Cleaved Iron Oxide Nanoparticles as T2 Contrast Agents for Magnetic Resonance Imaging

Iron oxide nanoparticles as contrast agents are reported to effectively improve magnetic resonance imaging of tissues and cells. In this work, cleaved iron oxide nanoparticles (CIONPs) were generated from hydrophobic FeO nanoparticles (HIONPs) by coating their surfaces with PEG‐phospholipids, oxidizing them under water, and slowly removing the residual FeO phase in phthalate buffer. The synthesized CIONPs showed good r₂ values of up to 258 s^?1 mM ^?1. Thus, the CIONPs can be employed as vectors for drug delivery due to their unique structure with an empty inner space, which enables their use in a wide range of applications.     

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.     

Enzyme‐Responsive Multifunctional Magnetic Nanoparticles for Tumor Intracellular Drug Delivery and Imaging

Enzyme‐responsive, hybrid, magnetic silica nanoparticles have been employed for multifunctional applications in selective drug delivery and intracellular tumor imaging. In this study, doxorubicin (Dox)‐conjugated, enzyme‐cleavable peptide precursors were covalently tethered onto the surface of uniform silica‐coated magnetic nanoparticles through click chemistry. This enzyme‐responsive nanoparticle conjugate demonstrated highly efficient Dox release upon specific enzyme interactions in vitro. It also exhibits multiple functions in selective tumor intracellular drug delivery and imaging in the tumor cells with high cathepsin B expression, whereas it exhibited lower cytotoxicity towards other cells without enzyme expression.     

Poly(acrylic acid)‐Modified Fe3O4 Microspheres for Magnetic‐Targeted and pH‐Triggered Anticancer Drug Delivery

Monodisperse poly(acrylic acid)‐modified Fe₃O₄ (PAA@Fe₃O₄) hybrid microspheres with dual responses (magnetic field and pH) were successfully fabricated. The PAA polymer was encapsulated into the inner cavity of Fe₃O₄ hollow spheres by a vacuum‐casting route and photo‐initiated polymerization. TEM images show that the samples consist of monodisperse porous spheres with a diameter around 200 nm. The Fe₃O₄ spheres, after modification with the PAA polymer, still possess enough space to hold guest molecules. We selected doxorubicin (DOX) as a model drug to investigate the drug loading and release behavior of as‐prepared composites. The release of DOX molecules was strongly dependent on the pH value due to the unique property of PAA. The HeLa cell‐uptake process of DOX‐loaded PAA@Fe₃O₄ was observed by confocal laser scanning microscopy (CLSM). After being incubated with HeLa cells under magnet magnetically guided conditions, the cytotoxtic effects of DOX‐loaded PAA@Fe₃O₄ increased. These results indicate that pH‐responsive magnetic PAA@Fe₃O₄ spheres have the potential to be used as anticancer drug carriers.     

General Protocol for the Synthesis of Functionalized Magnetic Nanoparticles for Magnetic Resonance Imaging from Protected Metal–Organic Precursors

The development of magnetic nanoparticles (MNPs) with functional groups has been intensively pursued in recent years. Herein, a simple, versatile, and cost‐effective strategy to synthesize water‐soluble and amino‐functionalized MNPs, based on the thermal decomposition of phthalimide‐protected metal–organic precursors followed by deprotection, was developed. The resulting amino‐functionalized Fe₃O₄, MnFe₂O₄, and Mn₃O₄ MNPs with particle sizes of about 14.3, 7.5, and 6.6 nm, respectively, had narrow size distributions and good dispersibility in water. These MNPs also exhibited high magnetism and relaxivities of r₂=107.25 mM^?1 s^?1 for Fe₃O₄, r₂=245.75 mM^?1 s^?1 for MnFe₂O₄, and r₁=2.74 mM^?1 s^?1 for Mn₃O₄. The amino‐functionalized MNPs were further conjugated with a fluorescent dye (rhodamine B) and a targeting ligand (folic acid: FA) and used as multifunctional probes. Magnetic resonance imaging and flow‐cytometric studies showed that these probes could specifically target cancer cells overexpressing FA receptors. This new protocol opens a new way for the synthesis and design of water‐soluble and amino‐functionalized MNPs by an easy and versatile route.     

All‐in‐One Target‐Cell‐Specific Magnetic Nanoparticles for Simultaneous Molecular Imaging and siRNA Delivery

Cancer‐cell‐targeted gene silencing was observed with a magnetic‐nanoparticle platform (MEIO, magnetism‐engineered iron oxide) on which a fluorescent dye, siRNA, and a RGD‐peptide targeting moiety were attached (see picture). The different functionalities enable the macroscopic (magnetic resonance) and microscopic (fluorescence) imaging of target cells. This system may be suitable for concurrent diagnostic and therapeutic applications.

     

Conjugated Polymer Nanoparticles with Appended Photo‐Responsive Units for Controlled Drug Delivery,Release, and Imaging

Carriers that can afford tunable physical and structural changes are envisioned to address critical issues in controlled drug delivery applications. Herein, photo‐responsive conjugated polymer nanoparticles (CPNs) functionalized with donor–acceptor Stenhouse adduct (DASA) and folic acid units for controlled drug delivery and imaging are reported. Upon visible‐light (λ=550 nm) irradiation, CPNs simultaneously undergo structure, color, and polarity changes that release encapsulated drugs into the cells. The backbone of CPNs favors FRET to DASA units boosting their fluorescence. Notably, drug‐loaded CPNs exhibit excellent biocompatibility in the dark, indicating perfect control of the light trigger over drug release. Delivery of both hydrophilic and hydrophobic drugs with good loading efficiency was demonstrated. This strategy enables remotely controlled drug delivery with visible‐light irradiation, which sets an example for designing delivery vehicles for non‐invasive therapeutics.     

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.     

Synthesis and Characterization of pH‐Sensitive Positive‐charge Silica Nanoparticles for Oral Anionic Drug Delivery

The objective of this study is to utilize the pH sensitivity of modified mesoporous silica nanoparticles (MSN) for oral drug delivery. In the first time, a pH‐sensitive ionic liquid was synthesized through the quaternization of 3‐aminopropyltrimethoxysilane (3‐ATMS) with sodium monochloroacetate (SMCA). Then, silica nanoparticle was modified by this pH‐sensitive ionic liquid and converted to a pH‐sensitive positive‐charge silica nanoparticle (PCSN). The nanoparticle was characterized by FTIR and SEM. Naproxen as anionic drug molecules was entrapped in this pH‐sensitive positive‐charge silica nanoparticles (PCSN) and the in vitro release profiles were established separately in both (SGF, pH 1) and (SIF, pH 7.4).     

Yoctowell Cavities on Magnetic Silica Nanoparticles for pH Stimuli‐Responsive Controlled Release of Drug Molecules

Drug‐delivery systems that medically transport active molecules to diseased cells, in a controlled manner, have gained much attention in recent years. Yoctowell (1 yL=8 nm³ that is, 10^?24 L volume) cavities on magnetic silica nanoparticles were used for the encapsulation and release of the drug molecule, “mitoxantrone ( MTZ )”, and controlled using naturally occurring stimuli, that is, pH. First, MTZ was encapsulated from a bulk solution under physiological conditions, and then released from the yoctowells, in a controlled manner, by manipulating the pH (7.2–3.0). The sustained release of MTZ , the recovery of active yoctowells after the release process and magnetic properties of nanoparticles provide potential for development of a new generation of drug‐delivery system.     

CXCR4‐Targeted and MMP‐Responsive Iron Oxide Nanoparticles for Enhanced Magnetic Resonance Imaging

MRI offers high spatial resolution with excellent tissue penetration but it has limited sensitivity and the commonly administered contrast agents lack specificity. In this study, two sets of iron oxide nanoparticles (IONPs) were synthesized that were designed to selectively undergo copper‐free click conjugation upon sensing of matrix metalloproteinase (MMP) enzymes, thereby leading to a self‐assembled superparamagnetic nanocluster network with T₂ signal enhancement properties. For this purpose, IONPs with bioorthogonal azide and alkyne surfaces masked by polyethylene glycol (PEG) layers tethered to CXCR4‐targeted peptide ligands were synthesized and characterized. The IONPs were tested in vitro and T₂ signal enhancements of around 160 % were measured when the IONPs were incubated with cells expressing MMP2/9 and CXCR4. Simultaneous systemic administration of the bioorthogonal IONPs in tumor‐bearing mice demonstrated the signal‐enhancing ability of these ‘smart’ self‐assembling nanomaterials.     

Synthesis and Evaluation of GdIII‐Based Magnetic Resonance Contrast Agents for Molecular Imaging of Prostate‐Specific Membrane Antigen

Magnetic resonance (MR) imaging is advantageous because it concurrently provides anatomic, functional, and molecular information. MR molecular imaging can combine the high spatial resolution of this established clinical modality with molecular profiling in vivo. However, as a result of the intrinsically low sensitivity of MR imaging, high local concentrations of biological targets are required to generate discernable MR contrast. We hypothesize that the prostate‐specific membrane antigen (PSMA), an attractive target for imaging and therapy of prostate cancer, could serve as a suitable biomarker for MR‐based molecular imaging. We have synthesized three new high‐affinity, low‐molecular‐weight Gd^III‐based PSMA‐targeted contrast agents containing one to three Gd^III chelates per molecule. We evaluated the relaxometric properties of these agents in solution, in prostate cancer cells, and in an in vivo experimental model to demonstrate the feasibility of PSMA‐based MR molecular imaging.     

Mussel‐Inspired Protein Nanoparticles Containing Iron(III)–DOPA Complexes for pH‐Responsive Drug Delivery

A novel bioinspired strategy for protein nanoparticle (NP) synthesis to achieve pH‐responsive drug release exploits the pH‐dependent changes in the coordination stoichiometry of iron(III)–3,4‐dihydroxyphenylalanine (DOPA) complexes, which play a major cross‐linking role in mussel byssal threads. Doxorubicin‐loaded polymeric NPs that are based on Fe^III–DOPA complexation were thus synthesized with a DOPA‐modified recombinant mussel adhesive protein through a co‐electrospraying process. The release of doxorubicin was found to be predominantly governed by a change in the structure of the Fe^III–DOPA complexes induced by an acidic pH value. It was also demonstrated that the fabricated NPs exhibited effective cytotoxicity towards cancer cells through efficient cellular uptake and cytosolic release. Therefore, it is anticipated that Fe^III–DOPA complexation can be successfully utilized as a new design principle for pH‐responsive NPs for diverse controlled drug‐delivery applications.     

Improved Transversal Relaxivity for Highly Crystalline Nanoparticles of Pure γ‐Fe2O3 Phase

Pure and highly crystalline γ‐Fe₂O₃ nanocrystals (NCs) are obtained when hydrolysis and oxidation of a Fe^II organometallic precursor are performed in successive steps. Their synthesis in pure alkylamine leads to NCs of about 6 nm. In aqueous solutions of poly(vinyl)pyrrolidone, such pristine NCs form aggregates of about 150 nm that exhibit a high transversal relaxivity (r₂=466 mM ^?1 s^?1) about four times higher than that of a commercial Feridex magnetic resonance imaging (MRI) contrast agent. Consequently, they provide a significant decrease in the NMR signal at very short echo time (8 ms), which is of paramount importance in clinical practice because of the reduced duration of MRI measurements.     

One‐Step Synthesis of Small‐Sized and Water‐Soluble NaREF4 Upconversion Nanoparticles for In Vitro Cell Imaging and Drug Delivery

Small (2–28 nm) NaREF₄ (rare earth (RE)=Nd–Lu, Y) nanoparticles (NPs) were prepared by an oil/water two‐phase approach. Meanwhile, hydrophilic NPs can be obtained through a successful phase‐transition process by introducing the amphiphilic surfactant sodium dodecylsulfate (SDS) into the same reaction system. Hollow‐structured NaREF₄ (RE=Y, Yb, Lu) NPs can be fabricated in situ by electron‐beam lithography on solid NPs. The MTT assay indicates that these hydrophilic NPs with hollow structures exhibit good biocompatibility. The as‐prepared hollow‐structured NPs can be used as anti‐cancer drug carriers for drug storage/release investigations. Doxorubicin hydrochloride (DOX) was taken as model drug. The release of DOX from hollow α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ exhibits a pH‐sensitive release patterns. Confocal microscopy observations indicate that the NPs can be taken up by HeLa cells and show obvious anti‐cancer efficacy. Furthermore, α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ NPs show bright‐red emission under IR excitation, making both the excitation and emission light fall within the “optical window” of biological tissues. The application of α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ in the luminescence imaging of cells was also investigated, which shows a bright‐red emission without background noise.     

超顺磁性Fe3O4纳米粒子在磁共振造影中的应用

超顺磁性Fe₃O₄纳米粒子由于其廉价、低毒及超顺磁等特性,已成为重要的一类磁共振造影剂.本文综述了超顺磁性Fe₃O₄纳米粒子的可控制备方法,归纳总结影响粒径、结晶度和磁性能的主要因素和影响规律;为进一步提高磁性能并实现多功能,总结了Fe₃O₄纳米粒子进一步组装和表面改性的方法和机理;系统讨论了Fe₃O₄纳米粒子的形貌、尺寸和表面性能等对磁性能和生物相容性的影响规律;并指出了Fe₃O₄纳米粒子在磁共振造影领域潜在的发展方向和研究热点.     

Multifunctional Core–Shell Silica Nanoparticles for Highly Sensitive 19F Magnetic Resonance Imaging

¹⁹F magnetic resonance imaging (¹⁹F MRI) is useful for monitoring particular signals from biological samples, cells, and target tissues, because background signals are missing in animal bodies. Therefore, highly sensitive ¹⁹F MRI contrast agents are in great demand for their practical applications. However, we have faced the following challenges: 1) increasing the number of fluorine atoms decreases the solubility of the molecular probes, and 2) the restriction of the molecular mobility attenuates the ¹⁹F MRI signals. Herein, we developed novel multifunctional core–shell nanoparticles to solve these issues. They are composed of a core micelle filled with liquid perfluorocarbon and a robust silica shell. These core–shell nanoparticles have superior properties such as high sensitivity, modifiability of the surface, biocompatibility, and sufficient in vivo stability. By the adequate surface modifications, gene expression in living cells and tumor tissue in living mice were successfully detected by ¹⁹F MRI.