Toujun Zou

A highly efficient and tumor vascular-targeting therapeutic technique with size-expansible gadofullerene nanocrystals

It has long been a dream to achieve tumor targeting therapy that can efficiently reduce the toxicity and severe side effects of conventional antitumor chemotherapeutic agents. Taking advantage of the abnormalities of tumor vasculature, we demonstrate here a new powerful tumor vascular-targeting therapeutic technique for solid cancers that applies advanced nanotechnology to cut off the nutrient supply of tumor cells by physically destroying the abnormal tumor blood vessels. Water soluble magnetic Gd@C82 nanocrystals of the chosen sizes are deliberately designed with abilities to penetrate into the leaky tumor blood vessels. By triggering the radiofrequency induced phase transition of gadofullerene nanocrystals while extravasating the tumor blood vessel, the explosive structural change of nanoparticles generates a devastating impact on abnormal tumor blood vessels, resulting in a rapid and extensive ischemia necrosis and shrinkage of the tumors. This unprecedented target-specific physiotherapy is found to work perfectly for advanced and refractory solid tumors.中文摘要本文报道了一种利用金属富勒烯纳米晶体快速高效治疗肿瘤的新技术. 从生物学上肿瘤血管和正常血管在结构上存在显著差异这一特点着手, 利用材料学上金属富勒烯纳米晶体在吸收射频能量后发生相变, 伴随着体积剧烈膨胀的特性, 高选择性地摧毁肿瘤血管. 研究表明, 经过1小时治疗后, 肿瘤部位血流即可发生快速阻断, 治疗2~4小时后, 肿瘤组织逐步发生出血性坏死, 肿瘤塌陷体积缩小; 并且对于多种实体肿瘤均有显著疗效. 该技术是一种快速、广谱、特异性高、毒副作用小的新型肿瘤治疗技术, 是一种具有巨大发展潜力的肿瘤治疗技术.

Synergistic Effect of Human Serum Albumin and Fullerene on Gd-DO3A for Tumor-Targeting Imaging

A macromolecular magnetic resonance imaging (MRI) contrast agent was successfully synthesized by conjugating the gadolinium/1,4,7,10-tetraazacyclododecane-1,4,7-tetracetic acid complex (Gd-DO3A) with 6,6-phenyl-C61 butyric acid (PC61BA) and upon further modification with human serum albumin (HSA). The final product, PC61BA-(Gd-DO3A)/HSA, has a high stability and exhibits a much higher relaxivity (r1 = 89.1 mM(-1) s(-1) at 0.5 T, 300 K) than Gd-DO3A (r1 = 4.7 mM(-1) s(-1)) does under the same condition, producing the synergistic positive effect of HSA and C60 on the relaxivity of Gd-DO3A. The in vivo MR images of PC61BA-(Gd-DO3A)/HSA-treated tumor-bearing mice show strong signal enhancement for the tumor area due to the enhanced permeability and retention effect. The maximum accumulation of PC61BA-(Gd-DO3A)/HSA at the tumor site was achieved at 4 h postinjection, which may guide surgery. The results from the hematology and histological observations indicate that PC61BA-(Gd-DO3A)/HSA has no obvious toxicity in vivo. These unique properties of PC61BA-(Gd-DO3A)/HSA enable them to be highly efficient for tumor-targeting MRI in vivo, possibly providing a good solution for tumor diagnosis.

A Versatile and Clearable Nanocarbon Theranostic Based on Carbon Dots and Gadolinium Metallofullerene Nanocrystals

Nanocarbons such as carbon nanotubes, graphene derivatives, and carbon nanohorns have illustrated their potential uses as cancer theranostics owing to their intrinsic fluorescence or NIR absorbance as well as superior cargo loading capacity. However, some problems still need to be addressed, such as the fates and long-term toxicology of different nanocarbons in vivo and the improvement of their performance in various biomedical imaging-guided cancer therapy systems. Herein, a versatile and clearable nanocarbon theranostic based on carbon dots (CDs) and gadolinium metallofullerene nanocrystals (GFNCs) is first developed, in which GFNCs enhance the tumor accumulation of CDs, and CDs enhance the relaxivity of GFNCs, leading to an efficient multimodal imaging-guided photodynamic therapy in vivo without obvious long-term toxicity. Furthermore, biochemical analysis reveals that the novel nanotheranostic can harmlessly eliminate from the body in a reasonable period of time after exerting diagnostic and therapeutic function.

Biodegradable, Hydrogen Peroxide, and Glutathione Dual Responsive Nanoparticles for Potential Programmable Paclitaxel Release

Reactive oxygen species (ROS) and glutathione (GSH) dual responsive nanoparticulate drug delivery systems (nano-DDSs) hold great promise to improve the therapeutic efficacy and alleviate the side effects of chemo drugs in cancer theranosis. Herein, hydrogen peroxide (H2O2) and GSH dual responsive thioketal nanoparticle (TKN) was rationally designed for paclitaxel (PTX) delivery. Compared to other stimuli-sensitive nano-DDSs, this dual responsive DDS is not only sensitive to biologically relevant H2O2 and GSH for on-demand drug release but also biodegradable into biocompatible byproducts after fulfilling its delivering task. Considering the heterogeneous redox potential gradient, the PTX loaded TKNs (PTX-TKNs) might first respond to the extracellular ROS and then to the intracellular GSH, achieving a programmable release of PTX at the tumor site. The selective toxicity of PTX-TKNs to tumor cells with high levels of ROS and GSH was verified both in vitro and in vivo.

Amino acid functionalized gadofullerene nanoparticles with superior antitumor activity via destruction of tumor vasculature in vivo

Researchers have been puzzled of the therapy of malignant tumors and the current therapeutic strategies are always accompanied by toxicity or side effects. Developing efficient nanodrugs could reduce the dosage and greatly improve the therapeutic effects in cancer treatments. Here we initially reported a novel kind of gadofullerene nanoparticles functionalized with amino acid (β-alanine), which exhibited a superior antitumor activity in hepatoma H22 models via a novel therapeutic mechanism. The involvement of β-alanine improved the tumor inhibition rate up to 76.85% for a single treatment by strengthening the interaction with radiofrequency (RF) and extending blood circulation time. It realized a highly antivascular treatment to cut off the nutrient supply of tumor cells by physically destroying the abnormal tumor blood vessels assisted by RF. In situ and real-time observation of the vascular change was conducted using the dorsal skin fold chamber model, which corresponded to the erythrocyte diapedesis in histopathological examination. The ultrastructural changes of vascular endothelial cells were further investigated by environmental scanning electron microscopy and transmission electron microscopy. Long-term toxicity evaluation showed that the GF-Ala nanoparticles could be eliminated from the mice after several days and no obvious toxicity was found to the main organs. All these encouraging results suggest GF-Ala nanoparticles are valuable for the significant therapeutic potential with high-efficacy and low-toxicity.

The effect of hemiketals on the relaxivity of endohedral gadofullerenols

Gadofullerenols have received much attention due to their high relaxivities and low-toxicity as magnetic resonance imaging (MRI) contrast agents. However, the relaxivities of gadofullerenols vary in different reports. In this study, Gd@C-82(OH)(x)O-y with different hemiketal content were synthesized and the influence of this factor on water proton relaxation was investigated. The results show that Gd@C-82(OH)(x)O-y with more hemiketals exhibit much higher relaxivities than those with fewer hemiketals. The hemiketal structure is supposed to promote the formation of intermolecular hydrogen bonds, and finally lead to large aggregates. This is consistent with a previous report that the relaxivities of endohedral gadofullerene derivatives are strongly associated with the aggregate size. Hence, this work provides an important strategy for the manipulation of the relaxivities of gadofullerene based MRI contrast agents by controlling the quantity of hemiketals on the carbon cage.

Real-time monitoring of tumor vascular disruption induced by radiofrequency assisted gadofullerene

The anti-vascular therapy has been extensively studied for high performance tumor therapy by suppressing the tumor angiogenesis or cutting off the existing tumor vasculature. We have previously reported a novel anti-tumor treatment technique using radiofrequency (RF)-assisted gadofullerene nanocrystals (GFNCs) to selectively disrupt the tumor vasculature. In this work, we further revealed the changes on morphology and functionality of the tumor vasculature during the high-performance RF-assisted GFNCs treatment in vivo. Here, a clearly evident mechanism of this technique in tumor vascular disruption was elucidated. Based on the H22 tumor bearing mice with dorsal skin flap chamber (DSFC) model and the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) technique, it was revealed that the GFNCs would selectively inset in the gaps of tumor vasculature due to the innately incomplete structures and unique microenvironment of tumor vasculature, and they damaged the surrounding endothelia cells excited by the RF to induce a phase transition accompanying with size expansion. Soon afterwards, the blood flow of the tumor blood vessels was permanently shut off, causing the entire tumor vascular network to collapse within 24 h after the treatment. The RF-assistant GFNCs technique was proved to aim at the tumor vasculature precisely, and was harmless to the normal vasculature. The current studies provide a rational explanation on the high efficiency anticancer activity of the RF-assisted GFNCs treatment, suggesting a novel technique with potent clinical application.摘要射频辅助金属富勒烯纳米晶体阻断肿瘤血管作为一项新兴的抗肿瘤技术, 因其高效安全的作用效果, 在癌症治疗的研究发展过程中表现出巨大的应用前景. 本文针对该技术, 提出了对其阻断肿瘤血管的实时原位研究方法, 清晰明确地揭示了高效靶向阻断肿瘤血管的机制. 通过建立小鼠肿瘤背部皮翼视窗模型, 实现了在治疗过程中肿瘤血管和正常血管的形态变化及血流情况的直观监测评价. 同时, 采用临床常用的动态增强磁共振成像手段对肿瘤血管功能进行实时定量评估, 借助相关参数Ktrans, 证明了肿瘤血管在治疗后发生了持续不可逆的破坏. 具体表现为局部肿瘤血管出血、 塌陷, 导致整个肿瘤血管网的血流停止, 切断了肿瘤组织与外界的营养交换, 进而致使肿瘤坏死, 而正常血管并不会受到损伤. 此研究结果是对该技术高效靶向治疗肿瘤的深入研究, 有利于促进其在临床上的转化和应用.

Size-tunable NaGdF4 nanoparticles as T2 contrast agents for high-field magnetic resonance imaging

It is important to get high-quality magnetic resonance images at high magnetic field (>3 T) for medical diagnoses. However, the efficiency of the commonly used magnetic resonance imaging (MRI) contrast agents (CAs) always decrease with the increasing of magnetic field intensity. Thus, it is necessary to design MRI CAs with high relaxivity at high magnetic field. In this study, the hydrophilic and biocompatible NaGdF4@SiO2 nanoparticles (NPs) were feasibly synthesized and exhibited highly effective T2 contrast imaging at 7 T magnetic field. Furthermore, the obtained NPs had a higher r2/r1 value than the other typical T2 CAs (such as Dy-based NPs and Fe-based NPs) at high magnetic field. The observed large r2 of the current NaGdF4@SiO2 was mainly ascribed to the increased particle sizes. For in vivo application, 250 nm NaGdF4@SiO2 (with the highest relaxivity) as T2-weighted MRI CAs was further assessed. Toxicity studies demonstrated that NaGdF4@SiO2 NPs exhibited little toxicity both in vitro and in vivo. Therefore, NaGdF4@SiO2 NPs with appropriate size could be used as high-performance T2 CAs in the high magnetic field.