Chemical Design of Nuclear‐Targeting Mesoporous Silica Nanoparticles for Intra‐nuclear Drug Delivery

Targeted drug delivery has been widely explored for efficient tumor therapy with desired efficacy but minimized side effects. It is widely known that large numbers of DNA‐toxins, such as doxorubicin, genes, reactive oxygen species, serving as therapeutic agents, can result in maximized therapeutic effects via the interaction directly with DNA helix. So after cellular uptake, these agents should be further delivered into cell nuclei to play their essential roles in damaging the DNA helix in cancer cells. Here, we demonstrate the first paradigm established in our laboratory in developing nuclear‐targeted drug delivery systems (DDSs) based on MSNs for enhanced therapeutic efficiency in the hope of speeding their translation into the clinics. Firstly, nuclear‐targeting DDSs based on MSNs, capable of intranuclear accumulation and drug release therein, were designed and constructed for the first time, resulting in much enhanced anticancer effects both in vitro and in vivo. Such an MSNs‐based and nuclear‐targeted drug/agent delivery strategy was further applied to overcome multidrug resistance (MDR) of malignant tumors, intra‐nuclearly deliver therapeutic genes, photosensitizers, radio‐enhancement agents and photothermal agents to realize efficient gene therapy, photodynamic therapy, radiation therapy and photothermal therapy, respectively.     

Bioresponsive Hyaluronic Acid‐Capped Mesoporous Silica Nanoparticles for Targeted Drug Delivery

In this paper, we present a facile strategy to synthesize hyaluronic acid (HA) conjugated mesoporous silica nanoparticles (MSP) for targeted enzyme responsive drug delivery, in which the anchored HA polysaccharides not only act as capping agents but also as targeting ligands without the need of additional modification. The nanoconjugates possess many attractive features including chemical simplicity, high colloidal stability, good biocompatibility, cell‐targeting ability, and precise cargo release, making them promising agents for biomedical applications. As a proof‐of‐concept demonstration, the nanoconjugates are shown to release cargoes from the interior pores of MSPs upon HA degradation in response to hyaluronidase‐1 (Hyal‐1). Moreover, after receptor‐mediated endocytosis into cancer cells, the anchored HA was degraded into small fragments, facilitating the release of drugs to kill the cancer cells. Overall, we envision that this system might open the door to a new generation of carrier system for site‐selective, controlled‐release delivery of anticancer drugs.     

Near‐Infrared Light and pH‐Responsive Polypyrrole@Polyacrylic acid/Fluorescent Mesoporous Silica Nanoparticles for Imaging and Chemo‐Photothermal Cancer Therapy

We have rationally designed a new theranostic agent by coating near‐infrared (NIR) light‐absorbing polypyrrole (PPY) with poly(acrylic acid) (PAA), in which PAA acts as a nanoreactor and template, followed by growing small fluorescent silica nanoparticles (fSiO₂ NPs) inside the PAA networks, resulting in the formation of polypyrrole@polyacrylic acid/fluorescent mesoporous silica (PPY@PAA/fmSiO₂) core–shell NPs. Meanwhile, DOX‐loaded PPY@PAA/fmSiO₂ NPs as pH and NIR dual‐sensitive drug delivery vehicles were employed for fluorescence imaging and chemo‐photothermal synergetic therapy in vitro and in vivo. The results demonstrate that the PPY@PAA/fmSiO₂ NPs show high in vivo tumor uptake by the enhanced permeability and retention (EPR) effect after intravenous injection as revealed by in vivo fluorescence imaging, which is very helpful for visualizing the location of the tumor. Moreover, the obtained NPs inhibit tumor growth (95.6 % of tumors were eliminated) because of the combination of chemo‐photothermal therapy, which offers a synergistically improved therapeutic outcome compared with the use of either therapy alone. Therefore, the present study provides new insights into developing NIR and pH‐stimuli responsive PPY‐based multifunctional platform for cancer theranostics.     

PLGA-Lipid Hybrid Nanoparticles for Overcoming Paclitaxel Tolerance in Anoikis-Resistant Lung Cancer Cells

Drug resistance and metastasis are two major obstacles to cancer chemotherapy. During metastasis, cancer cells can survive as floating cells in the blood or lymphatic circulatory system, due to the acquisition of resistance to anoikis—a programmed cell death activated by loss of extracellular matrix attachment. The anoikis-resistant lung cancer cells also develop drug resistance. In this study, paclitaxel-encapsulated PLGA-lipid hybrid nanoparticles (PLHNPs) were formulated by nanoprecipitation combined with self-assembly. The paclitaxel-PLHNPs had an average particle size of 103.0 ± 1.6 nm and a zeta potential value of −52.9 mV with the monodisperse distribution. Cytotoxicity of the nanoparticles was evaluated in A549 human lung cancer cells cultivated as floating cells under non-adherent conditions, compared with A549 attached cells. The floating cells exhibited anoikis resistance as shown by a lack of caspase-3 activation, in contrast to floating normal epithelial cells. Paclitaxel tolerance was evident in floating cells which had an IC₅₀ value of 418.56 nM, compared to an IC₅₀ value of 7.88 nM for attached cells. Paclitaxel-PLHNPs significantly reduced the IC₅₀ values in both attached cells (IC₅₀ value of 0.11 nM, 71.6-fold decrease) and floating cells (IC₅₀ value of 1.13 nM, 370.4-fold decrease). This report demonstrated the potential of PLHNPs to improve the efficacy of the chemotherapeutic drug paclitaxel, for eradicating anoikis-resistant lung cancer cells during metastasis.     

Bis‐clickable Mesoporous Silica Nanoparticles: Straightforward Preparation of Light‐Actuated Nanomachines for Controlled Drug Delivery with Active Targeting

Bis(clickable) mesoporous silica nanospheres (ca. 100 nm) were obtained by the co‐condensation of TEOS with variable amounts (2–5 % each) of two clickable organosilanes in the presence of CTAB. Such nanoparticles could be easily functionalized with two independent functions using the copper‐catalyzed alkyne‐azide cycloaddition (CuAAC) reaction to transform them into nanomachines bearing cancer cell targeting ligands with the ability to deliver drugs on‐demand. The active targeting was made possible after anchoring folic acid by CuAAC click reaction, whereas the controlled delivery was performed by clicked azobenzene fragments. Indeed, the azobenzene groups are able to obstruct the pores of the nanoparticles in the dark whereas upon irradiation in the UV or in the blue range, their trans‐to‐cis photoisomerization provokes disorder in the pores, enabling the delivery of the cargo molecules. The on‐command delivery was proven in solution by dye release experiments, and in vitro by doxorubicin delivery. The added value of the folic acid ligand was clearly evidenced by the difference of cell killing induced by doxorubicin‐loaded nanoparticles under blue irradiation, depending on whether the particles featured the clicked folic acid ligand or not.     

Erianin-Loaded Photo-Responsive Dendrimer Mesoporous Silica Nanoparticles: Exploration of a Psoriasis Treatment Method

Psoriasis is a chronic inflammatory skin disorder accompanied by excessive keratinocyte proliferation. Erianin (Eri) is an ideal drug candidate for inhibiting proliferation and inducing apoptosis in the treatment of psoriasis. However, Eri’s poor water solubility and low penetration activity across the skin hinder its application in local medicine. In this study, we developed a novel photo-responsive dendritic mesoporous silica nanoparticle-based carrier to deliver erianin, improved its bioavailability, and achieved sustained-release effects. Spiropyran (SP), 3-aminopropyltriethoxysilane (APTES), and perfluorodecyltriethoxysilane (PFDTES) were conjugated to the outer surface, which allowed Eri to be released in response to UV radiation. The physicochemical properties of photo-responsive dendritic mesoporous silica nanoparticles (Eri-DMSN@FSP) were characterized via multiple techniques, such as using a Fourier-transform infrared spectrometer, a high-resolution transmission electron microscope, and nuclear magnetic resonance (NMR) spectroscopy. The anti-proliferative properties and light-triggered release of erianin-loaded photo-responsive dendritic mesoporous silica nanoparticles were assessed via the MTT assay and a drug release study in vitro. Erianin-loaded photo-responsive dendritic mesoporous silica nanoparticles (UV) exhibit a significantly enhanced HaCat cell-inhibiting efficacy compared to other formulations, as demonstrated by their extremely low cell viability of 10.0% (concentration: 500 mg/mL), indicating their capability to release a drug that responds to UV radiation. The cellular uptake of photo-responsive dendritic mesoporous silica nanoparticles (DMSN@FSP) was observed via confocal laser scanning microscopy (CLSM). These experimental results show that Eri-DMSN@FSP could be effectively endocytosed into cells and respond to ultraviolet light to release Eri, achieving a more effective psoriasis treatment. Therefore, this drug delivery system may be a promising strategy for addressing the question of Eri’s delivery and psoriasis therapy.     

金粒子包封介孔二氧化硅杂化载药控释体系

靶向给药控释体系既可以增强药物在病灶部位的疗效, 又可以降低药物对正常部位的毒副作用. 基于介孔二氧化硅为"容器"-金纳米粒子为"开关"(MSN-AuNPs)的杂化纳米阀门体系同时具备两种纳米粒子的优良特性, 在化学、生物材料以及临床医药等多学科受到广泛关注. 本文根据刺激手段和应用功能分类, 介绍了单一功能和多重功能的MSN-AuNPs杂化纳米阀门体系的重要研究进展, 以及目前面临的挑战和今后的发展方向.     

Integrated Hollow Mesoporous Silica Nanoparticles for Target Drug/siRNA Co‐Delivery

A hollow mesoporous silica nanoparticle (HMSNP) based drug/siRNA co‐delivery system was designed and fabricated, aiming at overcoming multidrug resistance (MDR) in cancer cells for targeted cancer therapy. The as‐prepared HMSNPs have perpendicular nanochannels connecting to the internal hollow cores, thereby facilitating drug loading and release. The extra volume of the hollow core enhances the drug loading capacity by two folds as compared with conventional mesoporous silica nanoparticles (MSNPs). Folic acid conjugated polyethyleneimine (PEI‐FA) was coated on the HMSNP surfaces under neutral conditions through electrostatic interactions between the partially charged amino groups of PEI‐FA and the phosphate groups on the HMSNP surfaces, blocking the mesopores and preventing the loaded drugs from leakage. Folic acid acts as the targeting ligand that enables the co‐delivery system to selectively bind with and enter into the target cancer cells. PEI‐FA‐coated HMSNPs show enhanced siRNA binding capability on account of electrostatic interactions between the amino groups of PEI‐FA and siRNA, as compared with that of MSNPs. The electrostatic interactions provide the feasibility of pH‐controlled release. In vitro pH‐responsive drug/siRNA co‐delivery experiments were conducted on HeLa cell lines with high folic acid receptor expression and MCF‐7 cell lines with low folic acid receptor expression for comparison, showing effective target delivery to the HeLa cells through folic acid receptor meditated cellular endocytosis. The pH‐responsive intracellular drug/siRNA release greatly minimizes the prerelease and possible side effects of the delivery system. By simultaneously delivering both doxorubicin (Dox) and siRNA against the Bcl‐2 protein into the HeLa cells, the expression of the anti‐apoptotic protein Bcl‐2 was successfully suppressed, leading to an enhanced therapeutic efficacy. Thus, the present multifunctional nanoparticles show promising potentials for controlled and targeted drug and gene co‐delivery in cancer treatment.     

Chitosan‐Capped Mesoporous Silica Nanoparticles as pH‐Responsive Nanocarriers for Controlled Drug Release

Herein, we present a straightforward synthesis of pH‐responsive chitosan‐capped mesoporous silica nanoparticles (MSNs). These MCM‐41‐type MSNs could be used as nanocapsules to accommodate guest molecules. Subsequently, (3‐glycidyloxypropyl)trimethoxysilane was grafted onto the surface of the MSNs, which served as a bridge to link between MSNs and chitosan, which is ubiquitous in nature and commercially available. Owing to the pH‐responsive and biocompatible features of chitosan, the loading and release of an anti‐cancer drug, doxorubicin hydrochloride, were carried out in vitro, in which the composite chitosan‐capped MSNs (CS‐MSNs) showed excellent environmental response. As the pH value of the media decreased, the degree of drug release correspondingly increased. Moreover, thanks to the perfect biocompatibility of chitosan, the CS‐MSNs exhibited lower cytotoxicity than that of the naked MSNs in an MTT assay. In addition, the in vitro kill potency against MCF‐7 breast‐cancer cells was enhanced over time, as well as with increasing concentration of the drug‐loaded CS‐MSNs. These results indicate that CS‐MSNs are promising candidates for pH‐responsive drug delivery in cancer therapy.     

Gold Nanoparticles for Cancer Theranostics

Gold nanoparticles have seen unprecedented development in the biomedical field, particularly for cancer therapy. They have received extensive attention because of their easy preparation, functionalization, biocompatibility, non‐cytotoxicity, and detectability. Functionalized gold nanoparticles can be applied in the fields of drug and gene delivery, photothermal therapy, and bioimaging. This review introduces methods for preparing various shapes of gold nanoparticles and describes their current applications in the field of cancer treatment. Moreover, the review presents the development routes and current issues of gold nanoparticles in clinical theranostics.     

Periodic Mesoporous Organosilica Nanoparticles with Controlled Morphologies and High Drug/Dye Loadings for Multicargo Delivery in Cancer Cells

Despite the worldwide interest generated by periodic mesoporous organosilica (PMO) bulk materials, the design of PMO nanomaterials with controlled morphology remains largely unexplored and their properties unknown. In this work, we describe the first study of PMO nanoparticles (NPs) based on meta‐phenylene bridges, and we conducted a comparative structure–property relationship investigation with para‐phenylene‐bridged PMO NPs. Our findings indicate that the change of the isomer drastically affects the structure, morphology, size, porosity and thermal stability of PMO materials. We observed a much higher porosity and thermal stability of the para‐based PMO which was likely due to a higher molecular periodicity. Additionally, the para isomer could generate multipodal NPs at very low stirring speed and upon this discovery we designed a phenylene–ethylene bridged PMO with a controlled Janus morphology. Unprecedentedly high payloads could be obtained from 40 to 110 wt % regardless of the organic bridge of PMOs. Finally, we demonstrate for the first time the co‐delivery of two cargos by PMO NPs. Importantly, the cargo stability in PMOs did not require the capping of the pores, unlike pure silica, and the delivery could be autonomously triggered in cancer cells by acidic pH with nearly 70 % cell killing.     

Targeting Innate Immunity with dsRNA‐Conjugated Mesoporous Silica Nanoparticles Promotes Antitumor Effects on Breast Cancer Cells

We describe herein a Toll‐like receptor 3 (TLR3) targeting delivery system based on mesoporous silica nanoparticles capped with the synthetic double stranded RNA polyinosinic–polycytidylic acid (poly(I:C)) for controlled cargo delivery in SK‐BR‐3 breast carcinoma cells. Our results show that poly(I:C)‐conjugated nanoparticles efficiently targeted breast cancer cells due to dsRNA–TLR3 interaction. Such interaction also triggered apoptotic pathways in SK‐BR‐3, significantly decreasing cells viability. Poly(I:C) cytotoxic effect in breast carcinoma cells was enhanced by loading nanoparticles′ mesopores with the anthracyclinic antibiotic doxorubicin, a commonly used chemotherapeutic agent.     

Recent Trends and Developments in Multifunctional Nanoparticles for Cancer Theranostics

Conventional anticancer treatments, such as radiotherapy and chemotherapy, have significantly improved cancer therapy. Nevertheless, the existing traditional anticancer treatments have been reported to cause serious side effects and resistance to cancer and even to severely affect the quality of life of cancer survivors, which indicates the utmost urgency to develop effective and safe anticancer treatments. As the primary focus of cancer nanotheranostics, nanomaterials with unique surface chemistry and shape have been investigated for integrating cancer diagnostics with treatment techniques, including guiding a prompt diagnosis, precise imaging, treatment with an effective dose, and real-time supervision of therapeutic efficacy. Several theranostic nanosystems have been explored for cancer diagnosis and treatment in the past decade. However, metal-based nanotheranostics continue to be the most common types of nonentities. Consequently, the present review covers the physical characteristics of effective metallic, functionalized, and hybrid nanotheranostic systems. The scope of coverage also includes the clinical advantages and limitations of cancer nanotheranostics. In light of these viewpoints, future research directions exploring the robustness and clinical viability of cancer nanotheranostics through various strategies to enhance the biocompatibility of theranostic nanoparticles are summarised.     

Upconverting Nanoparticles with a Mesoporous TiO2 Shell for Near‐Infrared‐Triggered Drug Delivery and Synergistic Targeted Cancer Therapy

Malignant tumors remain a major health burden throughout the world and effective therapeutic strategies are urgently needed. Herein, we report the synthesis of upconverting nanoparticles with a mesoporous TiO₂ (mTiO₂) shell for near‐infrared (NIR)‐triggered drug delivery and synergistic targeted cancer therapy. The NaGdF₄:Yb,Tm could convert NIR light to UV light, which activated the mTiO₂ to produce reactive oxygen species for photodynamic therapy (PDT). Due to the large surface area and porous structure, the mTiO₂ shell endowed the nanoplatform with another functionality of anticancer drug loading for chemotherapy. The hyaluronic acid modified on the surface not only promised controlled drug release but also conferred targeted ability of the system toward cluster determinant 44 overexpressed cancer cells. More importantly, cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of breast carcinoma cells compared with that of single chemotherapy or PDT.     

Calcium Carbonate Mineralized Nanoparticles as an Intracellular Transporter of Cytochrome c for Cancer Therapy

A new intracellular delivery system based on an apoptotic protein‐loaded calcium carbonate (CaCO₃) mineralized nanoparticle (MNP) is described. Apoptosis‐inducing cytochrome c (Cyt c) loaded CaCO₃ MNPs (Cyt c MNPs) were prepared by block copolymer mediated in situ CaCO₃ mineralization in the presence of Cyt c. The resulting Cyt c MNPs had a vaterite polymorph of CaCO₃ with a mean hydrodynamic diameter of 360.5 nm and exhibited 60 % efficiency for Cyt c loading. The Cyt c MNPs were stable at physiological pH (pH 7.4) and effectively prohibited the release of Cyt c, whereas, at intracellular endosomal pH (pH 5.0), Cyt c release was facilitated. The MNPs enable the endosomal escape of Cyt c for effective localization of Cyt c in the cytosols of MCF‐7 cells. Flow cytometry showed that the Cyt c MNPs effectively induced apoptosis of MCF‐7 cells. These findings indicate that the CaCO₃ MNPs can meet the prerequisites for delivery of cell‐impermeable therapeutic proteins for cancer therapy.     

荧光介孔二氧化硅纳米粒子的合成及药物运输

合成了荧光介孔二氧化硅纳米粒子（MSNs-FITC）,并研究了其在持续药物释放和生物示踪成像方面的应用。首先,采用一步法合成出MSNs-FITC,结合SEM、TEM、FT-IR、XRD和氮气吸附脱附等表征技术进行表征。其次,将抗癌药物阿霉素（DOX）负载到MSNs-FITC中。载药粒子的药物释放行为具有明显的pH依赖性,酸性环境加速释放速率。同时,体外细胞毒性测试表明MSNs-FITC具有良好的生物相容性。激光共聚焦扫描显微镜（CLSM）图像表明,MSNs-FITC可以进入细胞并具有剂量依赖性,流式细胞术分析（FCM）进一步证明了这一结果。