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.     

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。     

Solvent Effect in PLA-PEG Based Nanoparticles Synthesis through Surfactant Free Polymerization

Summary: In this work one-pot synthesis of PEGylated PLA-based nanoparticles (NPs) without using any surfactant has been performed. Adopting ring opening polymerization of L,L–Lactide and 2-hydroxyethyl methacrylate (HEMA), vinyl end functionalized poly(lactic acid) macromonomers (HEMA-LA_n) have been produced with tunable number of lactic acid units (larger than 5) and a low molecular weight distribution. Macromonomers have been further copolymerized with modified PEG chains (HEMA-PEG_m) through a monomer starved semi-batch emulsion polymerization performed without using any surfactant. In these conditions, small and monodispersed NPs of around 150 nm are obtained. Since macromonomers with n larger than 5 are highly viscous at room temperature, they have to be dissolved in a solvent before their injection in the reactor. In this work the effects in changing the solvent adopted in the starved process (water miscible or non-miscible) and its amount have been investigated. Moreover, the effect of both PEG chains concentration and MW on the final NPs properties has been elucidated. The colloidal stability of the NPs produced using different solvents has been verified in phosphate buffered saline (PBS) solution via dynamic light scattering measurements; in addition the critical coagulation concentration of these PEGylated NPs has been determined.     

A facile preparation method for nanosized MOFs as a multifunctional material for cellular imaging and drug delivery

Tb-based metal-organic framework nanoparticles (Tb-MOF NPs) with good colloidal stability and stable fluorescence properties in an aqueous solution were prepared by a simple mechanical grinding of Tb-MOF with a biocompatible polymer surfactant (F127). The characteristic fluorescence property of Tb-MOF NPs allowed us to use this nanomaterial as a cell imaging probe. Efficient cellular uptake of Tb-MOF NPs apparently via an energy-dependent endocytosis was observed by confocal laser scanning microscopy. By taking advantage of the porous nature of the Tb-MOF NPs an anticancer drug (doxorubicin) was successfully loaded and delivered to kill cancer cells to demonstrate their usage as a drug delivery vehicle. This simple grinding method afforded a nanosized, multifunctional biomaterial that was used for cell imaging and drug delivery, and it can be extended to other MOFs to widen their applications.     

乳液聚合制备纳米银/聚苯乙烯核壳复合粒子

采用乳液聚合方法制备出纳米银／聚苯乙烯核壳复合粒子，并借助TEM、XPS、FTIR分析了其微观结构。研究了纳米银粒子存在下苯乙烯聚合反应转化率-时间关系，分析了纳米银／聚苯乙烯核壳复合粒子的形成机理。     

Selective Killing of Breast Cancer Cells by Doxorubicin‐Loaded Fluorescent Gold Nanoclusters: Confocal Microscopy and FRET

Fluorescent gold nanoclusters (AuNCs) capped with lysozymes are used to deliver the anticancer drug doxorubicin to cancer and noncancer cells. Doxorubicin‐loaded AuNCs cause the highly selective and efficient killing (90 %) of breast cancer cells (MCF7) (IC₅₀=155 nm ). In contrast, the killing of the noncancer breast cells (MCF10A) by doxorubicin‐loaded AuNCs is only 40 % (IC₅₀=4500 nm ). By using a confocal microscope, the fluorescence spectrum and decay of the AuNCs were recorded inside the cell. The fluorescence maxima (at ≈490–515 nm) and lifetime (≈2 ns), of the AuNCs inside the cells correspond to Au_10–13. The intracellular release of doxorubicin from AuNCs is monitored by Förster resonance energy transfer (FRET) imaging.     

Gold Nanoparticles for Biology and Medicine

Gold colloids have fascinated scientists for over a century and are now heavily utilized in chemistry, biology, engineering, and medicine. Today these materials can be synthesized reproducibly, modified with seemingly limitless chemical functional groups, and, in certain cases, characterized with atomic‐level precision. This Review highlights recent advances in the synthesis, bioconjugation, and cellular uses of gold nanoconjugates. There are now many examples of highly sensitive and selective assays based upon gold nanoconjugates. In recent years, focus has turned to therapeutic possibilities for such materials. Structures which behave as gene‐regulating agents, drug carriers, imaging agents, and photoresponsive therapeutics have been developed and studied in the context of cells and many debilitating diseases. These structures are not simply chosen as alternatives to molecule‐based systems, but rather for their new physical and chemical properties, which confer substantive advantages in cellular and medical applications.     

Single‐Vehicular Delivery of Antagomir and Small Molecules to Inhibit miR‐122 Function in Hepatocellular Carcinoma Cells by using “Smart” Mesoporous Silica Nanoparticles

MicroRNAs (miRNAs) regulate a variety of biological processes. The liver‐specific, highly abundant miR‐122 is implicated in many human diseases including cancer. Its inhibition has been found to result in a dramatic loss in the ability of Hepatitis C virus (HCV) to infect host cells. Both antisense technology and small molecules have been used to independently inhibit endogenous miR‐122 function, but not in combination. Intracellular stability, efficient delivery, hydrophobicity, and controlled release are some of the current challenges associated with these novel therapeutic methods. Reported herein is the first single‐vehicular system, based on mesoporous silica nanoparticles (MSNs), for simultaneous cellular delivery of miR‐122 antagomir and small molecule inhibitors. The controlled release of both types of inhibitors depends on the expression levels of endogenous miR‐122, thus enabling these drug‐loaded MSNs to achieve combination inhibition of its targeted mRNAs in Huh7 cells.     

Redox‐responsive Fluorescent Nanoparticles Based on Diselenide‐containing AIEgens for Cell Imaging and Selective Cancer Therapy

A fluorescent, diselenide‐containing 9,10‐distyrylanthracene (DSA) derivative (SeDSA) with aggregation‐induced emission (AIE) characteristic was successfully synthesized and SeDSA nanoparticles (NPs) were prepared through a nanoprecipitation method. SeDSA could coassemble with an antitumor prodrug, diselenide‐containing paclitaxel (SePTX), which could be obtained by precipitation, to form SeDSA‐SePTX Co‐NPs (Co‐NPs). Molecular dynamics (MD) simulations reveal that the driving forces for the self‐assembly behaviors of SeDSA NPs and SePTX NPs are π–π interactions and hydrophobic interactions, respectively, while the driving forces for Co‐NPs include hydrophobic interactions between SeDSA and SePTX, π–π interactions between SeDSA molecules and hydrophobic interactions between SePTX molecules. Meanwhile, Se‐Se bonds play a crucial role in balancing the intramolecular forces. These diselenide‐containing nanoparticles (SeDSA NPs, SePTX NPs and Co‐NPs) exhibit a high stability under physiological conditions and excellent reduction‐sensitivity in the presence of the redox agent glutathione (GSH) because of the selenium‐sulfur exchange reaction between diselenide and GSH. Both SeDSA NPs and Co‐NPs show strong orange fluorescence emissions on the account of the AIE feature of SeDSA and they were easily internalized by HeLa and HepG2 cells. Distinctively, the Co‐NPs combine the advantage of SeDSA and SePTX for cell imaging and antineoplastic activity, and exhibit selectivity of cytotoxicities between neoplasia cells and normal cells. This study highlights the development of diselenide‐containing AIEgens as a unique approach to prepare uniform and stable fluorescent nanoparticles for the application in cell imaging and tumor treatment.     

Synthesis of Composite Polystyrene/Silica Nanoparticles via Precipitation and Emulsion Polymerization Methods

Polystyrene/silica composite nanoparticles were synthesized via precipitation and emulsion polymerization methods, in the presence of a basic co‐monomer (e.g., 4‐VP and 1‐VID), and a colloidal aqueous silica solution. The effects of key process parameters, that is, solvent type, monomer/co‐monomer volume ratio and total monomers concentration for precipitation polymerization, and reaction temperature, pH value, initial silica‐sol concentration and initial monomer/co‐monomer molar ratio for emulsifier‐free emulsion polymerization on the particle morphology, silica content, and particle size distribution of the composite nanoparticles were experimentally investigated. Stable, spherical, and uniform in size composite nanoparticles were synthesized by both techniques. The average particle diameter varied from 108 to 182 nm for the emulsifier‐free emulsion polymerization and from 400 to 800 nm for the precipitation polymerization, while the silica content was as high as 38.3 wt.‐% for the former method and up to 15.5 wt.‐% for the later. The synthesized composite polymer/silica particles were then electrolytically co‐deposited with zinc on steel plates to improve the corrosion resistance of the metal's surface.

     

Multistimuli‐Responsive Bilirubin Nanoparticles for Anticancer Therapy

Although stimuli‐responsive materials hold potential for use as drug‐delivery carriers for treating cancers, their clinical translation has been limited. Ideally, materials used for the purpose should be biocompatible and nontoxic, provide “on‐demand” drug release in response to internal or external stimuli, allow large‐scale manufacturing, and exhibit intrinsic anticancer efficacy. We present multistimuli‐responsive nanoparticles formed from bilirubin, a potent endogenous antioxidant that possesses intrinsic anticancer and anti‐inflammatory activity. Exposure of the bilirubin nanoparticles (BRNPs) to either reactive oxygen species (ROS) or external laser light causes rapid disruption of the BRNP nanostructure as a result of a switch in bilirubin solubility, thereby releasing encapsulated drugs. In a xenograft tumor model, BRNPs loaded with the anticancer drug doxorubicin (DOX@BRNPs), when combined with laser irradiation of 650 nm, significantly inhibited tumor growth. This study suggests that BRNPs may be used as a drug‐delivery carrier as well as a companion medicine for effectively treating cancers.     

DNA四面体结构纳米材料及其应用

基于DNA纳米技术自组装的DNA四面体纳米材料,由于结构稳定、机械性能优越、分子修饰位点丰富等特点,逐渐成为DNA纳米材料领域的研究热点。此外,该DNA四面体纳米材料只需一步热变性即可自组装形成,具有合成方法简单、产率高的优点。可通过不同的设计,利用自组装方法将功能分子修饰在DNA四面体的顶点处,包裹在其笼状孔隙结构内,镶嵌或悬挂在双螺旋的边上,甚至通过引入发卡环结构等方式智能控制其结构变化。本文综述了DNA四面体结构纳米材料的设计和自组装原理、功能化修饰方法和结构的智能化,同时介绍了DNA四面体纳米材料在分子诊断、生物成像、分子输送和靶向给药等方面的应用研究,并探讨了此类纳米材料在今后应用研究中应关注的方面。     

pH-Responsive Self-assembled Nanoparticles of Simulated P(AA-co-SA)-g-PEG for Drug Release

Simulated graft copolymer of poly(acrylic acid-co-stearyl acylate) [P(AA-co-SA)] and poly(ethylene glycol) (PEG) was synthesized, where acrylic acid, stearyl acylate and PEG was employed as the pH-sensitive, hydrophobic and hydrophilic segment, respectively. Polymeric nanoparticles prepared by the dialysis of simulated graft copolymer solution in dimethylformamide against citrate buffer solution with different pH values were characterized by transmission electron microscopy (TEM), fluorescence technique and laser light scattering (LLS). TEM image revealed the spherical shape of the self-aggregates, which was further confirmed by LLS measurements. The critical aggregation concentration increased markedly (10 to 150 mg/L) with increasing pH (4.6 to 7.0), consistent with the de-protonation of carboxylic groups at higher pH. The hydrodynamic radius of polymeric nanoparticles decreased from 118 nm at pH 3.4 to 90 nm at pH 7.0. The controlled release of indomethacin from those nanoparticles was investigated, and the self-assembled nanoparticles exhibited improved performance in controlled drug release.     

One-Step Synthesis of Polyethylenimine-Coated Magnetic Nanoparticles and its Demulsification Performance in Surfactant-Stabilized Oil-in-Water Emulsion

In this study, polyethylenimine (PEI)-coated Fe₃O₄ magnetic nanoparticles (MNPs) were successfully synthesized via a one-step, solvo-thermal method. The synthetic PEI-coated MNPs were characterized by using multiple techniques and their demulsification efficiencies were evaluated in surfactant-stabilized, oil-in-water emulsions. The results showed that the synthesized MNPs successfully adsorbed to the emulsion’s O/W interfaces and, consequently, the oil droplets could be rapidly destabilized under an applied magnetic field. It was found that the demulsification efficiency was enhanced with the increased particle dosage. The opposite effect was found with the increase in pH value and surfactant concentration. The presence of electrolytes facilitated oil removal, presumably by reduction of the electrostatic repulsion or by altering the hydrophobicity of the MNPs. Recovery experiments at various pH levels indicated that the PEI-coated MNPs could be reused for up to ten times without significant reduction in demulsification efficiency. Altogether, the results suggested that the PEI-coated MNPs could provide a simple but powerful tool to remove emulsified oil from aqueous systems.     

Dual‐Targeted Selenium Nanoparticles for Synergistic Photothermal Therapy and Chemotherapy of Tumors

A combination of chemo‐ and photothermal therapy has emerged as a promising tactic for cancer therapy. However, the intricacy of accurate delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Hence, to assure that the chemotherapeutic drug and photothermal agent are synchronously delivered to a tumor area for their synergistic effect, dual‐target (RC‐12 and PG‐6 peptides) functionalized selenium nanoparticles loaded with both doxorubicin (DOX) and indocyanine green (ICG) were designed and successfully synthesized. The as‐synthesized nanoparticles exhibited good monodispersity, size stability, and consistent spectral characteristics compared with those of ICG or DOX alone. The nanoparticles underwent self‐immolated cleavage under irradiation from a near‐IR laser and released the loaded drug owing to sufficient hyperthermia. Moreover, the internalized nanoparticles triggered the overproduction of intracellular reactive oxygen species to induce cell apoptosis. Taken together, this study provides a sequentially triggered nanosystem to achieve precise drug delivery by chemo‐photothermal combination.     

纳米粒子在药物传递中的应用

目前,利用纳米粒子传递药物并用于恶性肿瘤组织的靶向识别,进一步提高肿瘤的诊断和治疗水平是一个比较热点的领域,人们期望用制备容易、价格便宜、毒性小的纳米技术来提高肿瘤的治疗效率。然而,由近年的报道来看,所摄入的纳米粒子仅有约0.7%能够到达肿瘤部位,传递效率较低,这无疑加大了治疗应用的难度。本综述中,我们分析了造成纳米粒子靶向药物转运效率较低的原因,包括纳米粒子的转运途径,纳米粒子转运过程中所遇到的屏障,纳米粒子在体内的清除途径等;随后我们介绍了较早应用的聚合物纳米粒子、磁性氧化铁纳米粒子以及目前广泛研究的介孔二氧化硅纳米粒子在药物传递系统构建中的应用情况,还介绍了细胞膜仿生纳米粒子在药物传递系统中的应用;最后,对纳米粒子在药物传递中的研究进行总结和展望。我们希望通过对纳米粒子传递药物的系统研究,进一步促进纳米粒子在药物传递上的研究,加速纳米药物的临床应用。     

Hybrid Nanoparticles as Drug Carriers for Controlled Chemotherapy of Cancer

Rapid developments in materials science and biological mechanisms have greatly boosted the research discoveries of new drug delivery systems. In the past few decades, hundreds of nanoparticle‐based drug carriers have been reported almost on a daily basis, in which new materials, structures, and mechanisms are proposed and evaluated. Standing out among the drug carriers, the hybrid nanoparticle systems offer a great opportunity for the optimization and improvement of conventional chemotherapy. By combining several features of functional components, these hybrid nanoparticles have shown excellent promises of improved biosafety, biocompatibility, multifunctionality, biodegradability, and so forth. In this Personal Account, we highlight the recent research advances of some representative hybrid nanoparticles as drug delivery systems and discuss their design strategies and responsive mechanisms for controlled drug delivery.     

A New Porphyrin for the Preparation of Functionalized Water-Soluble Gold Nanoparticles with Low Intrinsic Toxicity

A potential new photosensitizer based on a dissymmetric porphyrin derivative bearing a thiol group was synthesized. 5-[4-(11-Mercaptoundecyloxy)-phenyl-10,15,20-triphenylporphyrin (PR-SH) was used to functionalize gold nanoparticles in order to obtain a potential drug delivery system. Water-soluble multifunctional gold nanoparticles GNP-PR/PEG were prepared using the Brust–Schiffrin methodology, by immobilization of both a thiolated polyethylene glycol (PEG) and the porphyrin thiol compound (PR-SH). The nanoparticles were fully characterized by transmission electron microscopy and ¹H nuclear magnetic resonance spectroscopy, UV/Vis absorption spectroscopy, and X-ray photoelectron spectroscopy. Furthermore, the ability of GNP-PR/PEGs to induce singlet oxygen production was analyzed to demonstrate the activity of the photosensitizer. Cytotoxicity experiments showed the nanoparticles are nontoxic. Finally, cellular uptake experiments demonstrated that the functionalized gold nanoparticles are internalized. Therefore, this colloid can be considered to be a novel nanosystem that could potentially be suitable as an intracellular drug delivery system of photosensitizers for photodynamic therapy.