Ji Young Yhee

Drug delivery by a self-assembled DNA tetrahedron for overcoming drug resistance in breast cancer cells

A DNA tetrahedron is employed for efficient delivery of doxorubicin into drug-resistant breast cancer cells. The drug delivered with the DNA nanoconstruct is considerably cytotoxic, whereas free doxorubicin is virtually non-cytotoxic for the drug-resistant cells. Thus, the DNA tetrahedron, made of the inherently natural and biocompatible material, can be a good candidate for the drug carrier to overcome MDR in cancer cells.

pH-Controlled Gas-Generating Mineralized Nanoparticles: A Theranostic Agent for Ultrasound Imaging and Therapy of Cancers

We report a theranostic nanoparticle that can express ultrasound (US) imaging and simultaneous therapeutic functions for cancer treatment. We developed doxorubicin-loaded calcium carbonate (CaCO3) hybrid nanoparticles (DOX-CaCO3-MNPs) through a block copolymer templated in situ mineralization approach. The nanoparticles exhibited strong echogenic signals at tumoral acid pH by producing carbon dioxide (CO2) bubbles and showed excellent echo persistence. In vivo results demonstrated that the DOX-CaCO3-MNPs generated CO2 bubbles at tumor tissues sufficient for echogenic reflectivity under a US field. In contrast, the DOX-CaCO3-MNPs located in the liver or tumor-free subcutaneous area did not generate the CO2 bubbles necessary for US contrast. The DOX-CaCO3-MNPs could also trigger the DOX release simultaneously with CO2 bubble generation at the acidic tumoral environment. The DOX-CaCO3-MNPs displayed effective antitumor therapeutic activity in tumor-bearing mice. The concept described in this work may serve as a useful guide for development of various theranostic nanoparticles for US imaging and therapy of various cancers.

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.

Optical imaging of cancer-related proteases using near-infrared fluorescence matrix metalloproteinase-sensitive and cathepsin B-sensitive probes.

Cathepsin B and matrix metalloproteinase (MMP) play key roles in tumor progression by controlled degradation of extracellular matrix. Consequently, these proteases have been attracted in cancer research, and many imaging probes utilizing these proteases have been developed. Our groups developed cathepsin B and MMP imaging nanoprobes based on polymer nanoparticle platform. Both cathepsin B and MMP imaging probes used near-infrared fluorescence (NIRF) dye and dark-quencher to for high sensitivity, and protease-sensitive peptide sequence in each probe authorized high specificity of the probes. We compared the bioactivities of cathepsin B and MMP sensitive probes in cancer-related environments to investigate the biological property of the probes. As a result, cathepsin B probe showed fluorescence recovery after the probe entered the cytoplasm. This property could be useful to evaluate the cytoplasmic targeted delivery by using probe-conjugated nanoparticles in vivo. On the other hand, MMP probe was superior in specificity in vivo and tissue study. This comparative study will provide precise information about peptide-based optical probes, and allow their proper application to cancer diagnosis.

Self-assembled glycol chitosan nanoparticles for disease-specific theranostics

Hydrophobically modified glycol chitosan (hGC) conjugates spontaneously form self-assembled nanoparticles (NPs) in aqueous conditions, and glycol chitosan NPs (CNPs) have been extensively studied for the past few decades. For disease-specific theranostics, CNPs could be simply modified with imaging agents, and the hydrophobic domains of hGC are available for encapsulation of various drugs. Based on the excellent physiochemical and biological properties, CNPs have been investigated for multimodal imaging and target specific drug delivery. In particular, a recent application of CNPs has shown great potential as an efficient theranostic system because the CNPs could be utilized for a disease-specific theranostic delivery system of different imaging agents and therapeutics, simultaneously. Furthermore, various therapeutic agents including chemo-drugs, nucleotides, peptides, and photodynamic chemicals could be simply encapsulated into the CNPs through hydrophobic or charge-charge interactions. Under in vivo conditions, the encapsulated imaging agents and therapeutic drugs have been successfully delivered to targeted diseases. In this article, the overall research progress on CNPs is reviewed from early works. The current challenges of CNPs to overcome in theranostics are also discussed, and continuous studies would provide more opportunities for early diagnosis of diseases and personalized medicine.

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.

Self-crosslinked human serum albumin nanocarriers for systemic delivery of polymerized siRNA to tumors.

The safe and effective systemic delivery of siRNA is a prerequisite for the successful development of siRNA-based cancer therapeutics. For the enhanced delivery of siRNA, cationic lipids and polymers have been widely used as siRNA carriers to form electrolyte complexes with anionic siRNA. However, the considerable toxicity of strong cationic-charged molecules hampers their clinical use. In this study, we utilized human serum albumin (HSA), which is the most abundant of the plasma proteins, as a siRNA carrier for systemic tumor-targeted siRNA delivery. Both HSA and siRNA molecules were thiol-introduced to improve the binding affinity for each other. The resulting thiolated HSA (tHSA) and polymerized siRNA (psi) formed stable nanosized complexes (psi-tHSAs) by chemical crosslinking and self-crosslinking. After internalization, the psi-tHSAs showed target gene silencing activity in vitro comparable to conventional Lipofectamine™-siRNA complexes, without remarkable cytotoxicity. After intravenous injection in tumor-bearing mice, psi-tHSAs accumulated specifically at the tumor sites, leading to efficient gene silencing in the tumors in a sequential manner. The therapeutic VEGF siRNA was loaded into psi-tHSAs, which significantly inhibited tumor-related angiogenesis in PC-3 tumor xenografts and resulted in retarding the growth of PC-3 tumors. The results showed that self-crosslinked psi-tHSA nanocarriers might provide a promising approach for the systemic siRNA therapy of various human cancers.

Cathepsin B-sensitive nanoprobe for in vivo tumor diagnosis

We developed a cathepsin B-sensitive nanoprobe (CB-NP) with a cathepsin B substrate peptide probe and tumor-targeting glycol chitosan nanoparticles. The CB-NP could accumulate in tumor tissues, enter into tumor cells, and generate fluorescent signals in cytosol in response to cathepsin B. The results of non-invasive fluorescence imaging in a tumor-bearing mouse model demonstrated the potential of CB-NP for tumor diagnosis in clinical fields.

Co-delivery of VEGF and Bcl-2 dual-targeted siRNA polymer using a single nanoparticle for synergistic anti-cancer effects in vivo

Cancer is a multifactorial disease which involves complex genetic mutation and dysregulation. Combinatorial RNAi technology and concurrent multiple gene silencing are expected to provide advanced strategies for effective cancer therapy, but a safe and effective carrier system is a prerequisite to successful siRNA delivery in vivo. We previously developed an effective tumor-targeting siRNA delivery system for in vivo application. In response to the success of this development, herein we present a dual-gene targeted siRNA and its delivery system, to achieve synergistic effects in cancer therapy. Two different sequences of siRNA were chemically modified to be randomly copolymerized in a single backbone of siRNA polymer (Dual-poly-siRNA), and the resulting Dual-poly-siRNA was incorporated into tumor-homing glycol chitosan nanoparticles. Based on the stability in serum and delivery in a tumor-targeted manner, intravenously administered Dual-poly-siRNA carrying glycol chitosan nanoparticles (Dual-NP) demonstrated successful dual-gene silencing in tumors. Notably, co-delivery of VEGF and Bcl-2 targeting siRNA led to more effective cancer therapy for convenient application.

Multifunctional Chitosan Nanoparticles for Tumor Imaging and Therapy

Chitosan and its derivatives have been widely used for various biomedi- cal applications because of their unique chemical and biological characters. The amine groups in the backbone of chitosan allow chemical modification to change the physical properties of chitosan. Based on hydrophobic or charge interactions with this chitosan polymer backbone, stable self-assembled nanoparticles can be fabricated in aqueous condition. These nanosized structures enable intravenous injection and show large accumulation in tumor tissue, indicating great potential in imaging and drug delivery. The main objective of this review is to introduce various chitosan nanoparticles and their recent applications for tumor diagnosis and therapy.