Jianlin Shi

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.

Core/Shell Structured Hollow Mesoporous Nanocapsules: A Potential Platform for Simultaneous Cell Imaging and Anticancer Drug Delivery

A potential platform for simultaneous anticancer drug delivery and MRI cell imaging has been demonstrated by uniform hollow inorganic core/shell structured multifunctional mesoporous nanocapsules, which are composed of functional inorganic (Fe(3)O(4), Au, etc.) nanocrystals as cores, a thin mesoporous silica shell, and a huge cavity in between. The synthetic strategy for the creation of huge cavities between functional core and mesoporous silica shell is based on a structural difference based selective etching method, by which solid silica middle layer of Fe(2)O(3)@SiO(2)@mSiO(2) (or Au@SiO(2)@mSiO(2)) composite nanostructures was selectively etched away while the mesoporous silica shell could be kept relatively intact. The excellent biocompatibility of obtained multifunctional nanocapsules (Fe(3)O(4)@mSiO(2)) was demonstrated by very low cytotoxicity against various cell lines, low hemolyticity against human blood red cells and no significant coagulation effect against blood plasma. The cancer cell uptake and intracellular location of the nanocapsules were observed by confocal laser scanning microscopy and bio-TEM. Importantly, the prepared multifunctional inorganic mesoporous nanocapsules show both high loading capacity (20%) and efficiency (up to 100%) for doxorubicin simultaneously because of the formation of the cavity, enhanced surface area/pore volume and the electrostatic interaction between DOX molecules and mesoporous silica surface. Besides, the capability of Fe(3)O(4)@mSiO(2) nanocapsules as contrast agents of MRI was demonstrated both in vitro and in vivo, indicating the simultaneous imaging and therapeutic multifunctionalities of the composite nanocapsules. Moreover, the concept of multifunctional inorganic nanocapsules was extended to design and prepare Gd-Si-DTPA grafted Au@mSiO(2) nanocapsules for nanomedical applications, further demonstrating the generality of this strategy for the preparation of various multifunctional mesoporous nanocapsules.

NIR‐Triggered Anticancer Drug Delivery by Upconverting Nanoparticles with Integrated Azobenzene‐Modified Mesoporous Silica

Cancer is one of the most common causes of death in the world, and chemotherapy remains to be one of the most frequent treatments for many cancers. However, its success has been greatly limited because of systemic toxicity due to the toxic effects by the nonspecific distribution of anti-cancer drugs. The drug delivery systems with the features of sustained drug release have attracted much attention owing to their enhanced therapeutic efficacy and reduced side effect. For example, mesoporous silica nanoparticles (MSNs) with interesting properties, such as thermal and photostability, tunable sizes, high loading capacity, and the ease of functionalization according to currently available results, have made the MSNs one of the most promising carriers for drug delivery. Although MSNs-based drug delivery systems have been proven effective, however, the use of cytotoxic drugs that are only released in the target area is much more preferred in clinical application. One way to prevent any premature release of anticancer drugs before they reach the target cells is to develop stimuli-responsive systems with controlled release features. Over the past decade, researches on MSNs-based light-controlled drug delivery systems have been carried out extensively because light as an external stimulus offers controllable drug release both spatially and temporally and thus exhibits great potentials for further biomedical applications. However, most of them have achieved limited success in applications in vitro and in vivo mainly because of the easy damages to both biological samples and living tissues by UV light used to excite the photosensitizer and extremely quick attenuation of UV light in tissues. To tackle this issue, it is highly desirable to develop NIR remote-controllable MSNs-based system which can be used both in vitro and in vivo, which, however, has not been well addressed and remains a great challenge. Compared to UV light, near-infrared (NIR) light is much less damaging to biological specimens and living tissues involved and has remarkably deeper tissue penetration. For example, Parak and co-workers reported that polyelectrolyte multilayer capsules loaded with cargo and plasmonic (Au or Ag) NPs can be used to release the cargo by NIR-photothermal heating. The cargo can be easily released with high efficiency under NIR exposure in one second. However, the size of these capsules can be as large as several microns, which will inevitably suffer from phagocytosis by reticuloendothelial systems (RES) when these systems are intravenously injected. Recently, upconverting nanoparticles (UCNPs) have emerged as an appealing candidate for the application of NIR light. Because of the unique ladder-like energy level structures of lanthanide ions (such as Tm, Er, and Ho), UCNPs are able to absorb NIR light and convert it into highenergy photons in a very broad range from the UV to the NIR region. Such a unique and fascinating photoluminescence property enables UCNPs to function as a NIR-induced mediator by coating caged compounds on the nanoparticle surface, and as a NIR-controlled photoswitch for reversible ring-closing and ring-opening transformation of a dithienylethene compound. Very recently, Branda and co-workers successfully used the NIR laser to dissociate block copolymer micelles by encapsulating UCNPs inside micelles. Since the copolymer micelles will inevitably suffer from self-degradation in biological environment, a combination between UCNPs and micelles may find few opportunities in practical bio-applications for remote-controlled drug delivery using a NIR laser in vitro and in vivo. In more recent studies, our group successfully demonstrated UCNP/methylene bluebased photodynamic therapy (PDT) through controlled singlet oxygen release triggered by NIR light. However, in spite of all the above efforts, reports on the direct NIRlight-controlled anticancer drug release for cancer therapy from a UCNPs-containing structure has not been found in the literature to date, which remains a great challenge in lightcontrolled drug delivery studies. Herein, we report a novel and general strategy for NIR light-triggered anticancer drug release based on amesoporous silica-coated UCNPs structure, designated as UCNP@mSiO2. Figure 1a shows the synthetic procedure for UCNP@mSiO2. The strategy consists of preparing NaYF4: TmYb@NaYF4 core–shell nanoparticles and subsequently coating the Tmdoped core–shell UCNPs with mesoporous silica. After [*] J. N. Liu, Prof. W. B. Bu, L. M. Pan, Prof. J. L. Shi State Key Laboratory of High Performance Ceramics and Superfine Microstructure Shanghai Institute of Ceramics, Chinese Academy of Sciences 1295 Ding-Xi Road, Shanghai 200050 (China) E-mail: wbbu@mail.sic.ac.cn jlshi@sunm.shcnc.ac.cn

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.

Hollow-Structured Mesoporous Materials: Chemical Synthesis, Functionalization and Applications

Hollow-structured mesoporous materials (HMMs), as a kind of mesoporous material with unique morphology, have been of great interest in the past decade because of the subtle combination of the hollow architecture with the mesoporous nanostructure. Benefitting from the merits of low density, large void space, large specific surface area, and, especially, the good biocompatibility, HMMs present promising application prospects in various fields, such as adsorption and storage, confined catalysis when catalytically active species are incorporated in the core and/or shell, controlled drug release, targeted drug delivery, and simultaneous diagnosis and therapy of cancers when the surface and/or core of the HMMs are functionalized with functional ligands and/or nanoparticles, and so on. In this review, recent progress in the design, synthesis, functionalization, and applications of hollow mesoporous materials are discussed. Two main synthetic strategies, soft-templating and hard-templating routes, are broadly sorted and described in detail. Progress in the main application aspects of HMMs, such as adsorption and storage, catalysis, and biomedicine, are also discussed in detail in this article, in terms of the unique features of the combined large void space in the core and the mesoporous network in the shell. Functionalization of the core and pore/outer surfaces with functional organic groups and/or nanoparticles, and their performance, are summarized in this article. Finally, an outlook of their prospects and challenges in terms of their controlled synthesis and scaled application is presented.

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.

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.