Peptide‐Targeted Gold Nanoparticles for Photodynamic Therapy of Brain Cancer

Targeted drug delivery using epidermal growth factor peptide‐targeted gold nanoparticles (EGF_pep‐Au NPs) is investigated as a novel approach for delivery of photodynamic therapy (PDT) agents, specifically Pc 4, to cancer. In vitro studies of PDT show that EGF_pep‐Au NP‐Pc 4 is twofold better at killing tumor cells than free Pc 4 after increasing localization in early endosomes. In vivo studies show that targeting with EGF_pep‐Au NP‐Pc 4 improves accumulation of fluorescence of Pc 4 in subcutaneous tumors by greater than threefold compared with untargeted Au NPs. Targeted drug delivery and treatment success can be imaged via the intrinsic fluorescence of the PDT drug Pc 4. Using Pc 4 fluorescence, it is demonstrated in vivo that EGF_pep‐Au NP‐Pc 4 impacts biodistribution of the NPs by decreasing the initial uptake by the reticuloendothelial system (RES) and by increasing the amount of Au NPs circulating in the blood 4 h after IV injection. Interestingly, in vivo PDT with EGF_pep‐Au NP‐Pc 4 results in interrupted tumor growth when compared with EGF_pep‐Au NP control mice when selectively activated with light. These data demonstrate that EGF_pep‐Au NP‐Pc 4 utilizes cancer‐specific biomarkers to improve drug delivery and therapeutic efficacy over untargeted drug delivery.     

Human‐Serum‐Albumin‐Coated Prussian Blue Nanoparticles as pH‐/Thermotriggered Drug‐Delivery Vehicles for Cancer Thermochemotherapy

Constructing novel multimodal antitumor therapeutic nanoagents has attracted tremendous recent attention. In this work, a new drug‐delivery vehicle based on human‐serum‐albumin (HSA)‐coated Prussian blue nanoparticles (PB NPs) is synthesized. It is demonstrated that doxorubicin (DOX)/HSA is successfully loaded after in situ polymerization of dopamine onto PB NPs, and the PB@PDA/DOX/HSA NPs are highly compatible and stable in various physiological solutions. The NPs possess strong near‐infrared (NIR) absorbance, and excellent capability and stability of photothermal conversion for highly efficient photothermal therapy applications. Furthermore, a bimodal on‐demand drug release sensitively triggered by pH or NIR irradiation has been realized, resulting in a significant chemotherapeutic effect due to the preferential uptake and internalization of the NPs by cancer cells. Importantly, the thermochemotherapy efficacy of the NPs has been examined by a cell viability assay, revealing a remarkably superior synergistic anticancer effect over either monotherapy. Such multifunctional drug‐delivery systems composed of approved materials may have promising biomedical applications for antitumor therapy.     

Docetaxel‐Loaded Nanoparticles of Dendritic Amphiphilic Block Copolymer H40‐PLA‐b‐TPGS for Cancer Treatment

A dendritic amphiphilic block copolymer H40‐poly(d,l ‐lactide)‐block‐d‐α‐tocopheryl polyethylene glycol 1000 succinate (H40‐PLA‐b‐TPGS) is synthesized, which is then employed to develop a system of nanoparticles (NPs) loaded with docetaxel (DTX) as a model drug for cancer treatment due to its higher drug‐loading content and drug encapsulation efficiency, smaller particle size, faster drug release, and higher cellular uptake in comparison to the linear PLA polymer NPs and PLA‐b‐TPGS copolymer NPs. The drug‐loaded NPs are prepared by a modified nanoprecipitation method and characterized in terms of size and size distribution, surface morphology, drug release profile, and physical state of DTX. Cellular uptake of coumarin 6‐loaded NPs by MCF‐7 cancer cells is determined by flow cytometry and confocal laser scanning microscopy. The antitumor efficacy of the drug‐loaded NPs is investigated in vitro by MTT assay and in vivo by xenograft tumor model. The 72 h IC50 of the drug formulated in the PLA, PLA‐b‐TPGS, and H40‐PLA‐b‐TPGS NPs is found to be, 1.5 ± 0.3, 0.9 ± 0.1, and 0.15 ± 0.06 μg mL^?1, which are 7.3, 12.2, and 73.3‐fold effective than 11.0 ± 1.2 μg mL^?1 for Taxotere, respectively. Such advantages are further confirmed by the measurement of the tumor size and weight.     

Glutathione‐Mediated Degradation of Surface‐Capped MnO2 for Drug Release from Mesoporous Silica Nanoparticles to Cancer Cells

Owing to its higher concentration in cancer cells than that in the corresponding normal cells, glutathione (GSH) provides an effective and flexible mechanism to design drug delivery systems. Here a novel GSH‐responsive mesoporous silica nanoparticle (MSN) is reported for controlled drug release. In this system, manganese dioxide (MnO₂) nanostructure, formed by the reduction of KMnO₄ on the surface of carboxyl‐functionalized MSN can block the pores (MSN@MnO₂). By a redox reaction, the capped MnO₂ nanostructure can dissociate into Mn²⁺ in the presence of GSH molecules. The blocked pores are then uncapped, which result in the release of the entrapped drugs. As a proof‐of‐concept, doxorubicin (DOX) as model drug is loaded into MSN@MnO₂. DOX‐loaded MSN@MnO₂ shows an obvious drug release in 10 × 10^?3 m GSH, while no release is observed in the absence of GSH. In vitro studies using human hepatocellular liver carcinoma cell line (HepG2) prove that the DOX‐loaded MSN@MnO₂ can entry into HepG2 cells and efficiently release the loaded DOX, leading to higher cytotoxicity than to that of human normal liver cells (L02). It is believed that further developments of this GSH‐responsive drug delivery system will lead to a new generation of nanodevices for intracellular controlled delivery.     

Magnetic Field‐Controlled Release of Paclitaxel Drug from Functionalized Magnetoelectric Nanoparticles

Using magnetoelectric nanoparticles (MENs) for targeted drug delivery and on‐demand, field‐controlled release can overcome the control challenges of the conventional delivery approaches. The magnetoelectric effect provides a new way to use an external magnetic field to remotely control the intrinsic electric fields that govern the binding forces between the functionalized surface of the MEN and the drug load. Here, a study is reported in which the composition of the intermediate functionalized layer is tailored to control not only the toxicity of the new nanoparticles but also the threshold magnetic field for the dissociation of the drug from 30‐nm CoFe₂O₄–BaTiO₃ core–shell MENs in a controllably wide field range, from below 10 to over 200 Oe, as required to facilitate superficial, intermediate, and deep‐tissue drug delivery. Paclitaxel is used as a test drug. Specific experiments are described to maintain low toxicity levels and to achieve controllable dissociation of the drug molecules from the MENs' surface at three different subranges—low (<10 Oe), moderate (100 Oe), and high (>200 Oe)—by selecting the following 2‐nm intermediate layers: i) glycerol monooleate (GMO), ii) Tween‐20, and iii) ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC). Field‐dependent FTIR, absorption spectra, atomic force microscopy, magnetometry analysis, zeta‐potential measurements, and blood circulation experiments are used to study the described functionalization effects.     

Preparation of Photoluminescent Porous Silicon Nanoparticles by High‐Pressure Microfluidization

The use of high‐shear microfluidization as a rapid, reproducible, and high‐yield method to prepare nanoparticles of porous silicon (pSi) with a narrow size distribution is described. Porous films prepared by electrochemical etch of a single‐crystal silicon wafer are removed from the substrate, fragmented, dispersed in an aqueous solution, and then processed with a microfluidizer, which generates high yields (57%) of pSi nanoparticles of narrow size distribution (PDI = 0.263) without a filtration step. Preparation of pSi nanoparticles via microfluidization improves yields (by 2.4‐fold) and particle size uniformity (by 1.8‐fold), and it lowers the total processing time (by 36‐fold) over standard ultrasonication or ball milling methods. The average diameter of the nanoparticles can be adjusted over the range 150–350 nm by appropriate adjustment of processing steps. If the fluid carrier in the microfluidizer contains an oxidant for Si, the resulting pSi particles are prepared with a core–shell structure, in which an elemental Si core is encased in a silicon oxide shell. When an aqueous sodium tetraborate processing solution is used, microfluidization generates photoluminescent core–shell pSi particles with a quantum yield of 19% in a single step in less than 20 min.     

Enhanced Physiological Stability and Long‐Term Toxicity/Biodegradation In Vitro/In Vivo of Monodispersed Glycerolphosphate‐Functionalized Bioactive Glass Nanoparticles

Monodispersed bioactive glass nanoparticles (BGNs) have received much attention in various biomedical applications such as tissue regeneration, drug/gene delivery, bioimaging, and cancer therapy. However, the poor dispersion stability of BGNs in a physiological environment has limited their wide biomedical applications. The long‐term in vitro/in vivo toxicity and biodegradation of BGNs are also not clear. Monodispersed glycerolphosphate‐functionalized BGNs (GP‐BGN) are synthesized and their stability under physiological environment in vitro, and long‐term biodegradation behavior in vitro and in vivo are investigated herein. GP‐BGN shows significantly enhanced particles stability in physiological environment, good hemocompatibility and cellular biocompatibility, as well as high cellular uptake ability. GP‐BGN also exhibits long‐term biodegradation behavior in vitro/in vivo and negligible biotoxicity (tissue and blood toxicity). This study demonstrates that monodispersed surface‐functionalized BGNs could be used as biocompatible and biodegradable nanomaterials for long‐term safe bioimaging and disease therapy.     

Uptake and Intracellular Fate of Peptide Surface‐Functionalized Silica Hybrid Magnetic Nanoparticles In Vitro

Recently, the use of nanomaterials as intracellular targeting tools for theranostics has gained heightened interest. Despite the clear advantages posed by surface‐functionalized nanoparticles (NPs) in this regard, limited understanding currently exists due to difficulties in reliably synthesizing NPs with surface functionalizations adequate for use in such applications, as well as the manner of analytics used to assess the cellular uptake and intracellular localization of these NPs. In the present study, two key surface functionalities (a nuclear localization sequence (NLS) and integrin‐ligand (cRGD)) are attached to the surface of multifunctional, silica hybrid magnetic nanoparticles (SHMNPs) containing a polyethylene glycol (PEG) polymer coating using a well‐described, reliable, and reproducible microreactor set‐up. Subsequent analytical interpretation, via laser scanning confocal, transmission electron and dark‐field microscopy, as well as flow cytometry, of the interaction of SHMNPs‐PEG‐cRGD‐NLS with macrophage (J774A.1) and epithelial (HeLa) cells shows internalization of the SHMNPs‐PEG‐cRGD‐NLS in both cell types up to 24 h after 20 μg mL^?1 exposure, as well as increasing aggregation inside of vesicles over this time period. The findings of this study show that by incorporating a variety of state‐of‐the‐art analytical and imaging approaches, it is possible to determine the specific effectiveness of surface peptide and ligand sequences upon multifunctional SHMNPs.     

Fourier Transform Infrared Spectroscopic Analysis of Breast Cancer Tissues; Identifying Differences between Normal Breast,Invasive Ductal Carcinoma,and Ductal Carcinoma In Situ of the Breast

Abstract

A nondestructive method employing Fourier transform infrared (FTIR) microspectroscopy coupled with attenuated total reflectance (ATR) objective for the analysis of histopathological specimens is described. Malignant breast tissue specimens have been analyzed to demonstrate the hypothesis that chemical changes taking place in biological tissue can be reliably and reproducibly identified. This study is the first report to elucidate clear spectral differences between different ductal carcinoma in situ (DCIS) grades. Sixty individual cases of breast carcinoma including DCIS and invasive ductal carcinoma (IDC) and seven cases of normal breast tissues were studied using the FTIR-ATR spectroscopic technique. FTIR analysis of tissue sections has provided distinct spectra that can be used to distinguish between the nuclear grades of DCIS and IDC of the breast. It was concluded that FTIR could objectively and reproducibly discriminate between DCIS and IDC grades without sample destruction. In the future, applications of FTIR approaches should become feasible in the nondestructive express classification of grades and diagnosis of breast carcinoma.     

Static Magnetic Field Dictates Protein Corona Formation on the Surface of Glutamine‐Modified Superparamagnetic Iron Oxide Nanoparticles

Superparamagnetic iron oxide nanoparticles (SPIONs) have become important tools for the imaging and detecting of prevalent diseases for many years. Scientists usually harness their attraction to a static magnetic field (SMF) to increase targeting efficiency and minimize side effects. To prolong blood circulation time and minimize reticuloendothelial system clearance, SPIONs are increasingly designed with a negatively charged surface. Understanding how a SMF affects the SPIONs with a negative surface charge is fundamental to any potential downstream applications of SPIONs as drug delivery carriers and bio‐separation nanoparticles. The goal of our study is to investigate the effect of SMF treatment (204 mT) on the in vitro and in vivo protein corona formed on negatively charged SPIONs. The results reveal that the amount of protein and the composition of protein corona is directly related to the SMF treatment. Compared with the in vivo protein corona, SMF treatment exercises considerable influence on the composition of the in vitro protein corona. The in vitro protein corona formed on SPIONs modulates the secretion of inflammatory cytokines from cells. To the best of our knowledge, this report describes the first demonstration of a SMF as an influencing factor on protein corona formation in vivo. Our results help to elucidate the biological mechanisms of SPIONs with SMF treatment and suggest that the protein corona effect should be considered during the development of a magnetic target.     

Construction of a Dual Drug Carrier on the Basis of Hollow Structured Upconversion Nanoparticles for pH‐Responsive Drug Delivery and UCL/MRI Dual Mode Imaging

A series of Gd³⁺ doping hollow upconversion nanoparticles NaYF₄:Yb,Gd,Tm (h‐UNCP) are prepared successfully. The hollow NaYF₄:Yb,Gd,Tm possess excellent upconversion luminescence (UCL) and large longitudinal relativity (r₁ = 128.3 mm ^?1 s^?1), which can be potentially used for UCL/magnetic resonance imaging (MRI) dual mode imaging. On the basis of the optimal h‐UCNP, doxorubicin hydrochloride (DOX) and methotrexate (MTX) are used as drug models to prepare a dual drug carrier. After the encapsulation of DOX on the h‐UCNP, chitosan (CS) is further wrapped and then used to load MTX to obtain a dual drug carrier h‐UCNPs/DOX/CS/MTX. The pH responsive release of DOX and MTX is discussed. The MTX release climbs from 33% to 100% by regulating the pH from 5.8 to 7.4. The DOX release is different at different pH conditions. The synergistic effect of DOX and MTX on the cancer cells is confirmed by cell viability. The h‐UCNPs/DOX/CS/MTX are tracked by cells UCL imaging and vivo MRI imaging. The excellent performance of UCL imaging and positive MRI images demonstrates that h‐UCNPs/DOX/CS/MTX can be used for UCL/MRI dual mode imaging. All the results show the potential application of h‐UCNPs/DOX/CS/MTX in pH responsive release and UCL/MRI dual imaging.