed highly stable nanostructures and no significant change was observed in their particle size in the presence of serum for 6 days. When Ce6-GS-CNPs were intravenously injected into tumor-bearing mice, they exhibited prolonged circulation in the body and gradually accumulated in the tumor tissue. Under laser irradiation of the tumor site which could be recognized by the near-infrared fluorescence imaging system, Ce6-GS-CNPs effectively suppressed tumor growth. Overall, Ce6-GS-CNPs might have potential as nanomedicine for image-guided photodynamic cancer therapy.

Effects of tumor microenvironments on targeted delivery of glycol chitosan nanoparticles

ABSTRACT In cancer theranostics, the main strategy of nanoparticle‐based targeted delivery system has been understood by enhanced permeability and retention (EPR) effect of macromolecules. Studies on diverse nanoparticles provide a better understanding of different EPR effects depending on their structure, physicochemical properties, and chemical modifications. Recently the tumor microenvironment has been considered as another important factor for determining tumor‐targeted delivery of nanoparticles, but the correlation between EPR effects and tumor microenvironment has not yet been fully elucidated. Herein, ectopic subcutaneous tumor models presenting different tumor microenvironments were established by inoculation of SCC7, U87, HT29, PC3, and A549 cancer cell lines into athymic nude mice, respectively. In the five different types of tumor‐bearing mice, tumor‐targeted delivery of self‐assembled glycol chitosan nanoparticles (CNPs) were comparatively evaluated to identify the correlation between the tumor microenvironments and targeted delivery of CNPs. As a result, neovascularization and extents of intratumoral extracellular matrix (ECM) were both important in determining the tumor targeted delivery of CNPs. The EPR effect was maximized in the tumors which include large extent of angiogenic blood vessels and low intratumoral ECM content. This comprehensive study provides substantial evidence that the EPR effects based tumor‐targeted delivery of nanoparticles can be different depending on the tumor microenvironment in individual tumors. To overcome current limitations in clinical nanomedicine, the tumor microenvironment of the patients and EPR effects in clinical tumors should also be carefully studied. Graphical abstract Figure. No caption available.