Seunglee Kwon

Long-Circulating Au-TiO2 Nanocomposite as a Sonosensitizer for ROS-Mediated Eradication of Cancer

Although sonodynamic therapy (SDT) has emerged as a potential alternative to conventional photodynamic therapy, the low quantum yield of the sonosensitizer such as TiO2 nanoparticles (NPs) is still a major concern. Here, we have developed hydrophilized Au-TiO2 nanocomposites (HAu-TiO2 NCs) as sonosensitizers for improved SDT. The physicochemical properties of HAu-TiO2 NCs were thoroughly studied and compared with their counterparts without gold deposition. Upon exposure of HAu-TiO2 NCs to ultrasound, a large quantity of reactive oxygen species (ROS) were generated, leading to complete suppression of tumor growth after their systemic administration in vivo. Overall, it was evident that the composites of gold with TiO2 NPs significantly augmented the levels of ROS generation, implying their potential as SDT agents for cancer therapy.

In situ diselenide-crosslinked polymeric micelles for ROS-mediated anticancer drug delivery

Stimuli-responsive micelles have emerged as the drug carrier for cancer therapy since they can exclusively release the drug via their structural changes in response to the specific stimuli of the target site. Herein, we developed the in situ diselenide-crosslinked micelles (DCMs), which are responsive to the abnormal ROS levels of tumoral region, as anticancer drug carriers. The DCMs were spontaneously derived from selenol-bearing triblock copolymers consisting of polyethylene glycol (PEG) and polypeptide derivatives. During micelle formation, doxorubicine (DOX) was effectively encapsulated in the hydrophobic core, and diselenide crosslinks were formed in the shell. The DCMs maintained their structural integrity, at least for 6 days in physiological conditions, even in the presence of destabilizing agents. However, ROS-rich conditions triggered rapid release of DOX from the DOX-encapsulating DCMs (DOX-DCMs) because the hydrophobic diselenide bond was cleaved into hydrophilic selenic acid derivatives. Interestingly, after their systemic administration into the tumor-bearing mice, DOX-DCMs delivered significantly more drug to tumors (1.69-fold and 3.73-fold higher amount compared with their non-crosslinked counterparts and free drug, respectively) and effectively suppressed tumor growth. Overall, our data indicate that DCMs have great potential as drug carriers for anticancer therapy.

Gold-Nanoclustered Hyaluronan Nano-Assemblies for Photothermally Maneuvered Photodynamic Tumor Ablation

Optically active nanomaterials have shown great promise as a nanomedicine platform for photothermal or photodynamic cancer therapies. Herein, we report a gold-nanoclustered hyaluronan nanoassembly (GNc-HyNA) for photothermally boosted photodynamic tumor ablation. Unlike other supramolecular gold constructs based on gold nanoparticle building blocks, this system utilizes the nanoassembly of amphiphilic hyaluronan conjugates as a drug carrier for a hydrophobic photodynamic therapy agent verteporfin, a polymeric reducing agent, and an organic nanoscaffold upon which gold can grow. Gold nanoclusters were selectively installed on the outer shell of the hyaluronan nanoassembly, forming a gold shell. Given the dual protection effect by the hyaluronan self-assembly as well as by the inorganic gold shell, verteporfin-encapsulated GNc-HyNA (Vp-GNc-HyNA) exhibited outstanding stability in the bloodstream. Interestingly, the fluorescence and photodynamic properties of Vp-GNc-HyNA were considerably quenched due to the gold nanoclusters covering the surface of the nanoassemblies; however, photothermal activation by 808 nm laser irradiation induced a significant increase in temperature, which empowered the PDT effect of Vp-GNc-HyNA. Furthermore, fluorescence and photodynamic effects were recovered far more rapidly in cancer cells due to certain intracellular enzymes, particularly hyaluronidases and glutathione. Vp-GNc-HyNA exerted a great potential to treat tumors both in vitro and in vivo. Tumors were completely ablated with a 100% survival rate and complete skin regeneration over the 50 days following Vp-GNc-HyNA treatment in an orthotopic breast tumor model. Our results suggest that photothermally boosted photodynamic therapy using Vp-GNc-HyNA can offer a potent therapeutic means to eradicate tumors.

Tumor microenvironment-specific nanoparticles activatable by stepwise transformation

In an attempt to develop the tumor-targeted nanocarrier which can surmount major challenges for in vivo application, we prepared tumor microenvironment-specific nanoparticles which can be sequentially activated at the extracellular and intracellular levels of tumor tissue by stepwise transformation. This polymeric nanoparticle has been prepared using an amphiphilic polyethyleneimine derivative with the pH-responsive charge-convertible moiety and the reduction-responsive crosslink. Once reaching the tumor tissue in vivo after systemic administration, the surface charge of this nanoparticle can be converted from negative to positive by recognizing the mildly acidic extracellular matrix of tumor, allowing for the enhanced cellular uptake. After the cellular uptake, the nanoparticle can selectively release the drug at the intracellular level since it has the chemically crosslinked core by the disulfide bond which is cleaved in intracellular reductive environment. The tumor microenvironment-specific nanoparticle shows the high tumor targetability and dramatically improves the antitumor efficacy of the drug.

A PEGylated hyaluronic acid conjugate for targeted cancer immunotherapy

ABSTRACT The cell‐free approach to foreignizing tumor cells with non‐self antigens has received increasing attention as a method to induce cytotoxic T lymphocyte (CTL)‐mediated immunological rejection of tumors, because the clinical translation of the conventional CTL‐based cancer immunotherapies has been limited by a complicated manufacturing process and autotransplantation. In this study, we prepared matrix metalloproteinase 9 (MMP9)‐responsive polymeric conjugates consisting of PEGylated hyaluronic acid (HA) as the targeting moiety and ovalbumin (OVA) as the model foreign antigen. The MMP9‐cleavable linker was introduced between PEG and the HA backbone to facilitate the detachment of the PEG corona from the conjugate at the tumor site. From the in vitro cellular uptake study, it was revealed that the conjugate was effectively taken up by the CD44‐expressing TC‐1 cancer cells in the presence of MMP9 via receptor‐mediated endocytosis. When the conjugate was systemically administered into the tumor‐bearing mice with endogenous OVA‐specific CTLs, the tumor growth was markedly inhibited, which was attributed to the significant antigen presentation on the tumor cells. Overall, the MMP9‐responsive conjugates bearing foreign antigens might have the potential as an alternative to CTL‐based cancer immunotherapeutics. Graphical abstract Figure. No caption available.

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.

Intracellularly Activatable Nanovasodilators To Enhance Passive Cancer Targeting Regime

Conventional cancer targeting with nanoparticles has been based on the assumed enhanced permeability and retention (EPR) effect. The data obtained in clinical trials to date, however, have rarely supported the presence of such an effect. To address this challenge, we formulated intracellular nitric oxide-generating nanoparticles (NO-NPs) for the tumor site-specific delivery of NO, a well-known vasodilator, with the intention of boosting EPR. These nanoparticles are self-assembled under aqueous conditions from amphiphilic copolymers of poly(ethylene glycol) and nitrated dextran, which possesses inherent NO release properties in the reductive environment of cancer cells. After systemic administration of the NO-NPs, we quantitatively assessed and visualized increased tumor blood flow as well as enhanced vascular permeability than could be achieved without NO. Additionally, we prepared doxorubicin (DOX)-encapsulated NO-NPs and demonstrated consequential improvement in therapeutic efficacy over the control groups with considerably improved DOX intratumoral accumulation. Overall, this proof of concept study implies a high potency of the NO-NPs as an EPR enhancer to achieve better clinical outcomes.

Anti-Trop2 antibody-conjugated bioreducible nanoparticles for targeted triple negative breast cancer therapy

Trop2, a transmembrane glycoprotein, has emerged as a biomarker for targeted cancer therapy since it is overexpressed in 80% of triple negative breast cancer (TNBC) patients. For the site-specific delivery of the anticancer drug into TNBC, anti-Trop2 antibody-conjugated nanoparticles (ST-NPs) were prepared as the potential nanocarrier, composed of carboxymethyl dextran (CMD) derivatives with bioreducible disulfide bonds. Owing to its amphiphilicity, the CMD derivatives were self-assembled into nano-sized particles in an aqueous condition. Doxorubicin (DOX), chosen as a model anticancer drug, was effectively encapsulated into the nanoparticles. DOX-loaded ST-NPs (DOX-ST-NPs) rapidly released DOX in the presence of 10mM glutathione (GSH), whereas the DOX release is significantly retarded in the physiological condition (PBS, pH 7.4). Confocal microscopic images and flow cytometry analysis demonstrated that DOX-ST-NPs were selectively taken up by MDA-MB-231 as the representative Trop2-expressing TNBC cells. Consequently, DOX-ST-NPs exhibited higher toxicity to Trop2-positive MDA-MB-231 cancer cells, compared to DOX-loaded control nanoparticles without the disulfide bond or anti-Trop2 antibody. Overall, ST-NPs might be a promising carrier of DOX for targeted TNBC therapy.

Self-assembled hyaluronic acid nanoparticles: Implications as a nanomedicine for treatment of type 2 diabetes

ABSTRACT Self‐assembled hyaluronic acid nanoparticles (HA‐NPs) have been extensively investigated for biomedical and pharmaceutical applications owing to their biocompatibility and receptor‐binding properties. Here, we report that an empty HA‐NP itself not bearing any drug has therapeutic effects on adipose tissue inflammation and insulin resistance. HA‐NPs inhibited not only the receptor‐mediated internalization of low‐molecular‐weight (LMW) free HA but also LMW free HA‐induced pro‐inflammatory gene expression in mouse primary bone marrow‐derived macrophages (BMDMs) isolated from wild‐type mice, but not in CD44‐null (CD44−/−) BMDMs. An in vivo biodistribution study showed the distribution of HA‐NPs and their co‐localization with CD44 in adipose tissues including epididymal white adipose tissues (eWATs), but these were rarely observed in the eWATs of CD44−/− mice. In addition, CD44 expression and HA‐NP accumulation in the eWATs were increased in mice with diet‐induced obesity (DIO) compared to lean mice. Interestingly, treatment with HA‐NPs in DIO mice suppressed adipose tissue inflammation as indicated by reduced macrophage content, the production of proinflammatory cytokines and NLRP3 inflammasome activity in eWATs, leading to improved insulin sensitivity and normalized blood glucose levels. Collectively, these results suggest that an empty HA‐NP itself can be a therapeutic agent for the treatment of type 2 diabetes.

Ultrasmall gold nanosatellite-bearing transformable hybrid nanoparticles for deep tumor penetration

Since delivering drugs to an entire tumoral region leads to high therapeutic efficacy and good prognosis, achieving deep tumoral penetration of drugs is a major issue in cancer treatment. In this regard, conventional nanomedicines (>50 nm) have shown limitations in cancer therapy, primarily attributed to the heterogeneous distribution of drugs because of the physiological barrier of the tumor interstitial space. To address this issue, we prepared transformable hybrid nanoparticles (TNPs) consisting of a pH-responsive nanocarrier (PEG-PBAE) and doxorubicin (DOX)-conjugated ultrasmall (<3 nm) gold nanoparticles (nanosatellites). It has been shown that PEG-PBAE can serve as a reservoir for nanosatellites and release them in mildly acidic conditions (pH 6.5), mimicking the tumor microenvironment. When DOX-loaded TNPs (DOX-TNPs) were intravenously injected into tumor-bearing mice, they successfully accumulated and dissociated at the extracellular level of the tumor, leading to the disclosure of nanosatellites and free DOX. While the free DOX accumulated in tumor tissue near blood vessels, the deeply diffused nanosatellites were taken up by the tumor cell, followed by the release of DOX via cleavage of pH-responsive ester linkages in the nanosatellites at the intracellular level. Consequently, the DOX-TNPs effectively suppressed tumor growth through improved tumor penetration of DOX, suggesting their promising potential as a cancer nanomedicine. STATEMENT OF SIGNIFICANCE Deep tumor penetration of anticancer drug is an important issue for high therapeutic efficacy. If the drugs cannot reach cancer cells in a sufficient concentration, their effectiveness will be limited. In this regard, conventional nanomedicine showed only modest therapeutic efficacy since they cannot deliver their payloads to the deep site of tumor tissue. This heterogeneous distribution of the drug is primarily attributed to the physiological barriers of the tumor microenvironment, including a dense extracellular matrix. To surmount this challenge, we developed tumor acidity-triggered transformable nanoparticles. By encapsulating doxorubicin-conjugated ultrasmall gold nanosatellites into the nanoparticles, the drug was not significantly bound to genetic materials, resulting in its minimal sequestration near the vasculature and deep tumor penetration. Our strategy could resolve not only the poor penetration issue of the drug but also its restricted tumor accumulation, suggesting the potential as an effective nanotherapeutics.