Ultra‐Small Iron Oxide Doped Polypyrrole Nanoparticles for In Vivo Multimodal Imaging Guided Photothermal Therapy

Recently, near‐infrared (NIR) absorbing conjugated polymeric nanoparticles have received significant attention in photothermal therapy of cancer. Herein, polypyrrole (PPy), a NIR‐absorbing conjugate polymer, is used to coat ultra‐small iron oxide nanoparticles (IONPs), obtaining multifunctional IONP@PPy nanocomposite which is further modified by the biocompatible polyethylene glycol (PEG) through a layer‐by‐layer method to acquire high stability in physiological solutions. Utilizing the optical and magnetic properties of the yielded IONP@PPy‐PEG nanoparticles, in vivo magnetic resonance (MR) and photoacoustic imaging of tumor‐bearing mice are conducted, revealing strong tumor uptake of those nanoparticles after intravenous injection. In vivo photothermal therapy is then designed and carried out, achieving excellent tumor ablation therapeutic effect in mice experiments. These results promise the use of multifunctional NIR‐absorbing organic‐inorganic hybrid nanomaterials, such as IONP@PPy‐PEG presented here, for potential applications in cancer theranostics.     

Protoporphyrin IX (PpIX)‐Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters for Magnetic Resonance Imaging and Photodynamic Therapy

The ability to produce nanotherapeutics at large‐scale with high drug loading efficiency, high drug loading capacity, high stability, and high potency is critical for clinical translation. However, many nanoparticle‐based therapeutics under investigation suffer from complicated synthesis, poor reproducibility, low stability, and high cost. In this work, a simple method for preparing multifunctional nanoparticles is utilized that act as both a contrast agent for magnetic resonance imaging and a photosensitizer for photodynamic therapy for the treatment of cancer. In particular, the photosensitizer protoporphyrin IX (PpIX) is used to solubilize small nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs) without the use of any additional carrier materials. These nanoclusters are characterized with a high PpIX loading efficiency; a high loading capacity, stable behavior; high potency; and a synthetic approach that is amenable to large‐scale production. In vivo studies of photodynamic therapy (PDT) efficacy show that the PpIX‐coated SPION nanoclusters lead to a significant reduction in the growth rate of tumors in a syngeneic murine tumor model compared to both free PpIX and PpIX‐loaded poly(ethylene glycol)‐polycaprolactone micelles, even when injected at 1/8th the dose. These results suggest that the nanoclusters developed in this work can be a promising nanotherapeutic for clinical translation.     

Ultrasmall Water‐Soluble and Biocompatible Magnetic Iron Oxide Nanoparticles as Positive and Negative Dual Contrast Agents

Monodispersed water‐soluble and biocompatible ultrasmall magnetic iron oxide nanoparticles (UMIONs, D = 3.3 ± 0.5 nm) generated from a high‐temperature coprecipitation route are successfully used as efficient positive and negative dual contrast agents of magnetic resonance imaging (MRI). Their longitudinal relaxivity at 4.7 T (r₁ = 8.3 mM^?1 s^?1) is larger than that of clinically used T₁‐positive agent Gd‐DTPA (r₁ = 4.8 mM^?1 s^?1), and three times that of commercial contrast agent SHU‐555C (r₁ = 2.9 mM^?1 s^?1). The transversal relaxivity (r₂ = 35.1 mM^?1 s^?1) is six times that of Gd‐DTPA (r₂ = 5.3 mM^?1 s^?1), half of SHU‐555C (r₂ = 69 mM^?1 s^?1). The in vivo results show that the liver signal from T₁‐weighted MRI is positively enhanced 26%, and then negatively decreased 20% after injection of the iron oxide nanoparticles, which is stronger than those obtained from Gd‐DTPA (<10%) using the same dosage. The kidney signal is positively enhanced up to 35%, similar to that obtained from Gd‐DTPA. Under T₂‐weighted conditions, the liver signal is negatively enhanced ?70%, which is significantly higher than that from Gd‐DTPA (?6%). These results demonstrate the great potential of the UMIONs in dual contrast agents, especially as an alternative to Gd‐based positive contrast agents, which have risks of inducing side effects in patients.     

Gadolinium‐Doped Persistent Nanophosphors as Versatile Tool for Multimodal In Vivo Imaging

Recent breakthroughs in the rational development of multifunctional nanocarriers have highlightened the advantage of combining the complementary forces of several imaging modalities into one single nanotool fully dedicated to the biomedical field and diagnosis applications. A novel multimodal optical‐magnetic resonance imaging nanoprobe is introduced. Designed on the basis of a spinel zinc gallate structure doped with trivalent chromium and gadolinium, this nanocrystal bears the ability to serve as both a highly sensitive persistent luminescence nanoprobe for optical imaging, and a negative contrast agent for highly resolved magnetic resonance imaging (MRI). Additional proof is given that surface coverage can be modified in order to obtain stealth nanoparticles highly suitable for real‐time in vivo application in mice, showing delayed reticulo‐endothelial uptake and longer circulation time after systemic injection.     

Conjugated Polymer Based Nanoparticles as Dual‐Modal Probes for Targeted In Vivo Fluorescence and Magnetic Resonance Imaging

A facile strategy is developed to synthesize dual‐modal fluorescent‐magnetic nanoparticles (NPs) with surface folic acid by co‐encapsulation of a far‐red/near‐infrared (FR/NIR)‐emissive conjugated polymer (PFVBT) and lipid‐coated iron oxides (IOs) into a mixture of poly(lactic‐co‐glycolic‐acid)‐poly(ethylene glycol)‐folate (PLGA‐PEG‐FOL) and PLGA. The obtained NPs exhibit superparamagnetic properties and high fluorescence, which indicates that the lipid coated on IOs is effective at separating the conjugated polymer from IOs to minimize fluorescence quenching. These NPs are spherical in shape with an average diameter of ≈180 nm in water, as determined by laser light scattering. In vitro studies reveal that these dual‐modal NPs can serve as an effective fluorescent probe to achieve targeted imaging of MCF‐7 breast cancer cells without obvious cytotoxicity. In vivo fluorescence and magnetic resonance imaging results suggest that the NPs are able to preferentially accumulate in tumor tissues to allow dual‐modal detection of tumors in a living body. This demonstrates the potential of conjugated polymer based dual‐modal nanoprobes for versatile in vitro and in vivo applications in future.     

Silica‐Coated Manganese Oxide Nanoparticles as a Platform for Targeted Magnetic Resonance and Fluorescence Imaging of Cancer Cells

Monodisperse silica‐coated manganese oxide nanoparticles (NPs) with a diameter of ～35 nm are synthesized and are aminated through silanization. The amine‐functionalized core–shell NPs enable the covalent conjugation of a fluorescent dye, Rhodamine B isothiocyanate (RBITC), and folate (FA) onto their surface. The formed Mn₃O₄@SiO₂(RBITC)–FA core–shell nanocomposites are water‐dispersible, stable, and biocompatible when the Mn concentration is below 50 µg mL^?1 as confirmed by a cytotoxicity assay. Relaxivity measurements show that the core–shell NPs have a T₁ relaxivity (r₁) of 0.50 mM ^?1 s^?1 on the 0.5 T scanner and 0.47 mM ^?1 s^?1 on the 3.0 T scanner, suggesting the possibility of using the particles as a T₁ contrast agent. Combined flow cytometry, confocal microscopy, and magnetic resonance imaging studies show that the Mn₃O₄@SiO₂(RBITC)–FA nanocomposites can specifically target cancer cells overexpressing FA receptors (FARs). Findings from this study suggest that the silica‐coated Mn₃O₄ core–shell NPs could be used as a platform for bimodal imaging (both magnetic resonance and fluorescence) in various biological systems.     

Superoleophilic Magnetic Iron Oxide Nanoparticles for Effective Hydrocarbon Removal from Water

Various hydrocarbons are efficiently extracted from water by using a new sorbent material based on covalently functionalized magnetic nanoparticles. The functionalization of the magnetite nanoparticles with a self‐assembled monolayer of hexadecylphosphonic acid renders the nanoparticles oleophilic and the magnetic nature of magnetite allows for simple extraction of the hydrocarbon‐soaked sorbent. The sorbent material is capable of extracting single contaminants such as alkanes and aromatics and complex hydrocarbon mixtures such as crude oils in high extraction rates of up to 14 times the sorbent volume. Experimental results are explained by molecular dynamics simulations on the adsorption of single components from a hydrocarbon‐water mixture to the alkylphosphonic acid layer on the nanoparticles. The core–shell sorbent material is highly stable and therefore, reusable over several successive extraction cycles without degradation. The extraction performance is determined at different water temperatures, different water sources, and different magnetic core materials and evaluated compared to heptadecanoic acid functionalized magnetite. The new sorbent material provides the opportunity for an efficient, reliable, inexpensive, and environmental friendly removal of hydrocarbons from water.     

Nitrogen‐Doped Carbon Quantum Dot Stabilized Magnetic Iron Oxide Nanoprobe for Fluorescence,Magnetic Resonance,and Computed Tomography Triple‐Modal In Vivo Bioimaging

Multimodal imaging, which combines complementary information of two or more imaging modalities, offers huge advantages. In this paper, the synthesis, characterization, and application of superparamagnetic nitrogen‐doped carbon‐iron oxide hybrid quantum dots (C‐Fe₃O₄ QDs) is reported for triple‐modal bioimaging through fluorescence/magnetic resonance/computed tomography (FL/MR/CT). Especially, C‐Fe₃O₄ QDs are synthesized by using poly (γ‐glutamic acid) as a precursor and stabilizer via a green and facile one‐pot hydrothermal approach. The as‐prepared C‐Fe₃O₄ QDs exhibit excellent water dispersibility, wavelength‐tunable FL property with high quantum yield of about 21.6%, good photostability, strong superparamagnetic property as well as favorable biocompatibility. Meanwhile, these C‐Fe₃O₄ QDs also show a transverse relaxivity value (r ₂) of 154.10 mm ^?1 s^?1 for T₂‐weighted MR imaging mode and an observable X‐ray attenuation effect for CT imaging mode. Moreover, the in vivo bioimaging of tumor‐bearing nude mice by combining FL, MR, and CT images further demonstrates that the as‐prepared C‐Fe₃O₄ QDs can be readily and efficiently used in FL/MR/CT triple‐modal tumor imaging. Hence, the new and facile one‐pot synthesis strategy for preparing multifunctional C‐Fe₃O₄ QDs nanoprobes provides a convenient way for achieving an effective and versatile agent for tumorous bioimaging/or diagnostics.     

Robust Red Organic Nanoparticles for In Vivo Fluorescence Imaging of Cancer Cell Progression in Xenografted Zebrafish

Bright and red‐emissive organic nanoparticles (NPs) are demonstrated as promising for in vivo fluorescence imaging. However, most red organic dyes show greatly weakened or quenched emission in the aggregated state. In this work, a robust red fluorophore (t‐BPITBT‐TPE) with strong aggregate‐state photoluminescence and good biocompatibility is presented. The NPs comprised of t‐BPITBT‐TPE aggregates encapsulated within 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol) (DSPE‐mPEG) micelles exhibit a photoluminescence peak at 660 nm with a high fluorescence quantum yield of 32% in aqueous media. The NPs can be facilely charged by using the same polymeric matrix with different terminal groups, e.g., methoxy (DSPE‐mPEG), amine (DSPE‐PEG‐NH₂), or carboxymethyl (DSPE‐PEG‐COOH) groups. The biocompatibility, toxicity, circulation, and biodistribution of the NPs are assessed using the zebrafish model through whole embryo soaking and intravenous delivery. Furthermore, HeLa and MCF‐7 cells tagged with t‐BPITBT‐TPE in DSPE‐PEG‐NH₂‐TAT polymer NPs are xenografted into zebrafish larvae to successfully track the cancer cell proliferation and metastasis, demonstrating that these new NPs are efficient cancer cell trackers. In addition, the NPs also show good in vivo imaging ability toward 4T1 tumors in xenografted BALB/c mice.     

Accelerated Iron Oxide Nanoparticle Degradation Mediated by Polyester Encapsulation within Cellular Spheroids

Nanomaterials including gold nanoparticles, polymeric nanoparticles, and magnetic iron oxide nanoparticles are utilized in tissue engineering for imaging, drug delivery, and maturation. Prolonged presence of these nanomaterials within biological systems remains a concern due to potential adverse affects on cell viability and phenotype. Accelerating nanomaterial degradation within biological systems is expected to reduce the potential adverse effects in the tissue. Similar to biodegradable polymeric scaffolds, the ideal nanomaterial remains stable for sufficient time to accomplish its desired task, and then rapidly degrades once that task is completed. Here, surface modifications are reported to accelerate iron oxide MNP degradation mediated by polymer encapsulation, in which iodegradable coatings composed of FDA approved polymers with different degradation rates are used: poly(lactide) (PLA) or copolymer poly(lactide‐co‐glycolide) (PLGA). Results demonstrate that degradation of MNPs can be controlled by varying the content and composition of the polymeric nanoparticles used for MNP encapsulation (PolyMNPs). Incorporated into cellular spheroids, PolyMNPs maintain a high viability compared to non‐coated MNPs, and are also useful in magnetically patterning cellular spheroids into fused tissues for tissue engineering applications. Accelerated degradation compared to non‐coated MNPs makes PolyMNPs a viable alternative for removing nanomaterials from tissues after accomplishing their desired role.     

PEGylated Polypyrrole Nanoparticles Conjugating Gadolinium Chelates for Dual‐Modal MRI/Photoacoustic Imaging Guided Photothermal Therapy of Cancer

Polypyrrole nanoparticles conjugating gadolinium chelates were successfully fabricated for dual‐modal magnetic resonance imaging (MRI) and photoacoustic imaging guided photothermal therapy of cancer, from a mixture of pyrrole and pyrrole‐1‐propanoic acid through a facile one‐step aqueous dispersion polymerization, followed by covalent attachment of gadolinium chelate, using polyethylene glycol as a linker. The obtained PEGylated poly­pyrrole nanoparticles conjugating gadolinium chelates (Gd‐PEG‐PPy NPs), sized around around 70 nm, exhibited a high T₁ relaxivity coefficient of 10.61 L mm ^?1 s^?1, more than twice as high as that of the relating free Gd³⁺ complex (4.2 L mm ^–1 s^?1). After 24 h intravenous injection of Gd‐PEG‐PPy NPs, the tumor sites exhibited obvious enhancement in both T₁‐weighted MRI intensity and photoacoustic signal compared with that before injection, indicating the efficient accumulation of Gd‐PEG‐PPy NPs due to the introduction of the PEG layer onto the particle surface. In addition, tumor growth could be effectively inhibited after treatment with Gd‐PEG‐PPy NPs in combination with near‐infrared laser irradiation. The passive targeting and high MRI/photo­acoustic contrast capability of Gd‐PEG‐PPy NPs are quite favorable for precise cancer diagnosing and locating the tumor site to guide the external laser irradiation for photothermal ablation of tumors without damaging the surrounding healthy tissues. Therefore, Gd‐PEG‐PPy NPs may assist in better monitoring the therapeutic process, and contribute to developing more effective “personalized medicine,” showing great potential for cancer diagnosis and therapy.     

Enhanced Collective Magnetic Properties Induced by the Controlled Assembly of Iron Oxide Nanoparticles in Chains

1D assemblies of magnetic nanoparticles are of great potential for designing novel nanostructured materials with enhanced collective magnetic properties. In that challenging context, a new assembly strategy is presented to prepare chains of magnetic nanoparticles that are well‐defined in structure and in spatial arrangement. The 1D assembly of iron oxide nanoparticles onto a substrate is controlled using “click” chemistry under an external magnetic field. Co‐aligned single nanoparticle chains separated by regular distances can be obtained by this strategy. The intrinsic high uniaxial anisotropy results in a strong enhancement of magnetic collective properties in comparison to 2D monolayers or isolated nanoparticles. In contrast to the intensively studied bundle chains of nanoparticles, the finely tuned chain structure reported here allows evidencing a first order intrachain dipolar interaction and a second order interchain magnetic coupling. This study offers new insights into the collective magnetic properties of highly anisotropic particulate assemblies which have been investigated by combining superconducting quantum interference device magnetometry, magnetic force microscopy, and ferromagnetic resonance.     

PEGylated Micelle Nanoparticles Encapsulating a Non‐Fluorescent Near‐Infrared Organic Dye as a Safe and Highly‐Effective Photothermal Agent for In Vivo Cancer Therapy

Photothermal therapy (PTT), as a minimally invasive and highly effective cancer treatment approach, has received widespread attention in recent years. Tremendous effort has been devoted to explore various types of photothermal agents with high near‐infrared (NIR) absorbance for PTT cancer treatment. Despite many exciting progresses in the area, effective yet safe photothermal agents with good biocompatibility and biodegradability are still highly desired. In this work, a new organic PTT agent based on polyethylene glycol (PEG) coated micelle nanoparticles encapsulating a heptamethine indocyanine dye IR825 is developed, showing a strong NIR absorption band and a rather low quantum yield, for in vivo photothermal treatment of cancer. It is found that the IR825–PEG nanoparticles show ultra‐high in vivo tumor uptake after intravenous injection, and appear to be an excellent PTT agent for tumor ablation under a low‐power laser irradiation, without rendering any appreciable toxicity to the treated animals. Compared with inorganic nanomaterials and conjugated polymers being explored in PTT, the NIR‐absorbing micelle nanoparticles presented here may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications.     

Biocompatible Nanomotors as Active Diagnostic Imaging Agents for Enhanced Magnetic Resonance Imaging of Tumor Tissues In Vivo

The limited penetration of imaging agents in solid tumor tissue and cells remains a great challenge to achieve ideal visibility in cancer diagnosis. Herein, a near infrared (NIR) light-driven Janus mesoporous silica nanomotor (JMS nanomotor) to promote magnetic resonance (MR) imaging in vivo is developed. The JMS nanomotors are prepared by depositing Au on the half-sphere surface of gadolinium-doped mesoporous silica nanoparticles. Under NIR irradiation, the nanomotors achieve efficient propulsion through thermophoresis in biological media. To prove the ability of nanomotors as active diagnostic imaging agents, both in vitro and in vivo experiments are carried out. In vitro studies confirm that NIR light can actively propel the JMS nanomotors to effectively seek, adhere to, and mechanically perforate the tumor cells to enhance the cellular uptake and MR imaging. To move a step further, in vivo investigations show that the JMS nanomotors also exhibit improved accumulation and deep penetration in the solid tumor model when exposed to NIR laser, where the MR imaging contrast is significantly enhanced in the majority of tumor tissue. Such JMS nanomotors provide new insight in precise cancer diagnosis and meanwhile MR imaging offers a new tool for real-time tracking of nanomotors in vivo.     

Triggering Mechanism for DNA Electrical Conductivity: Reversible Electron Transfer between DNA and Iron Oxide Nanoparticles

A new category of iron oxide nanoparticles (surface active maghemite nanoparticles (SAMNs, γ‐Fe₂O₃)) allows the intimate chemical and electrical contact with DNA by direct covalent binding. On these basis, different DNA‐nanoparticle architectures are developed and used as platform for studying electrical properties of DNA. The macroscopic 3D nanobioconjugate, constituted of 5% SAMNs, 70% water, and 25% DNA, shows high stability, electrochemical reversibility and, moreover, electrical conductivity (70–80 Ω cm^?1). Reversible electron transfer at the interface between nanoparticles and DNA is unequivocally demonstrated by Mössbauer spectroscopy, which shows the appearance of Fe(II) atoms on nanoparticles following nanobioconjugate formation. This represents the first example of permanent electron exchange by DNA, as well as, of DNA conductivity at a macroscopic scale. Finally, the most probable configuration of the binding is tentatively modeled by density functional theory (DFT/UBP86/6‐31+G*), showing the occurrence of electron transfer from the organic orbitals of DNA to surface exposed Fe(III) on nanoparticles, as well as the generation of defects (holes) on the DNA bases. The unequivocal demonstration of DNA conduction provides a new perspective in the five decades long debate about electrical properties of this biopolymer, further suggesting novel approaches for DNA exploitation in nanoelectronics.     

Novel Redox‐Responsive Polymeric Magnetosomes with Tunable Magnetic Resonance Property for In Vivo Drug Release Visualization and Dual‐Modal Cancer Therapy

Monitoring of in vivo drug release from nanotheranostics by noninvasive approaches remains very challenging. Herein, novel redox‐responsive polymeric magnetosomes (PolyMags) with tunable magnetic resonance imaging (MRI) properties are reported for in vivo drug release monitoring and effective dual‐modal cancer therapy. The encapsulation of doxorubicin (DOX) significantly decreases PolyMags' T₂‐contrast enhancement and transverse relaxation rate R₂, depending on the drug loading level. The T₂ enhancement and R₂ can be recovered once the drug is released upon PolyMags' disassembly. T₂‐ and T₂*‐MRI and diffusion‐weighted imaging (DWI) are utilized to quantitatively study the correlation between MRI signal changes and drug release, and discover the MR tuning mechanisms. The in vivo drug release pattern is visualized based on such tunable MRI capability via monitoring the changes in T₂‐weighted images, T₂ and T₂* maps, and R₂ and R₂* values. Interestingly, the PolyMags possess excellent photothermal effect, which can be further enhanced upon DOX loading. The PolyMags are highly efficacious to treat breast tumors on xenograft model with tumor‐targeted photothermal‐ and chemotherapy, achieving a complete cure rate of 66.7%. The concept reported here is generally applicable to other micellar and liposomal systems for image‐guided drug delivery and release applications toward precision cancer therapy.     

In Vivo Photoacoustic Imaging of Livers Using Biodegradable Hyaluronic Acid‐Conjugated Silica Nanoparticles

The diagnosis of liver diseases is generally carried out via ultrasound imaging, computed tomography, and magnetic resonance imaging. The emerging photoacoustic imaging is an attractive alternative to diagnose even early stage of liver diseases providing high‐resolution anatomical and functional information in deep tissue noninvasively. However, the liver has insufficient photoacoustic contrast due to low optical absorbance in the near‐infrared windows. Here, a new hyaluronate–silica nanoparticle (HA–SiNP) conjugate for liver‐specific delivery and imaging for the diagnosis of liver diseases is developed. The HA–SiNP conjugates show high liver‐specific targeting efficiency, strong optical absorbance near‐infrared windows, excellent biocompatibility, and biodegradability. The liver‐specific targeting efficiency is verified by in vitro cellular uptake test, and in vivo and ex vivo photoacoustic imaging. In vivo photoacoustic imaging shows that photoacoustic amplitude in the liver injected with HA–SiNP conjugates is 4.4 times higher than that of the liver injected with SiNP. The biocompatibility and biodegradability of HA–SiNP conjugates are verified by cell viability test, optical spectrum analysis of urine, and inductively coupled plasma‐mass spectroscopy (ICP‐MS) analysis. Taken together, HA–SiNP conjugates may be developed as a promising liver targeted photoacoustic imaging contrast agent and liver‐targeted drug delivery agent.     

A Hybrid Silica Nanoreactor Framework for Encapsulation of Hollow Manganese Oxide Nanoparticles of Superior T1 Magnetic Resonance Relaxivity

A new hybrid nanoreactor framework with poly(ethylene oxide)‐perforated silica walls is designed to encapsulate hollow manganese oxide nanoparticles (MONs) of high distinctness and homogeneity. Achieved by an interfacial templating scheme, the nanoreactor ensures that acidic etching of MONs by an acetate buffer solution is highly controlled for precise control of the hollow interior. As such, hollow MONs with different nanostructures are developed successfully through a facile acetate buffer solution etching. The resultant hollow MONs are integrated within the hybrid nanoreactor and demonstrate superior r₁ relativity of up to 2.58 mm ^?1 s^?1 for T₁ magnetic resonance imaging (MRI). By modifying the nanoreactor architecture, it is also demonstrated that the efficacy of MONs as T₁ MRI contrast agents can be significantly improved if an optimal cluster of hollow MONs is encapsulated into the hybrid silica framework. The evolution of core morphology with time is studied to elucidate the etching mechanism. It is revealed that the hollow formation arises due to the surface stabilization of MONs by acetate ions and the subsequent acidic etching of the interior core in a sporadic manner. This is different from the commonly reported nanoscale Kirkendall effect or the selective etching of the core–shell MnO/Mn₃O₄ structure.