Breaking the pH Limitation of Nanozymes: Mechanisms, Methods, and Applications.

Although nanozymes have drawn great attention over the past decade, the activities of peroxidase-like, oxidase-like, and catalase-like nanozymes are often pH dependent with elusive mechanism, which largely restricts their application. Therefore, a systematical discussion on the pH-related catalytic mechanisms of nanozymes together with the methods to overcome this limitation is in need. In this review, various nanozymes exhibiting pH-dependent catalytic activities are collected and the root causes for their pH dependence are comprehensively analyzed. Subsequently, regulatory concepts including catalytic environment reconstruction and direct catalytic activity improvement to break this pH restriction are summarized. Moreover, applications of pH-independent nanozymes in sensing, disease therapy, and pollutant degradation are overviewed. Finally, current challenges and future opportunities on the development of pH-independent nanozymes are suggested. It is anticipated that this review will promote the further design of pH-independent nanozymes and broaden their application range with higher efficiency.

Camouflaged Nanoreactors Mediated Radiotherapy-Adjuvant Chemodynamic Synergistic Therapy.

Chemodynamic therapy based on the Fenton-like catalysis ability of Fe3O4 has the advantages of no involvement of chemical drugs and minimal adverse effects as well as the limitation of depletable efficacy. Radiotherapy based on high-energy radiation offers the convenience of treatment and cost-effectiveness but lacks precision and cellular adaptation of tumor cells. Approaching such dilemmas from a nanoscale materials perspective, we aim to bridge the weaknesses of both treatment methods by combining the principles of two therapeutics reciprocally. We have designed a camouflaged Fe3O4@HfO2 composite nanoreactor (FHCM), which combines a chemodynamic therapeutic agent Fe3O4 and a radiosensitizer HfO2 that both has passed clinical trials and was inspired by a cell membrane biomimetic technique. FHCM is employed as conceived radiotherapy-adjuvant chemodynamic synergistic therapy of malignant tumors, which has undergone dual scrutiny from both the physical and biological aspects. Experimental results obtained at different levels, including theory, material characterizations, and in vitro and in vivo verifications, suggest that FHCM effectively impaired tumor cells through physical and molecular biological mechanisms involving a HfO2-Fe3O4 photoelectron-electron transfer chain and DNA damage-ferroptosis-immunity chain. It is worth noting that compared to single therapies such as only chemodynamic therapy or radiotherapy, FHCM-mediated radiotherapy-adjuvant chemodynamic synergistic therapy exhibits stronger tumor inhibition efficacy. It significantly addresses the inherent limitations of chemodynamic therapy and radiotherapy and underscores the feasibility and importance of using existing clinical weapons, such as radiotherapy, as auxiliary strategies to overcome certain flaws of emerging antitumor therapeutics like chemodynamic therapy.

Modulation of blood-brain tumor barrier for delivery of magnetic hyperthermia to brain cancer.

Glioblastoma (GBM) is the most invasive brain tumor and remains lack of effective treatment. The existence of blood-brain tumor barrier (BBTB) constitutes the greatest barrier to non-invasive delivery of therapeutic agents to tumors in the brain. Here, we propose a novel approach to specifically modulate BBTB and deliver magnetic hyperthermia in a systemic delivery mode for the treatment of GBM. BBTB modulation is achieved by targeted delivering fingolimod to brain tumor region via dual redox responsive PCL-SeSe-PEG (poly (ε-caprolactone)-diselenium-poly (ethylene glycol)) polymeric nanocarrier. As an antagonist of sphingosine 1-phosphate receptor-1 (S1P1), fingolimod potently inhibits the barrier function of BBB by blocking the binding of sphingosine 1-phosphate (S1P) to S1P1 in endothelial cells. We found that the modulated BBTB showed slight expression level of tight junction proteins, allowing efficient accumulation of zinc- and cobalt- doped iron oxide nanoclusters (ZnCoFe NCs) with enhanced magnetothermal conversion efficiency into tumor tissues through the paracellular pathway. As a result, the co-delivery of heat shock protein 70 inhibitor VER-155008 with ZnCoFe NCs could realize synergistic magnetic hyperthermia effects upon exposure to an alternating current magnetic field (ACMF) in both GL261 and U87 brain tumor models. This modulation approach brings new ideas for the treatment of central nervous system diseases that require delivery of therapeutic agents across the blood-brain barrier (BBB).

Targeted Delivery of Chemo-Sonodynamic Therapy via Brain Targeting, Glutathione-Consumable Polymeric Nanoparticles for Effective Brain Cancer Treatment.

Glioblastoma (GBM) is the most aggressive tumor of the central nervous system and remains universally lethal due to lack of effective treatment options and their inefficient delivery to the brain. Here the development of multifunctional polymeric nanoparticles (NPs) for effective treatment of GBM is reported. The NPs are synthesized using a novel glutathione (GSH)-reactive poly (2,2″-thiodiethylene 3,3″-dithiodipropionate) (PTD) polymer and engineered for brain penetration through neutrophil elastase-triggered shrinkability, iRGD-mediated targeted delivery, and lexiscan-induced autocatalysis. It is found that the resulting lexiscan-loaded, iRGD-conjugated, shrinkable PTD NPs, or LiPTD NPs, efficiently penetrate brain tumors with high specificity after intravenous administration. Furthermore, it is demonstrated that LiPTD NPs are capable of efficient encapsulation and delivery of chemotherapy doxorubicin and sonosensitizer chlorin e6 to achieve combined chemotherapy and sonodynamic therapy (SDT). It is demonstrated that the capability of GSH depletion of LiPTD NPs further augments the tumor cell killing effect triggered by SDT. As a result, treatment with LiPTD NPs effectively inhibits tumor growth and prolongs the survival of tumor-bearing mice. This study may suggest a potential new approach for effective GBM treatment.

Brain Targeting, Antioxidant Polymeric Nanoparticles for Stroke Drug Delivery and Therapy.

Ischemic stroke is a leading cause of death and disability and remains without effective treatment options. Improved treatment of stroke requires efficient delivery of multimodal therapy to ischemic brain tissue with high specificity. Here, this article reports the development of multifunctional polymeric nanoparticles (NPs) for both stroke treatment and drug delivery. The NPs are synthesized using an reactive oxygen species (ROS)-reactive poly (2,2'-thiodiethylene 3,3'-thiodipropionate) (PTT) polymer and engineered for brain penetration through both thrombin-triggered shrinkability and AMD3100-mediated targeted delivery. It is found that the resulting AMD3100-conjugated, shrinkable PTT NPs, or ASPTT NPs, efficiently accumulate in the ischemic brain tissue after intravenous administration and function as antioxidant agents for effective stroke treatment. This work shows ASPTT NPs are capable of efficient encapsulation and delivery of glyburide to achieve anti-edema and antioxidant combination therapy, resulting in therapeutic benefits significantly greater than those by either the NPs or glyburide alone. Due to their high efficiency in brain penetration and excellent antioxidant bioactivity, ASPTT NPs have the potential to be utilized to deliver various therapeutic agents to the brain for effective stroke treatment.

Targeted disruption of tumor vasculature via polyphenol nanoparticles to improve brain cancer treatment.

Despite being effective for many other solid tumors, traditional anti-angiogenic therapy has been shown to be insufficient for the treatment of malignant glioma. Here, we report the development of polyphenol nanoparticles (NPs), which not only inhibit the formation of new vessels but also enable targeted disruption of the existing tumor vasculature. The NPs are synthesized through a combinatory iron-coordination and polymer-stabilization approach, which allows for high drug loading and intrinsic tumor vessel targeting. We study a lead NP consisting of quercetin and find that the NP after intravenous administration preferentially binds to VEGFR2, which is overexpressed in tumor vasculature. We demonstrate that the binding is mediated by quercetin, and the interaction of NPs with VEGFR2 leads to disruption of the existing tumor vasculature and inhibition of new vessel development. As a result, systemic treatment with the NPs effectively inhibits tumor growth and increases drug delivery to tumors.

Vessel-Targeting Nanoclovers Enable Noninvasive Delivery of Magnetic Hyperthermia-Chemotherapy Combination for Brain Cancer Treatment.

Despite being promising, the clinical application of magnetic hyperthermia for brain cancer treatment is limited by the requirement of highly invasive intracranial injections. To overcome this limitation, here we report the development of gallic acid-coated magnetic nanoclovers (GA-MNCs), which allow not only for noninvasive delivery of magnetic hyperthermia but also for targeted delivery of systemic chemotherapy to brain tumors. GA-MNCs are composed of clover-shaped MNCs in the core, which can induce magnetic heat in high efficiency, and polymerized GA on the shell, which enables tumor vessel-targeting. We demonstrate that intravenous administration of GA-MNCs following alternating magnetic field exposure effectively inhibited brain cancer development and preferentially disrupted tumor vasculature, making it possible to efficiently deliver systemic chemotherapy for further improved efficacy. Due to the noninvasive nature and high efficiency in killing tumor cells and enhancing systemic drug delivery, GA-MNCs have the potential to be translated for improved treatment of brain cancer.

Targeted NIRF/MR dual-mode imaging of breast cancer brain metastasis using BRBP1-functionalized ultra-small iron oxide nanoparticles.

Tumor metastasis to brain is the main clinical manifestation of patients with advanced breast cancer, leading to poor survival prognosis. In order to detect the early incidence of brain metastasis, it is urgent to develop hypersensitive contrast agents for multimode imaging. In this study, PEG-phospholipids coated, a phage play derived peptide, BRBP1 peptide modified ultra-small iron oxide nanoparticles were prepared for targeted NIRF and MR imaging of breast cancer brain metastasis. The nanoparticles showed 10 nm core-shell, high relaxivity values and photon emission efficiency in vitro. The nanoparticles offered a T2 contrast imaging effect and near-infrared fluorescent signal enhancement. Compared with control peptide modified nanoparticles, the MR/NIRF imaging signal of BRBP1-modified nanoparticles in tumor tissue was significantly enhanced, which should be induced by the targeting ability of BRBP1 peptide. These results indicated that BRBP1-SPIO@mPEG (DiR) nanoparticles could be applied as an effective targeted delivery system for diagnosis of breast cancer brain metastasis.

Copresentation of Tumor Antigens and Costimulatory Molecules via Biomimetic Nanoparticles for Effective Cancer Immunotherapy.

Nanoparticle (NP)-based cancer immunotherapy has been extensively explored. However, the efficacy of existing strategies is often limited by the lack of effective tumor-specific antigens or the inability to present costimulatory signal or both. Here, we report a novel approach to overcoming these limitations through surface coating with dendritic-tumor fusion cell membranes, which present whole repertories of tumor-associated antigens in the presence of costimulatory molecules. Because antigen-presenting and costimulatory molecules are displayed on their surface, these NPs can efficiently penetrate immune organs and activate T cells. We show that these NPs can be utilized to prevent tumor development and regress established tumors, including tumors in the brain. We demonstrate that encapsulation of immune adjuvants further improves their efficacy. Due to their significant efficacy, the whole tumor antigen-presenting costimulatory NPs have the potential to be translated into clinical applications for treatment of various cancers.

Rituximab conjugated iron oxide nanoparticles for targeted imaging and enhanced treatment against CD20-positive lymphoma.

Since its launch in 1997, rituximab (RTX) has extensively improved the treatment of CD20-positive follicular and diffuse large B cell non-Hodgkin lymphoma (NHL). The application of RTX is limited usually by the failed therapy because of resistance. Iron oxide nanomaterials have been explored for cancer detection and treatment in recent years. In this study, a multivalent nanoprobe comprising one Fe3O4 nanoparticle and several RTX antibodies was constructed for the targeted imaging and enhanced treatment of NHL. Poly(ethylene glycol) (PEG)-coated Fe3O4 nanoparticles were fabricated via a thermal decomposition method and ligand exchange. RTX was conjugated onto the surface of the Fe3O4-PEG nanoparticles to form Fe3O4-PEG-nAb (n = 2, 5 or 8) multivalent nanoprobes. These multivalent nanoprobes, with a core size of approximately 11 nm and a hydrodynamic diameter of about 22 nm, showed colloidal stability in buffer solution. The r2 relaxation rate of Fe3O4-PEG-nAb was similar to that of Fe3O4-PEG (309 ± 3.08 mM-1 s-1). The specificity of nanoprobes for CD20-positive Raji cells was assessed on a clinical magnetic resonance imaging scanner. The receptor binding site of one multivalent nanoprobe was more than that of one RTX, exhibiting valence-dependent induction of Raji cell apoptosis, and this effect could be enhanced by complement activation from blood serum added. A similar activity was observed in vivo in a NHL xenograft model. The multivalent nanoprobe treatment significantly reduced tumor burden and enhanced survival in comparison to the RTX group. Our studies demonstrate that the appropriate design and preparation of anticancer antibody-nanoparticle conjugates enable the generation of improved anticancer nanomedicines and could thus provide an efficient cancer theranostic strategy.

Enhanced Tumor Synergistic Therapy by Injectable Magnetic Hydrogel Mediated Generation of Hyperthermia and Highly Toxic Reactive Oxygen Species.

Nanoparticle-mediated tumor magnetic induction hyperthermia has received tremendous attention. However, it has been a challenge to improve the efficacy at 42 °C therapeutic temperatures without resistance to induced thermal stress. Therefore, we designed a magnetic hydrogel nanozyme (MHZ) utilizing inclusion complexation between PEGylated nanoparticles and α-cyclodextrin, which can enhance tumor oxidative stress levels by generating reactive oxygen species through nanozyme-catalyzed reactions based on tumor magnetic hyperthermia. MHZ can be injected and diffused into the tumor tissue due to shear thinning as well as magnetocaloric phase transition properties, and magnetic heat generated by the Fe3O4 first gives 42 °C of hyperthermia to the tumor. Fe3O4 nanozyme exerts peroxidase-like properties in the acidic environment of tumor to generate hydroxyl radicals (•OH) by the Fenton reaction. The hyperthermia promotes the enzymatic activity of Fe3O4 nanozyme to produce more •OH. Simultaneously, •OH further damages the protective heat shock protein 70, which is highly expressed in hyperthermia to enhance the therapeutic effect of hyperthermia. This single magnetic nanoparticle exerts dual functions of hyperthermia and catalytic therapy to synergistically treat tumors, overcoming the resistance of tumor cells to induced thermal stress without causing severe side effects to normal tissues at 42 °C hyperthermia.

Magnetic targeting combined with active targeting of dual-ligand iron oxide nanoprobes to promote the penetration depth in tumors for effective magnetic resonance imaging and hyperthermia.

The combination of multi-targeting magnetic nanoprobes and multi-targeting strategies has potential to facilitate magnetic resonance imaging (MRI) and magnetic induction hyperthermia of the tumor. Although the thermo-agents based on magnetic iron oxide nanoparticles (MION) have been successfully used in the form of intratumoral injection in clinical cure of glioblastoma, the tumor-targeted thermotherapy by intravenous administration remains challenging. Herein, we constructed a c(RGDyK)- and d-glucosamine-grafted bispecific molecular nanoprobe (Fe3O4@RGD@GLU) with a magnetic iron oxide core of size 22.17 nm and a biocompatible shell of DSPE-PEG2000, which can specially target the tumor vessel and cancer cells. The selection of c(RGDyK) could make the nanoprobe enter the neovascularization endotheliocyte through αvß3-mediated endocytosis, which drastically reduced the dependence on the enhanced permeability and retention (EPR) effect in tumor. This dual-ligand nanoprobe exhibited strong magnetic properties and favorable biocompatibility. In vitro studies confirmed the anti-phagocytosis ability against macrophages and the specific targeting capability of Fe3O4@RGD@GLU. Then, the imaging effect and anti-tumor efficacy were compared using different targeting strategies with untargeted nanoprobes, dual-targeted nanoprobes, and magnetic targeting combined with dual-targeted nanoprobes. Moreover, the combination strategy of magnetic targeting and active targeting promoted the penetration depth of nanoprobes in addition to the increased accumulation in tumor tissue. Thus, the dual-targeted magnetic nanoprobe together with the combined targeting strategy could be a promising method in tumor imaging and hyperthermia through in vivo delivery of theranostic agents. STATEMENT OF SIGNIFICANCE: Magnetic induction hyperthermia based on iron oxide nanoparticles has been used in clinic for adjuvant treatment of recurrent glioblastoma. Nonetheless, this application is limited to intratumoral injection, and tumor-targeted hyperthermia by intravenous injection remains challenging. In this study, we developed a multi-targeted strategy by combining magnetic targeting with active targeting of dual-ligand magnetic nanoprobes. This combination mode acquired optimum contrast imaging effect through MRI and tumor-suppressive effect through hyperthermia under an alternating current magnetic field. The design of the nanoprobe was suitable for targeting most tumor lesions, which enabled it to be an effective theranostic agent with extensive uses. This study showed significant enhancement of the penetration depth and accumulation of nanoprobes in the tumor tissue for efficient imaging and hyperthermia.

Apoptosis-promoting effect of rituximab-conjugated magnetic nanoprobes on malignant lymphoma cells with CD20 overexpression.

BACKGROUND: Cancer targeting nanoprobes with precisely designed physicochemical properties may show enhanced pharmacological targeting and therapeutic efficacy. As a widely used commercialized antibody, rituximab has been in clinical use for three decades and has lengthened or even saved thousands of lives. However, many people cannot benefit from rituximab treatment because of drug resistance or side effects. METHODS: In this study, a 13-nm rituximab-conjugated magnetic nanoparticle was developed as a therapeutic nanoprobe targeting CD20 overexpressing malignant lymphoma cells to enhance the treatment effects of rituximab. The magnetic cores (2,3-dimercaptosuccinicacid modified Fe3O4 nanoparticles, Fe3O4@DMSA) of the nanoprobes with an average diameter of 6.5 nm were synthesized using a co-precipitation method. Rituximab was then conjugated on the surface of Fe3O4@DMSA using a cross-linking agent (carbodiimide/N-hydroxysulfosuccinimide sodium salt). Based on theoretical calculations, approximately one antibody was coupled with one nanoparticle, excluding the multivalent antibody effect. RESULTS: Cell targeting experiments and magnetic resonance (MR) signal and T2 measurements showed that the Fe3O4@DMSA@Ab nanoprobes have specific binding affinity for CD20-positive cells. Compared to rituximab and Fe3O4@DMSA, Fe3O4@DMSA@Ab nanoprobes significantly reduced cell viability and promoted Raji cell apoptosis. Initiating events of apoptosis, including increased intracellular calcium and reactive oxygen species, were observed in nanoprobe-treated Raji cells. Nanoprobe-treated Raji cells also showed the most drastic decrease in mitochondrial membrane potential and Bcl-2 expression, compared to rituximab and Fe3O4@DMSA-treated Raji cells. CONCLUSION: These results indicate that Fe3O4@DMSA@Ab nanoprobes have the potential to serve as MRI tracers and therapeutic agents for CD20-positive cells.

Polyethyleneimine-coated Iron Oxide Nanoparticles as a Vehicle for the Delivery of Small Interfering RNA to Macrophages In Vitro and In Vivo.

Because of their critical role in regulating immune responses, macrophages have continuously been the subject of intensive research and represent a promising therapeutic target in many disorders, such as autoimmune diseases, atherosclerosis, and cancer. RNAi-mediated gene silencing is a valuable approach of choice to probe and manipulate macrophage function; however, the transfection of macrophages with siRNA is often considered to be technically challenging, and, at present, few methodologies dedicated to the siRNA transfer to macrophages are available. Here, we present a protocol of using polyethyleneimine-coated superparamagnetic iron oxide nanoparticles (PEI-SPIONs) as a vehicle for the targeted delivery of siRNA to macrophages. PEI-SPIONs are capable of binding and completely condensing siRNA when the Fe:siRNA weight ratio reaches 4 and above. In vitro, these nanoparticles can efficiently deliver siRNA into primary macrophages, as well as into the macrophage-like RAW 264.7 cell line, without compromising cell viability at the optimal dose for transfection, and, ultimately, they induce siRNA-mediated target gene silencing. Apart from being used for in vitro siRNA transfection, PEI-SPIONs are also a promising tool for delivering siRNA to macrophages in vivo. In view of its combined features of magnetic property and gene-silencing ability, systemically administered PEI-SPION/siRNA particles are expected not only to modulate macrophage function but also to enable macrophages to be imaged and tracked. In essence, PEI-SPIONs represent a simple, safe, and effective nonviral platform for siRNA delivery to macrophages both in vitro and in vivo.

Injectable magnetic supramolecular hydrogel with magnetocaloric liquid-conformal property prevents post-operative recurrence in a breast cancer model.

Locoregional recurrence of breast cancer after tumor resection represents several clinical challenges. Here, we demonstrate that co-delivery of chemotherapy and thermotherapeutic agents by a magnetic supramolecular hydrogel (MSH) following tumor resection prevents tumor recurrence in a breast cancer mouse model. The self-assembled MSH was designed through the partial inclusion complexation associated with the threading of α-CD on the copolymer moieties on the surface of the PEGylated iron oxide (Fe3O4) nanoparticles, which enables shear-thinning injection and controllable thermoreversible gel-sol transition. MSH was injected to the postoperative wound uniformly, which became mobile and perfect match with irregular cavity without blind angle due to the magnetocaloric gel-sol transition when exposed to alternating current magnetic field (ACMF). The magnetic nanoparticle-mediated induction heat during the gel-sol transition process caused the triggered release of dual-encapsulated chemotherapeutic drugs and provided an effect of thermally induced cell damage. The hierarchical structure of the MSH ensured that both hydrophobic and hydrophilic drugs can be loaded and consecutively delivered with different release curves. The hydrogel nanocomposite might provide a potential locally therapeutic approach for the precise treatment of locoregional recurrence of cancer. STATEMENT OF SIGNIFICANCE: Tumor recurrence after resection represents several clinical challenges. In this study, we prepared shear-thinning injectable magnetic supramolecular hydrogel (MSH) and demonstrated their therapeutic applications in preventing the post-operative recurrence of breast cancer with facile synthesis and minimally invasive implantation in vivo. MSH was injected to the postoperative wound uniformly, which become mobile and perfect match with irregular cavity without blind angle through magnetocaloric gel-sol transition when exposed to ACMF. The magnetic nanoparticles mediated induction heat during the gel-sol transition process caused the triggered release of dual-encapsulated chemotherapeutic drugs as well as thermally induced cell damage. This study demonstrates that MSH with the controlled administration of combined thermo-chemotherapy exhibit great superiority in terms of preventing post-operation cancer relapse.

Using PEGylated magnetic nanoparticles to describe the EPR effect in tumor for predicting therapeutic efficacy of micelle drugs.

Micelle drugs based on a polymeric platform offer great advantages over liposomal drugs for tumor treatment. Although nearly all of the nanomedicines approved in the clinical use can passively target to the tumor tissues on the basis of an enhanced permeability and retention (EPR) effect, the nanodrugs have shown heterogenous responses in the patients. This phenomenon may be traced back to the EPR effect of tumor, which is extremely variable in the individuals from extensive studies. Nevertheless, there is a lack of experimental data describing the EPR effect and predicting its impact on therapeutic efficacy of nanoagents. Herein, we developed 32 nm magnetic iron oxide nanoparticles (MION) as a T2-weighted contrast agent to describe the EPR effect of each tumor by in vivo magnetic resonance imaging (MRI). The MION were synthesized by a thermal decomposition method and modified with DSPE-PEG2000 for biological applications. The PEGylated MION (Fe3O4@PEG) exhibited high r2 of 571 mM-1 s-1 and saturation magnetization (Ms) of 94 emu g-1 Fe as well as long stability and favorable biocompatibility through the in vitro studies. The enhancement intensities of the tumor tissue from the MR images were quantitatively measured as TNR (Tumor/Normal tissue signal Ratio) values, which were correlated with the delay of tumor growth after intravenous administration of the PLA-PEG/PTX micelle drug. The results demonstrated that the group with the smallest TNR values (TNR < 0.5) displayed the best tumor inhibitory effect. In addition, there was a superior correlation between TNR value and relative tumor delay in individual mice. These analysis results indicated that the TNR value of the tumor region enhanced by Fe3O4@PEG (d = 32 nm) could be used to predict the therapeutic efficacy of the micelle drugs (d ≤ 32 nm) in a certain period of time. Fe3O4@PEG has a potential to serve as an ideal MRI contrast agent to visualize the EPR effect in patients for accurate medication guidance of micelle drugs in the future treatment of tumors.

Sparks fly between ascorbic acid and iron-based nanozymes: A study on Prussian blue nanoparticles.

Herein we reported Prussian blue nanoparticles (PBNPs) possess ascorbic acid oxidase (AAO)- and ascorbic acid peroxidase (APOD)-like activities, which suppressed the formation of harmful H2O2 and finally inhibited the anti-cancer efficiency of ascorbic acid (AA). This newly revealed correlation between iron and AA could provide new insight for the studies of nanozymes and free radical biology.

Improving sensitivity of magnetic resonance imaging by using a dual-targeted magnetic iron oxide nanoprobe.

Developing an ultrasensitive and high-efficient molecular imaging probe for detection of malignant tumors is extremely needed in clinical and remains a big challenge. Here, we report a novel bispecific nanoprobe for dual-targeted T2-weighed magnetic resonance imaging (MRI) of COLO-205 colorectal cancer in vivo. First, the magnetic iron oxide nanoparticles (Fe3O4@OA) were synthesized by a thermal decomposition method. Then, PEGylation of the hydrophobic Fe3O4@OA was implemented by amphiphilic DSPE-PEG2000-COOH, producing water-soluble nanoparticles (Fe3O4@PEG). Lastly, arginine-glycine-asparticacid-tumornecrosis factor-related apoptosis-inducing ligand (RGD-TRAIL), a bispecific fusion protein, was conjugated with the nanoparticle to construct molecularly multi-targeted nanoprobe, which was defined as Fe3O4@RGD-TRAIL. This Fe3O4@RGD-TRAIL was proven to exhibit extremely high relaxation property (r2=534mM-1s-1) and saturation magnetization value (Ms=92 emu/g Fe). In vitro studies showed its dual-targeting combination capacity, favorable biocompatibility and strong ability to resist against the non-specific phagocytosis. Owing to these excellent advantages, high sensitive and efficient imaging of tumor was achieved in vivo. Therefore, this RGD-TRAIL conjugated nanoprobe could be developed as a multi-targeted contrast enhancement agent for magnetic resonance molecular imaging in detection of cancer.

Injectable thermosensitive magnetic nanoemulsion hydrogel for multimodal-imaging-guided accurate thermoablative cancer therapy.

Ferrofluid-based magnetic hyperthermia of cancers has gained significant attention in recent years due to its excellent efficacy, few deleterious side effects and unlimited tissue penetration capacity. However, the high tumor osmotic pressure causes injection leakage and thus position imprecision because of the fluidity of the ferrofluid and the absence of multimodal imaging guidance, which create tremendous challenges for clinical application. Here, a body temperature-induced gelation strategy is constructed for accurate localized magnetic tumor regression based on the unique behaviors of a magnetic nanoemulsion hydrogel (MNH) within tumors. The rapid intra-tumor gelation can securely restrict the MNH in tumor tissue without diffusion and leakage. The magnetically induced nanoparticle assembly-enhanced heating in the hydrogel and the heat accumulation caused by crosslinking among the nanoemulsion droplets further increased the heating efficiency. Meanwhile, US/MR/NIR multimodal imaging can guide the whole therapeutic process, achieving excellent magnetic hyperthermia therapeutic efficiency. This work highlights the great promise for improving the magnetic hyperthermia efficiency and the precision of the injection site for localized tumor therapy.

Size-Dependent Biodistribution of lodinated Oil Nanoemulsions Observed by Dual-Modal Imaging in Rats.

Sizes of nanoscale contrast agents play an important role in targeting specific organs and distribution in organisms. lodinated oil nanoemulsions with uniform size distribution and containing indocyanine green (ICG) fluorescent dye (25 nm, 60 nm, 100 nm) were synthesized by stirring, combined with ultrasonic emulsification technique. Rats were intravenously injected with the iodinated oil nanoemulsions with different sizes, used as contrast agents, and investigated with enhanced computed tomography (CT) and fluorescence imaging. Through experiments, the distribution and metabolism of the contrast agents in rat's bodies were studied, and their influence on enhanced CT imaging of different organs was compared. The results demonstrated that target accumulating organs for the iodinated oil nanoemulsions were liver and spleen, with obvious dosage-dependence. Large sized nanoemulsion preferred to accumulate into spleen, and liver, and the phagocytosis was getting weaker with the decrease of the nanoemulsion size. The CT imaging of the inferior vena cava was rapidly enhanced and reached the highest point after administration of the nanoemulsion. The nanoemulsion gradually gathered and metabolized in the spleen and liver, resulting in rapidly decreased CT imaging, with weak rebound, of the inferior vena cava.