Qianjun He

Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles

Most present nanodrug delivery systems have been developed to target cancer cells but rarely nuclei. However, nuclear-targeted drug delivery is expected to kill cancer cells more directly and efficiently. In this work, TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time. Monodispersed MSNs-TAT of varied particle sizes have been synthesized to investigate the effects of particle size and TAT conjugation on the nuclear membrane penetrability of MSNs. MSNs-TAT with a diameter of 50 nm or smaller can efficiently target the nucleus and deliver the active anticancer drug doxorubicin (DOX) into the targeted nucleus, killing these cancer cells with much enhanced efficiencies. This study may provide an effective strategy for the design and development of cell-nuclear-targeted drug delivery.

Mesoporous silica nanoparticle based nano drug delivery systems: synthesis, controlled drug release and delivery, pharmacokinetics and biocompatibility

The biomedical applications of mesoporous silica nanoparticles (MSNs) as efficient drug delivery carriers have attracted great attention in the last decade. The structure, morphology, size, and surface properties of MSNs have been found to be facilely tunable for the purposes of drug loading, controlled drug release and delivery, and multifuctionalization. Meanwhile, the biosafety and in vivo drug efficiency of MSN-based nano drug delivery systems (nano-DDSs), involving biocompatibility (including cytotoxicity, blood and tissue compatibility) and pharmacokinetics (including biodistribution, biodegradation, retention, excretion, blood circulation) are also drawing increasing attention because of their clinical application prospects. Herein, we review the most recent research progresses on the synthesis, controlled drug release and delivery, pharmacokinetics and biocompatibility of MSNs.

In vivo biodistribution and urinary excretion of mesoporous silica nanoparticles: effects of particle size and PEGylation.

The in vivo biodistribution and urinary excretion of spherical mesoporous silica nanoparticles (MSNs) are evaluated by tail-vein injection in ICR mice, and the effects of the particle size and PEGylation are investigated. The results indicate that both MSNs and PEGylated MSNs of different particle sizes (80-360 nm) distribute mainly in the liver and spleen, a minority of them in the lungs, and a few in the kidney and heart. The PEGylated MSNs of smaller particle size escape more easily from capture by liver, spleen, and lung tissues, possess longer blood-circulation lifetime, and are more slowly biodegraded and correspondingly have a lower excreted amount of degradation products in the urine. Neither MSNs nor PEGylated MSNs cause tissue toxicity after 1 month in vivo.

Multifunctional nanoprobes for upconversion fluorescence, MR and CT trimodal imaging

Early diagnosis probes that combine fluorescence, X-ray computed tomography (CT) and magnetic resonance (MR) imagings are anticipated to give three dimensional (3D) details of tissues and cells of high resolution and sensitivity. However, how to combine these three modalities together within a sub-50 nm sized structure is technically challenging. Here we report a trimodal imaging probe of PEGylated NaY/GdF(4): Yb, Er, Tm @SiO(2)-Au@PEG(5000) nanopaticles of uniform size of less than 50 nm. The as-designed nanoprobes showed (1) strong emissions ranging from the visible (Vis) to near infrared (NIR) for fluorescent imaging, (2) T(1)-weighted MRI by shorting T(1) relaxation time and (3) enhanced HU value as a CT contrast agent. The structure was optimized based on a comprehensive investigation on the influence of the distance between the NaY/GdF(4): Yb, Er, Tm core and Au nanoparticles (NPs) at the surface. The potential of trimodal imaging for cancerous cells and lesions was further demonstrated both in vitro and in vivo.

The effect of PEGylation of mesoporous silica nanoparticles on nonspecific binding of serum proteins and cellular responses

Highly ordered MCM-41-type mesoporous silica nanoparticles (MSNs) with particle sizes of 150 +/- 20 nm were prepared and PEGylated by covalently grafting PEGxk chains of different molecular weights (x = 4, 6, 10, 20) and chain densities (0.05 wt%-3.75 wt%) on the outer surface. The influence of molecular weights and chain densities of PEGxk on the nonspecific binding of PEGylated MSNs to human serum protein (HSA) was investigated. The results revealed that the optimal molecular weights should be not less than 10k, and the corresponding optimal chain densities for PEG10k-MSNs and PEG20k-MSNs were 0.75 wt% and 0.075 wt%, respectively, and the resultant minimum HSA adsorbance (2.5%) on PEGxk-MSNs was far less than that on MSNs (18.7%) without PEGylation. Under the optimal conditions for the minimum HSA adsorbance, the phagocytosis of human THP-1 monocytic leukemia cell line-derived macrophages (THP-1 macrophages) and the hemolysis of human red blood cells (HRBCs) were investigated with MSNs and PEGylated MSNs. A minimum THP-1 phagocytosis percentage (0.1%) and a very low HRBCs hemolysis percentage (0.9%) of PEG10k-MSNs were obtained, which were much lower than those (8.6% and 14.2%, respectively) of MSNs.

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.

MSN Anti‐Cancer Nanomedicines: Chemotherapy Enhancement, Overcoming of Drug Resistance, and Metastasis Inhibition

In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs.

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.

Intracellular Localization and Cytotoxicity of Spherical Mesoporous Silica Nano- and Microparticles

This work evaluates the cytotoxicity of spherical mesoporous silica (MS) nano- and microparticles and investigates the effects of particle size, concentration, biodegradation products of MS, residual surfactant, and surfactant removal by extraction and calcination on the cytotoxicity. The results from the intracellular localization of spherical MS nano- and microparticles with different sizes reveal the mechanism for their cytotoxicity and that the smaller particles in nanoscale are more easily endocytosed and consequently located within lysosomes.

Intelligent MnO2 Nanosheets Anchored with Upconversion Nanoprobes for Concurrent pH-/H2O2-Responsive UCL Imaging and Oxygen-Elevated Synergetic Therapy.

Dr. W. Fan, Prof. W. Bu, Dr. Q. He, Dr. Z. Cui, Dr. Y. Liu, Prof. J. Shi State Key Laboratory of High Performance Ceramics and Superfi ne Microstructures 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 Prof. W. Bu Jiangsu Collaborative Innovation Center for Advanced Inorganic Functional Composites Nanjing Tech University Nanjing 210009 , P. R. China Dr. B. Shen Institute of Radiation Medicine Fudan University Shanghai 200032 , P. R. China Dr. X. Zheng Department of Radiation Oncology Shanghai Huadong Hospital Fudan University Shanghai 200040 , P. R. China Dr. K. Zhao Department of Radiology Shanghai Cancer Hospital Fudan University Shanghai 200032 , P. R. China