Tumor-targeted Magnetic Resonance Imaging Research Articles

Cyclodextrin-conjugated low-molecular-weight polyethyleneimine as a macromolecular contrast agent for tumor-targeted magnetic resonance imaging.

Macromolecular contrast agents (CAs) usually possess excellent contrast ability and tumor-targeting ability in comparison with small-molecule CAs, especially for early tumor detection. Herein, cyclodextrin-conjugated low-molecular-weight polyethyleneimine was synthesized as a macromolecular backbone. Afterward, a linear polymer with adamantane terminal and Gd chelates was synthesized, followed by conjugating with the backbone via host-guest interaction. Finally, folic acid was conjugated onto the as-prepared CAs through bioorthogonal chemistry, which endowed the CAs with the capability to accumulate into the tumor region. Compared to Magnevist (r1 = 4.25 mM-1 s-1) used in clinic, the PC/Ad-PEG2000-PLL(DTPA-Gd)-FA exhibited higher longitudinal relaxivity (r1 = 11.62 mM-1 s-1) with excellent biocompatibility. Furthermore, in vivo experiments demonstrated that PC/Ad-PEG2000-PLL(DTPA-Gd)-FA could effectively accumulate in the tumor region and produce a brighter image than that of Magnevist. The H&E staining and metabolic data further illustrated that this CA possessed excellent biocompatibility in vivo. Finally, these results above suggest that this macromolecular CA could be a potential candidate as a MRI CA for tumor-targeted diagnosis.

DNA aptamer functionalized monodisperse Eu/Mn-WH nanoparticle for in vivo magnetic resonance and fluorescence imaging

Because of its biocompatibility, non-immunogenicity, bioactivity, and biodegradability, Whitlockite (WH) plays a crucial role in biomedical fields. However, a layer of oleic acid molecules is attached to the surface of WH synthesized by liquid–solid–solution (LSS) method, which hinders its application in biomedicine field. In this paper, we successfully synthesized hydrophilic nanoparticles with bright red fluorescence and excellent magnetic properties (Eu/Mn-WH-Apt NPs) via the ions doping and ligand exchange strategy. In vitro/vivo experiments show that Eu/Mn-WH-Apt nanoparticles have excellent biocompatibility, dispersion stability, tumor targeting ability, satisfactory fluorescence, and magnetic resonance imaging capabilities. Therefore, the prepared multifunctional Eu/Mn-WH-Apt NPs may provide a new strategy and insights for accurately diagnosing clinical cancer.

Folic acid-decorated vitamin E Poly(ethylene glycol) monoplatinum ester with disulfide bond as theranostic nanoparticle for drug resistant tumor diagnosis and treatment

Vitamin E Poly(ethylene glycol) monoplatinum ester (TPGS) nanoparticles have attracted much attention in recent years for overcome multidrug resistance. Herein, a well-defined folic acid (FA)-conjugated and disulfide bond-linked polymer (FA-SS-TPGS) was synthesized. These polymer nanoparticles were utilized as theranostic agents for tumor-targeted magnetic resonance imaging (MRI) and chemotherapy. By loading doxorubicin (DOX) and superparamagnetic iron oxide (SPIO) particles into TPGS nanoparticles, FA-SS-TPGS@DOX/SPIO nanoparticles are obtained. In vitro drug release studies revealed that under a reducing environment in the presence of glutathione (GSH), approximately 100% of the doxorubicin (DOX) was released from the disulfide bond-linked theranostic nanoparticles within 24 h. DOX and SPIO were efficiently delivered into HepG2-ADM cells due to the folate receptor-mediated endocytosis process of the nanoparticles. Additionally, the presence of glutathione (GSH) triggered the cleaving of the disulfide bonds, further facilitating the delivery of DOX and SPIO into the cells. Furthermore, the FA-SS-TPGS @DOX-SPIO nanoparticles exhibited strong MRI contrast enhancement properties. In conclusion, FA-SS-TPGS@DOX/SPIO are potential nanoparticles for tumor-targeted MRI and chemotherapy, which can also overcome multidrug resistance.

Chiral Iron Oxide Supraparticles Enable Enantiomer-Dependent Tumor-Targeted Magnetic Resonance Imaging.

The chemical, physical and biological effects of chiral nanomaterials have inspired general interest and demonstrated important advantages in fundamental science. Here, chiral iron oxide supraparticles (Fe3 O4 SPs) modified by chiral penicillamine (Pen) molecules with g-factor of ≈2 × 10-3 at 415nm are fabricated, and these SPs act as high-quality magnetic resonance imaging (MRI) contrast agents. Therein, the transverse relaxation efficiency and T2 -MRI results demonstrated chiral Fe3 O4 SPs have a r2 relaxivity of 157.39 ± 2.34 mM-1 ·S-1 for D-Fe3 O4 SPs and 136.21 ± 1.26 mM-1 ·S-1 for L-Fe3 O4 SPs due to enhanced electronic transition dipole moment for D-Fe3 O4 SPs compared with L-Fe3 O4 SPs. The in vivo MRI results show that D-Fe3 O4 SPs exhibit two-fold lower contrast ratio than L-Fe3 O4 SPs, which enhances targeted enrichment in tumor tissue, such as prostate cancer, melanoma and brain glioma tumors. Notably, it is found that D-Fe3 O4 SPs have 7.7-fold higher affinity for the tumor cell surface receptor cluster-of-differentiation 47 (CD47) than L-Fe3 O4 SPs. These findings uncover that chiral Fe3 O4 SPs act as a highly effective MRI contrast agent for targeting and imaging broad tumors, thus accelerating the practical application of chiral nanomaterials and deepening the understanding of chirality in biological and non-biological environments.

Chiral Gd-DOTA as a Versatile Platform for Hepatobiliary and Tumor Targeting MRI Contrast Agents.

The leakage of gadolinium ions (Gd3+) from commercial Gd3+-based contrast agents (GBCAs) in patients is currently the major safety concern in clinical magnetic resonance imaging (MRI) scans, and the lack of task-specific GBCAs limits its usage in the early detection of disease and imaging of specific biological regions. Herein, ultrastable GBCAs were constructed via decorating chiral Gd-DOTA with a phenylic analogue to one of the pendent arms, and the stability constant was determined as high as 27.08, accompanied by negligible decomplexation in 1 M of HCl over 2 years. A hepatic-specific chiral Gd-DOTA was screened out as a potential alternative to commercial Gd-EOB-DTPA, while combination with functional molecules favored chiral Gd-DOTA as tumor targeting probes. Therefore, the novel chiral Gd-DOTA is believed to be an ideal platform for designing the next generation of GBCAs for various clinical purposes due to its outstanding inert nature.

A tumor microenvironment-responsive core-shell tecto dendrimer nanoplatform for magnetic resonance imaging-guided and cuproptosis-promoted chemo-chemodynamic therapy.

Theranostic nanoplatforms for combination tumor therapy have gained lots of attention recently due to the optimized therapeutic efficiency and simultaneous diagnosis performance. Herein, a novel tumor microenvironment (TME)-responsive core-shell tecto dendrimer (CSTD) was assembled by phenylboronic acid- and mannose-modified poly(amidoamine) dendrimers via the phenylboronic ester bonds that are responsive to low pH and reactive oxygen species (ROS), and efficiently loaded with copper ions and chemotherapeutic drug disulfiram (DSF) for tumor-targeted magnetic resonance (MR) imaging and cuproptosis-promoted chemo-chemodynamic therapy. The formed CSTD-Cu(II)@DSF could be specifically taken up by MCF-7 breast cancer cells, accumulated to the tumor model after circulation, and released drugs in response to the weakly acidic TME with overexpressed ROS. The enriched intracellular Cu(II) ions could induce the oligomerization of lipoylated proteins and proteotoxic stress for cuproptosis, and lipid peroxidation for chemodynamic therapy as well. Moreover, the CSTD-Cu(II)@DSF could cause the dysfunction of mitochondria and arrest the cell cycle at the G2/M phase, leading to enhanced DSF-mediated cell apoptosis. As a result, CSTD-Cu(II)@DSF could effectively inhibit the growth of MCF-7 tumors by a combination therapy strategy integrating chemotherapy with cuproptosis and chemodynamic therapy. Lastly, the CSTD-Cu(II)@DSF also displays Cu(II)-associated r1 relaxivity, allowing for T1-weighted real-time MR imaging of tumors in vivo. The developed tumor-targeted and TME-responsive CSTD-based nanomedicine formulation may be developed for accurate diagnosis and synergistic treatment of other cancer types. STATEMENT OF SIGNIFICANCE: Constructing an effective nanoplatform for the combination of therapeutic effects and real-time tumor imaging remains a challenge. In this study, we reported for the first time an all-in-one tumor-targeted and tumor microenvironment (TME) responsive nanoplatform based on core-shell tecto dendrimer (CSTD) for the cuproptosis-promoted chemo-chemodynamic therapy and enhanced MR imaging. The efficient loading, selective tumor-targeting, and TME-responsive release of Cu(II) and disulfiram could enhance the intracellular accumulation of drugs, induce cuproptosis of cancer cells, and amplify the synergistic chemo-chemodynamic therapeutic effect, resulting in enhanced MR imaging and accelerated tumor eradication. This study sheds new light on the development of theranostic nanoplatforms for early accurate diagnosis and effective treatment of cancers.

PDGF-B conjugating mesoporous IO/GdO nanocomposites for accurate diagnosis of orthotopic prostatic cancer through T1-T2 dual-modal MRI contrast enhancement

The development of highly efficient magnetic resonance imaging (MRI) contrast agent contributes to the early and accurate diagnosis of cancer. Herein, we developed a novel iron oxide and gadolinium oxide (IO/GdO) nanocomposite as T1-T2 dual modal MRI contrast agent through hydrothermal synthesis method. Subsequently, tumor-targeting ligand (PDGFB-PEG) was further conjugated to the surface of IO/GdO nanocomposite (PDGFB-pIO/GdO) to fabricate tumor-targeting MRI probe for accurate diagnosis of orthotopic prostatic cancer. IO/GdO nanocomposite exhibited obvious mesoporous structure, which would promote the contact between water molecules and Gd or Fe centers and enhance the T1 relaxation rate (r1) and T2 relaxation rate (r2) of IO/GdO composite. In addition, the r1 and r2 values of IO/GdO composite were up to be 11.6 mM−1s−1 and 102.7 mM−1s−1, respectively, and the r2/r1 ratio of IO/GdO nanocomposite was calculated to be 8.85, demonstrating a great potential as dual-mode MRI contrast agent. Further study indicated that PDGFB-pIO/GdO exhibited an excellent biocompatibility. Besides, PDGFB-pIO/GdO presented a higher accumulation in tumor than untargeted pIO/GdO, confirming its excellent in vivo tumor-targeting ability. Lastly, in orthotopic prostatic cancer model, the systemic delivery of PDGFB-pIO/GdO significantly enhanced T1- and T2-weighted signal of orthotopic prostatic cancer, achieving high quality of MR images and realizing accurate diagnosis of orthotopic prostatic cancer. Collectively, we proposed a rational designed nanoplatform, PDGF-B conjugating mesoporous IO/GdO nanocomposites, suggesting potential for diagnostic identification of prostate cancer via T1-T2 dual-modal MRI contrast enhancement.

An all-in-one biomimetic iron-small interfering RNA nanoplatform induces ferroptosis for cancer therapy

Iron-dependent ferroptosis is a promising therapeutic strategy for cancers. However, the sustained overexpression of the antioxidant glutathione (GSH) in cancer cells substantially limits its therapeutic effect. Seeking efficient approaches that can perform high GSH depletion efficiency remains a significant task. Herein, we construct an all-in-one nanoplatform with functions of tumor targeting, monitoring and treatment for cancer ferroptosis therapy by constructing a homotypic cancer cell membrane-camouflaged iron-small interfering RNA nanohybrid (CM-Fe-siR). The SLC7A11-targeted siRNA in the nanohybrid inhibits the biosynthesis of GSH by cutting off the supply of intracellular cystine, an essential ingredient in GSH synthesis, which subsequently results in the accumulation of reactive oxygen species (ROS) that are generated from Fenton reaction induced by iron. Meanwhile, the intracellular deficiency of GSH inactivates glutathione peroxidase 4 (GPX4, a lipid repair enzyme), which further increases the accretion of lipid peroxides to enhance iron-induced ferroptosis. This biomimetic nanohybrid shows a remarkable anti-cancer effect by triggering sustainable and efficient ferroptosis via these multiple synergistic actions. Besides, the nanohybrids enable in vivo magnetic resonance imaging (MRI) monitoring of therapy. The biomimetic CM-Fe-siR all-in-one nanoplatform may provide an efficient means of ferroptosis therapy for cancers. Statement of SignificanceFerroptosis therapy based on the Fenton reaction of iron nanomaterials has aroused much attention in cancer treatment; however, the therapeutic efficacy is greatly inhibited by the sustained overexpression of the antioxidant GSH in cancer cells. It is of great importance to exploit more reagents or techniques performing high GSH depletion efficiency. Here, we facilely construct an all-in-one cancer cell membrane-camouflaged iron-siRNA nanoplatform, which possesses good biosafety, tumor-targeting, and noninvasive MRI monitoring capabilities. It effectively inhibits the GSH synthesis, and further simultaneously promotes the ROS accumulation and GPX4 inactivation, leading to enhanced cancer ferroptosis. This work highlights that the biomimetic iron-siRNA nanohybrids have a high potential in clinical application for imaging-guided cancer ferroptosis therapy.

Construction of ultrasmall gold nanoparticles based contrast agent via Host-Guest interaction for Tumor-targeted magnetic resonance imaging

In order to overcome the shortcomings of small-molecule contrast agents (CAs) in clinic, gadolinium-based CAs have attracted increasingly interesting in tumor diagnosis. Herein, β-cyclodextrin-modified ultrasmall gold nanoparticle (AuNP@CD) was prepared as a functional core, which provided a large number of binding sites through host–guest interaction. Afterward, AD-PEG2000-PLL(Gd-DTPA) was anchored on the surface of AuNP@CD followed by the conjugation of folic acid through bioorthogonal chemistry, which endowed the AuNP with the capability to targeting tumor cells. Compared to Magnevist (Gd-DTPA, r1 = 4.25 mM−1 s−1) used in clinic, the AuNP nanocomposite exhibited higher longitudinal relaxivity (r1 = 19.47 mM−1 s−1), and presented excellent biocompatibility. Furthermore, in vivo studies indicated that AuNP@CD-AD-PEG2000-PLL (DTPA-Gd) nanocomposite could effectively permeate through tumor and accumulate in the tumor region, thus acquiring MR images with high resolution. These results suggest that this AuNP nanocomposite could be a potential candidate as MRI CA for tumor-targeted diagnosis.

Functionalized Lanthanide Oxide Nanoparticles for Tumor Targeting, Medical Imaging, and Therapy.

Recent progress in functionalized lanthanide oxide (Ln2O3) nanoparticles for tumor targeting, medical imaging, and therapy is reviewed. Among the medical imaging techniques, magnetic resonance imaging (MRI) is an important noninvasive imaging tool for tumor diagnosis due to its high spatial resolution and excellent imaging contrast, especially when contrast agents are used. However, commercially available low-molecular-weight MRI contrast agents exhibit several shortcomings, such as nonspecificity for the tissue of interest and rapid excretion in vivo. Recently, nanoparticle-based MRI contrast agents have become a hot research topic in biomedical imaging due to their high performance, easy surface functionalization, and low toxicity. Among them, functionalized Ln2O3 nanoparticles are applicable as MRI contrast agents for tumor-targeting and nontumor-targeting imaging and image-guided tumor therapy. Primarily, Gd2O3 nanoparticles have been intensively investigated as tumor-targeting T1 MRI contrast agents. T2 MRI is also possible due to the appreciable paramagnetic moments of Ln2O3 nanoparticles (Ln = Dy, Ho, and Tb) at room temperature arising from the nonzero orbital motion of 4f electrons. In addition, Ln2O3 nanoparticles are eligible as X-ray computed tomography contrast agents because of their high X-ray attenuation power. Since nanoparticle toxicity is of great concern, recent toxicity studies on Ln2O3 nanoparticles are also discussed.

Preparation of Magnetic Resonance Nano Contrast Agent and Its Adoption in Diagnosis of Breast Cancer

This study aimed to explore the value of preoperative mammography in the differential diagnosis of benign and malignant tumors of nipple discharge. A biocompatible T1 contrast agent KMnF3 nanoparticle was first developed in the research, and then RGD-coupled KMnF3 nanoparticles were further synthesized as a highly sensitive tumor-targeted magnetic resonance imaging (MRI) contrast agent. While the nanoparticle was characterized physically, cytotoxicity test and MRI test in breast cancer mice were performed, and the excised tumors were subjected to immunostaining and tumor electron microscope section processing. At the same time, 60 patients with nipple discharge were screened to participate in the research, and the prepared MRI nano contrast agent was used for the differential diagnosis of breast benign/malignant tumors of nipple discharge. In the experiment, the synthetic nanoparticles were tested by Fourier transformed infrared (FTIR), which proved that the designed RGDtu/KMnF3 nanoparticles were successfully synthesized. The quantitative analysis of the synthesized nanoparticles showed that the relaxation efficiency reached 23.12 mM−1s−1, and there was no obvious toxicity. After staining, the microscope showed that the tumor was proliferating. After intravenous injection of low-dose RGDtu/KMnF3 contrast agent, nanoparticles were found in the tumor tissue. It was found that the synthesized nanoparticles enhanced the contrast of tumors with a volume of less than 50 mm3 by observing tumor slices. The imaging of the patient’s breast showed that the X-ray classification of galactography based on this contrast agent was statistically significant in distinguishing benign/malignant lesions of nipple discharge (X2 = 58.700, P < 0.01).

NIR-II Responsive Hollow Magnetite Nanoclusters for Targeted Magnetic Resonance Imaging-Guided Photothermal/Chemo-Therapy and Chemodynamic Therapy.

Phototherapy in the second near-IR (1000-1700nm, NIR-II) window has achieved much progress because of its high efficiency and relatively minor side effects. In this paper, a new NIR-II responsive hollow magnetite nanocluster (HMNC) for targeted and imaging-guided cancer therapy is reported. The HMNC not only provides a hollow cavity for drug loading but also serves as a contrast agent for tumor-targeted magnetic resonance imaging. The acid-induced dissolution of the HMNCs can trigger a pH-responsive drug release for chemotherapy and catalyze the hydroxyl radical (·OH) formation from the decomposition of hydrogen peroxide for chemodynamic therapy. Moreover, the HMNCs can adsorb and convert NIR-II light into local heat (photothermal conversion efficacy: 36.3%), which can accelerate drug release and enhance the synergistic effect of chemo-photothermal therapy. The HMNCs show great potential as a versatile nanoplatform for targeted imaging-guided trimodal cancer therapy.

Sericin-based gadolinium nanoparticles as synergistically enhancing contrast agents for pH-responsive and tumor targeting magnetic resonance imaging

It is of great significance to develop gadolinium (Gd) contrast agents (CAs) for pH-responsive and tumor targeting magnetic resonance imaging (MRI). Silkworm sericin (SS) is a natural biomacromolecule from silkworm cocoon with good biocompatibility, biodegradability, and a variety of biological activities. Here, sericin was covalently cross-linked with gadolinium acetate (GAH) via Schiff's base reaction, and then blended with gadolinium chloride (GdCl3) through electrostatic adsorption to yield SS@GAH-GdCl3 nanoparticles. Zeta potential showed SS@GAH-GdCl3 could respond pH change naturally, and freely realize the transition from negative surface potential in pH 7.5 to positive surface potential in pH 5.8. The T1 weighted MR images in solution indicated that SS@GAH-GdCl3 has higher T1 relaxivity in pH 5.8 than that in pH 7.4, and magnevist under 3.0 T magnetic field. Further, the T1 weighted MR images in vivo suggested that SS@GAH-GdCl3 could target tumors and accumulate around tumor tissues to achieve MR imaging on the tumor up to 2 h. Moreover, SS@GAH-GdCl3 is stable without any leakage of gadolinium ions. SS@GAH-GdCl3 is cytocompatible and does not cause hemolysis, inflammation, tissue damage, and the change of serum biochemical indicators and body weight in vivo. SS@GAH-GdCl3 has exhibited great potentials as a high-performance GdCA for pH-responsive and tumor targeting MRI.

Extremely Small Iron Oxide Nanoparticle-Encapsulated Nanogels as a Glutathione-Responsive T1 Contrast Agent for Tumor-Targeted Magnetic Resonance Imaging.

Activatable magnetic resonance imaging (MRI) contrast agents that can be selectively stimulated at a tumor region are urgently demanded to realize the efficient and accurate diagnosis of cancers. Here, extremely small iron oxide nanoparticles (ESIONPs) modified with citric acid (ESIONPs-CA) are encapsulated in disulfide-cross-linked poly(carboxybetaine methacrylate) (poly(CBMA)) nanogels, and a cyclo[Arg-Gly-Asp-d-Tyr-Lys] (c(RGD)) ligand is further introduced to obtain ESIONP-packaged poly(CBMA) nanogels equipped with tumor-targeted c(RGD) (ICNs-RGD). On the basis of the transformation of the clustered ESIONPs into dispersed ones induced by the reducing glutathione (GSH), ICNs-RGD can complete the conversion from a T2 contrast agent to a T1 one, realizing the selective activation of the T1 contrasting effect. The GSH-dependent MRI signal conversion of ICNs-RGD is feasible in the tumor cell and tissue. Moreover, ICNs-RGD exhibits obvious targeting specificity and favorable biocompatibility. In the MRI experiments of tumor-bearing mice, benefiting from the stimuli-responsiveness toward GSH and targeting specificity, the T1 contrasting effect of tumor tissues can be selectively enhanced after the intravenous injection of ICNs-RGD. Therefore, tumor-targeted ICNs-RGD with a switchable MRI signal derived from the activation of GSH is a potential contrast agent for the efficient and precise tumor diagnosis in the clinic.

Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy

AbstractBiohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe3O4 NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O2 generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.

Activatable Cell-Penetrating Peptide Conjugated Polymeric Nanoparticles with Gd-Chelation and Aggregation-Induced Emission for Bimodal MR and Fluorescence Imaging of Tumors.

Activatable cell-penetrating peptide (ACPP) conjugated polymeric nanoparticles containing gadolinium (Gd)-chelates and aggregation-induced emission fluorogens (AIEgens) have been synthesized and applied as a magnetic resonance imaging (MRI) and fluorescence imaging (FI) bimodal imaging probe with active tumor targeting. The polymeric nanoparticles have been generated by dissolving presynthesized linear block copolymers into water directly. With AIEgens, N-BP5-Gd-ACPPs showed tumor cell penetration, which can be characterized by in vitro FI. Preliminary in vivo experiments of Gd-chelated nanoparticles have demonstrated promising characteristics as a tumor-targeting MRI contrast agent with good biocompatibility. This study impacts the synthesis of functional copolymers and polymeric nanoparticles for their applications in bioimaging.

Redox-responsive nanoparticles from disulfide bond-linked poly-(N-ε-carbobenzyloxy-l-lysine)-grafted hyaluronan copolymers as theranostic nanoparticles for tumor-targeted MRI and chemotherapy

Redox-responsive theranostic nanoparticles based on poly-(N-ε-carbobenzyloxy-l-lysine) (PZLL) grafted hyaluronan (HA) (HA-g-SS-PZLL) copolymers were constructed for hepatocellular carcinoma diagnosis and therapy. These hyaluronan derivatives formed nanoparticles via a self-assembly process in aqueous solution at low concentration. Theranostic nanoparticles were obtained after loading hydrophobic doxorubicin (DOX) and superparamagnetic iron oxide (SPIO) into the core of the nanoparticles via a dialysis method. Theranostic nanoparticles exhibited redox triggered DOX release behavior, and faster DOX released from theranostic nanoparticles was detected under a reducing environment compared with slow DOX release under a normal physiological environment. Confocal laser scanning microscopy (CLSM), flow cytometry and Prussian blue staining against HepG2 cells demonstrated that HA-g-SS-PZLL theranostic nanoparticles were capable of delivering DOX and SPIO into the cells. The analysis of the anticancer effect revealed that the HA-g-SS-PZLL theranostic nanoparticles shown higher cytotoxicity against HepG2 cells than DOX-loaded HA-g-PZLL nanoparticles. In vitro T2 magnetic resonance imaging (MRI) results exhibited that theranostic nanoparticles showed a good contrast enhancement effect, and the r2 relaxivity value was approximately 231 Fe mM−1 s−1. Finally, the theranostic nanoparticles acted as nanoprobes for HepG2 tumor-bearing BALB/c mice for in vivo MRI. Therefore, HA-g-SS-PZLL copolymers have great potential as theranostic nanoparticles for tumor-targeted diagnosis and treatment.

Preparation and Properties of Tumor-Targeting MRI Contrast Agent Based on Linear Polylysine Derivatives.

We developed a tumor-targeted contrast agent based on linear polylysine (PLL) by conjugating a small molecular imaging agent, fluorescent molecule and targeting agent amino phenylboronic acid onto the amino groups of polylysine, which can specifically target monosaccharide sialic acid residues overexpressing on the surface of tumor cell membranes. Further, 3,4,5,6-Tetrahydrophthalic anhydride (DCA) was attached to the free amino groups of the polylysine to change to a negative charge at physiology pH to lower the cytotoxicity, but it soon regenerated to a positive charge again once reaching the acidic intratumoral environment and therefore increased cell uptake. Laser confocal microscopy images showed that most of the polymeric contrast agents were bound to the cancer cell membrane. Moreover, the tumor targeting contrast agent showed the same magnetic resonance imaging (MRI) contrasting performance in vitro as the small molecule contrast agent used in clinic, which made it a promising tumor-targeting polymeric contrast agent for cancer diagnosis.

Zwitterionic Polydopamine-Coated Manganese Oxide Nanoparticles with Ultrahigh Longitudinal Relaxivity for Tumor-Targeted MR Imaging.

We present the design of antifouling zwitterion-functionalized manganese oxide (Mn3O4) nanoparticles (NPs) modified with folic acid (FA) for targeted tumor magnetic resonance (MR) imaging. In the current work, diethylene glycol-stabilized Mn3O4 NPs were initially prepared via a solvothermal approach, coated with polydopamine (PDA), fluorescently labeled with rhodamine B, conjugated with FA via amide bond formation, and finally covered with zwitterions of l-lysine (Lys). The thus-generated multifunctional Mn3O4 NPs display excellent water dispersibility and colloidal stability, good protein resistance ability, and desirable cytocompatibility. With the PDA and Lys modifications, the multifunctional Mn3O4 NPs own an ultrahigh r1 relaxivity (89.30 mM-1 s-1) and enable targeted tumor MR imaging, owing to the linked FA ligands. The designed antifouling zwitterion-functionalized Mn3O4 NPs may be employed as an excellent MR contrast agent for targeted MR imaging of other biological systems.

Preparation and characterization of peptide modified ultrasmall superparamagnetic iron oxides used as tumor targeting MRI contrast agent.

As desirable contrast agents for magnetic resonance imaging (MRI), ultrasmall superparamagnetic iron oxides (USPIOs) are required to exhibit both low cytotoxicity and specific targetability besides superparamagnetism to achieve better imaging contrast at lower dose, and cladding with biocompatible polymers and modification with targeting ligands are considered to be the most effective strategies. In this study, novel dextran wrapped and peptide WSGPGVWGASVK (peptide-WSG) grafted USPIOs were meticulously prepared and systematically characterized. Firstly, dextran (Dex) cladded USPIOs (USPIOs@Dex) were synthesized with a well-designed co-precipitation procedure in which the biocompatible dextran played dual roles of grain inhibitor and cladding agent. After that, sodium citrate was applied to carboxylize the hydroxyls of the dextran molecules via an esterification reaction, and then tumor targeting peptide-WSG was grafted to the carboxyl groups by the EDC method. The XRD, TEM, and FTIR results showed that inverse spinel structure Fe3O4 crystallites were nucleated and grown in aqueous solution, and the catenulate dextran molecules gradually bound on their surface, meanwhile the growth of grains was inhibited. The size of original crystallite grains was about 7 nm, but the mean size of USPIOs@Dex aggregates was 165.20 nm. After surface modification by sodium citrate and peptide-WSG with ultrasonic agitation, the size of the USPIOs@Dex-WSG aggregates was smaller (66.06 nm) because the hydrophilicity was improved, so USPIOs@Dex-WSG could evade being eliminated by RES more easily, and prolong residence time in blood circulation. The VSM and T2-weighted MRI results showed that USPIOs@Dex-WSG were superparamagnetic with a saturation magnetization of 44.65 emu g−1, and with high transverse relaxivity as the R2 relaxivity coefficient value was 229.70 mM−1 s−1. The results of MTT assays and the Prussian blue staining in vitro revealed that USPIOs@Dex-WSG exhibited nontoxicity for normal cells such as L929 and HUVECs, and were specifically targeted to the SKOV-3 cells. Thus, the novel dextran wrapped and WSG-peptide grafted USPIOs have potential to be applied as tumor active targeting contrast agents for MRI.