Qingfeng Xiao

A core/satellite multifunctional nanotheranostic for in vivo imaging and tumor eradication by radiation/photothermal synergistic therapy.

To integrate photothermal ablation (PTA) with radiotherapy (RT) for improved cancer therapy, we constructed a novel multifunctional core/satellite nanotheranostic (CSNT) by decorating ultrasmall CuS nanoparticles onto the surface of a silica-coated rare earth upconversion nanoparticle. These CSNTs could not only convert near-infrared light into heat for effective thermal ablation but also induce a highly localized radiation dose boost to trigger substantially enhanced radiation damage both in vitro and in vivo. With the synergistic interaction between PTA and the enhanced RT, the tumor could be eradicated without visible recurrence in 120 days. Notably, hematological analysis and histological examination unambiguously revealed their negligible toxicity to the mice within a month. Moreover, the novel CSNTs facilitate excellent upconversion luminescence/magnetic resonance/computer tomography trimodal imagings. This multifunctional nanocomposite is believed to be capable of playing a vital role in future oncotherapy by the synergistic effects between enhanced RT and PTA under the potential trimodal imaging guidance.

Dual-targeting upconversion nanoprobes across the blood-brain barrier for magnetic resonance/fluorescence imaging of intracranial glioblastoma

Surgical resection, one of the main clinical treatments of intracranial glioblastoma, bears the potential risk of incomplete excision due to the inherent infiltrative character of the glioblastoma. To maximize the accuracy of surgical resection, the magnetic resonance (MR) and fluorescence imaging are widely used for the tumor preoperative diagnosis and intraoperative positioning. However, present commercial MR contrast agents and fluorescent dyes can only function for single mode of imaging and are subject to poor blood-brain barrier (BBB) permeability and nontargeting-specificity, resulting in the apparent risks of inefficient diagnosis and resection of glioblastoma. Considering the unique MR/upconversion luminescence (UCL) bimodal imaging feature of upconversion nanoparticles (UCNPs), herein, we have developed a dual-targeting nanoprobe (ANG/PEG-UCNPs) to cross the BBB, target the glioblastoma, and then function as a simultaneous MR/NIR-to-NIR UCL bimodal imaging agent, which showed a much enhanced imaging performance in comparison with the clinically used single MRI contrast (Gd-DTPA) and fluorescent dye (5-ALA). Moreover, their biocompatibility, especially to brains, was systematically assessed by the histological/hematological examination, indicating a negligible in vivo toxicity. As a proof-of-concept, the ANG/PEG-UCNPs hold the great potential in MR diagnosis and fluorescence positioning of glioblastoma for the efficient tumor surgery.

Rattle-Structured Multifunctional Nanotheranostics for Synergetic Chemo-/Radiotherapy and Simultaneous Magnetic/Luminescent Dual-Mode Imaging

Most hypoxic tumors are insensitive to radiation, which is a major obstacle in the development of conventional radiotherapy for tumor treatment. Some drugs, such as cisplatin (CDDP), have been extensively used both as an anticancer drug and clinically as a radiosensitizer to enhance radiotherapy. Herein, we develop rattle-structured multifunctional up-conversion core/porous silica shell nanotheranostics (UCSNs) for delivering CDDP to tumors for synergetic chemo-/radiotherapy by CDDP radiosensitization and magnetic/luminescent dual-mode imaging. UCSNs had a dynamic light scattering diameter of 79.1 nm and excellent water dispersity and stability. In vitro studies showed that CDDP loaded in UCSNs (UCSNs-CDDP) was more effective than free CDDP as a radiosensitizer. After injection, UCSNs-CDDP also demonstrated unambiguously enhanced radiotherapy efficacy in vivo. Our report aims at presenting a novel strategy in biomedical nanotechnology that allows simultaneous dual-mode imaging and localized therapy via synergetic chemo-/radiotherapy, which may achieve optimized therapeutic efficacy in cancer treatment.

Hypoxia Induced by Upconversion‐Based Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors

Local hypoxia in tumors is an undesirable consequence of photodynamic therapy (PDT), which will lead to greatly reduced effectiveness of this therapy. Bioreductive pro-drugs that can be activated at low-oxygen conditions will be highly cytotoxic under hypoxia in tumors. Based on this principle, double silica-shelled upconversion nanoparticles (UCNPs) nanostructure capable of co-delivering photosensitizer (PS) molecules and a bioreductive pro-drug (tirapazamine, TPZ) were designed (TPZ-UC/PS), with which a synergetic tumor therapeutic effect has been achieved first by UC-based (UC-) PDT under normal oxygen environment, immediately followed by the induced cytotoxicity of activated TPZ when oxygen is depleted by UC-PDT. Treatment with TPZ-UC/PS plus NIR laser resulted in a remarkably suppressed tumor growth as compared to UC-PDT alone, implying that the delivered TPZ has a profound effect on treatment outcomes for the much-enhanced cytotoxicity of TPZ under PDT-induced hypoxia.

A uniform sub-50 nm-sized magnetic/upconversion fluorescent bimodal imaging agent capable of generating singlet oxygen by using a 980 nm laser.

Upconverting nanoparticles (UCNPs) with fascinating properties hold great potential as nanotransducers for solving the problems that traditional photodynamic therapy (PDT) has been facing. In this report, by using well-selected bifunctional gadolinium (Gd)-ion-doped UCNPs and water-soluble methylene blue (MB) combined with the water-in-oil reverse microemulsion technique, we have succeeded in developing a new kind of UCNP/MB-based PDT drug, NaYF(4):Er/Yb/Gd@SiO(2)(MB), with a particle diameter less than 50 nm. Great efforts have been made to investigate the drug-formation mechanism and provide detailed physical and photochemical characterizations and the potential structure optimization of the as-designed PDT drug. We envision that such a PDT drug will become a potential theranostic nanomedicine for future near-infrared laser-triggered photodynamic therapy and simultaneous magnetic/optical bimodal imaging.

Radiopaque fluorescence-transparent TaOx decorated upconversion nanophosphors for in vivo CT/MR/UCL trimodal imaging

To address the intractable issues such as the low performance or biocompatibility frequently encountered in previous CT, magnetic resonance (MR) and fluorescence trimodal imaging nanoprobes, a nanocomposite has been constructed by decorating gadolinium ions doped upconversion nanoparticle (Gd-doped UCNP) with radiopaque but fluorescence-transparent tantalum oxide (TaO(x), x ≈ 1). The as-synthesized water-soluble nanoparticle showed a litchi-like shape with an average size of ~30 nm and demonstrated extraordinarily high longitudinal and transverse relaxivity values (r(1) = 11.45 mM(-1)s(-1) and r(2) = 147.3 mM(-1)s(-1)) compared with the reported Gd-doped UCNPs to date. Obvious CT contrast enhancement was obtained by the combined effect between the radiopaque TaO(x) shell and the Gd-doped UCNP inner core. Strong upconversion luminescence (UCL) signal could unobstructedly penetrate out in virtue of high transparency of the TaO(x) shell. No mutual interference among different modalities of the upconversion nanolitchi (UCNL) was found, which ensured that the individual merits of every imaging modality could be brought into full play, demonstrated by in vitro and in vivo imagings. Furthermore, UCNLs showed only a slight effect on macrophages and RBCs in vitro and tissue in vivo.

Ultrasmall NaGdF4 Nanodots for Efficient MR Angiography and Atherosclerotic Plaque Imaging

Dr. H. Xing, Prof. W. Bu, Dr. L. Wang, Dr. Q. Xiao, Dr. D. Ni, Prof. J. Shi State Key Laboratory of High Performance Ceramics and Superfi ne Microstructure Shanghai Institute of Ceramics Chinese Academy of Sciences Shanghai 200050 , P.R. China E-mail: wbbu@mail.sic.ac.cn; jlshi@mail.sic.ac.cn Dr. S. Zhang, Prof. L. Zhou, Prof. W. Peng, Prof. K. Zhao Department of radiology Shanghai Cancer Hospital Fudan University Shanghai 200032 , P.R. China Prof. X. Zheng, Prof. Y. Hua Department of radiation oncology Shanghai Huadong Hospital Fudan University Shanghai 200040 , P.R. China Dr. J. Zhang Shanghai (Red Cross) Blood Center Shanghai Institute of Blood Transfusion Shanghai 200051 , P.R. China

Computed tomography imaging-guided radiotherapy by targeting upconversion nanocubes with significant imaging and radiosensitization enhancements

The clinical potentials of radiotherapy could not be achieved completely because of the inaccurate positioning and inherent radioresistance of tumours. In this study, a novel active-targeting upconversion theranostic agent (arginine-glycine-aspartic acid-labelled BaYbF5: 2% Er3+ nanocube) was developed for the first time to address these clinical demands. Heavy metal-based nanocubes (~10 nm) are potential theranostic agents with bifunctional features: computed tomography (CT) contrast agents for targeted tumour imaging and irradiation dose enhancers in tumours during radiotherapy. Remarkably, they showed low toxicity and excellent performance in active-targeting CT imaging and CT imaging-guided radiosensitizing therapy, which could greatly concentrate and enlarge the irradiation dose deposition in tumours to enhance therapeutic efficacy and minimize the damage to surrounding tissues.

Radiation-/hypoxia-induced solid tumor metastasis and regrowth inhibited by hypoxia-specific upconversion nanoradiosensitizer.

Tumor resistance to ionizing irradiation and cancer cells metastasis stimulated by radiation often lead to anti-cancer failure, and can be negatively caused by a key role--cellular hypoxia. In this regard, the exploitation of hypoxia-specific cytotoxic agents which assist to potentiate the anti-tumor effect of radiotherapy (RT) as well as efficiently counteract radiation-/hypoxia-induced cancer cell metastasis, becomes especially important, but has been widely overlooked. Herein, a core/shell-structured multifunctional nanoradiosensitizer with upconversion nanoparticle (UCNP) as an inside core, mesoporous silica as the shell and a cavity in between, has been constructed, in which UCNP core serves as radiation dose amplifiers and bio-reductive pro-drug--tirapazamine (TPZ) loaded in cavity is an hypoxia-selective cytotoxin and the silica shell provides the protection and diffusion path for TPZ. Such nanoradiosensitizer has been employed to inhibit the hypoxia-reoxygenation and the subsequent replication of cancer cells that often occurs after a single unaccompanied RT at low doses, and to silence the expression of transcription factors that support the progression of malignancy in cancer. This study confirms the radiotherapeutic benefits of utilizing nanoradiosensitizer as adjuvant to low-dose RT, and the results demonstrate the highly efficient hypoxia-specific killing in oxygen-dependent anti-tumor therapies.

Single W18O49 nanowires: A multifunctional nanoplatform for computed tomography imaging and photothermal/photodynamic/radiation synergistic cancer therapy

Combination therapy is a promising cancer treatment strategy that is usually based on the utilization of complicated nanostructures with multiple components functioning as photo-thermal energy transducers, photo-sensitizers, or dose intensifiers for photothermal therapy (PTT), photodynamic therapy (PDT), or radiation therapy (RT). In this study, ultrathin tungsten oxide nanowires (W18O49) were synthesized using a solvothermal approach and examined as a multifunctional theranostic nanoplatform. In vitro and in vivo analyses demonstrated that these nanowires could induce extensive heat- and singlet oxygen-mediated damage to cancer cells under 980 nm near infrared (NIR)-laser excitation. They were also shown to function as radiation dose intensifying agents that enhance irradiative energy deposition locally and selectively during radiation therapy. Compared to NIR-induced PTT/PDT and RT alone, W18O49-based synergistic tri-modal therapy eradicated xenograft tumors and no recurrence was observed within a 9-month follow up. Moreover, the strong X-ray attenuation ability of the tungsten element (Z = 74, 4.438 cm2·g–1, 100 KeV) qualified these nanowires as excellent contrast agents in X-ray-based imaging, such as diagnostic computed tomography (CT) and cone-beam CT for image-guided radiation therapy. Toxicity studies demonstrated minimal adverse effects on the hematologic system and major organs of mice within one month. In conclusion, these nanowires have shown significant potential for cancer therapy with inherent image guidance and synergistic effects from phototherapy and radiation therapy, which warrants further investigation.