MRI-guided photothermal/photodynamic immune activation combined with PD-1 inhibitor for the multimodal combination therapy of melanoma and metastases.

Non-invasive image-guided precise photothermal/photodynamic therapy (PTT/PDT) has been proven to be an effective local treatment modality but incompetent against metastases. Hence, the combination of local PTT/PDT and systemic immunotherapy would be a promising strategy for tumor eradication. Herein, a magnetic resonance imaging (MRI)-visualized PTT/PDT agent (SIDP NMs) was constructed, and the efficacy of its multimodal combination with a programmed cell death 1 (PD-1) inhibitor in the treatment of melanoma and metastases was studied. Due to the hydrophobic encapsulation of indocyanine green within the micellar core, SIDP NMs exhibited excellent photothermal/photodynamic properties and stability under an 808 nm near-infrared laser. In vitro cell experiments showed that SIDP NMs had a good killing effect. After incubating with B16-F10 cells for 24 h and irradiating with an 808-nm laser for 10 min, cell viability decreased significantly. Magnetic resonance imaging experiments in melanoma-bearing mice have shown that the dynamic distribution of SIDP NMs in tumor tissue could be monitored by T2WI and T2-MAP non-invasively due to the presence of superparamagnetic iron oxide nanocrystal in SIDP NMs. When the 808 nm laser was irradiated at the maximum focusing time point shown by MRI, the temperature of the tumor area rapidly increased from 32°C to 60.7°C in 5 min. In mouse melanoma ablation and distant tumor immunotherapy studies, SIDP NMs provided excellent MRI-guided PTT/PDT results and, when combined with PD-1 inhibitor, have great potential to cure primary tumors and eradicate metastases.

Carbonic Anhydrase IX Targeting Mn(II)-Based Magnetic Resonance Molecular Imaging Probe for Hypoxia Tumors.

Physiological hypoxic conditions in the tumor microenvironment and consequential overexpression of carbonic anhydrase IX (CA IX) are two characteristics shared by numerous types of solid malignant tumors. Early detection with hypoxia assessment is crucial to improve the prognosis and therapy outcomes of hypoxia tumors. Herein, using acetazolamide (AZA) as a CA IX-targeting moiety, we design and synthesize an Mn(II)-based MR imaging probe (named AZA-TA-Mn) incorporating AZA and two Mn(II) chelates of Mn-TyEDTA on a rigid triazine (TA) scaffold. The per Mn relaxivity of AZA-TA-Mn is 2-fold higher than its monomeric Mn-TyEDTA, which allows it for low-dose imaging of hypoxic tumors. In a xenograft mice model of esophageal squamous cell carcinoma (ESCC), a low dosage of AZA-TA-Mn (0.05 mmol/kg) can selectively produce prolonged and stronger contrast enhancement in the tumor compared to the non-specific Gd-DTPA (0.1 mmol/kg). A competition study of co-injection of free AZA and Mn(II) probes confirms the in vivo tumor selectivity of AZA-TA-Mn, resulting in a more than 2.5-fold decreased tumor-to-muscle contrast-to-noise ratio (ΔCNR) at 60 min post-injection. MR imaging results were further supported by the quantitative analysis of Mn tissue levels, as the co-injection of free AZA resulted in significantly reduced Mn accumulation in tumor tissues. Finally, immunofluorescence staining of tissue sections confirms the positive correlation between the tumor accumulation of AZA-TA-Mn and CA IX overexpression. Hence, using CA IX as the hypoxia biomarker, our results illustrate a practical strategy for the development of novel imaging probes for hypoxic tumors.

Dopamine multivalent-modified polyaspartic acid for MRI-guided near-infrared photothermal therapy.

Nanophotothermal agents that provide efficient and precise treatment at tumor sites are attracting increasing attention in biomedicine. In particular, the method combination of nanophotothermal agents and magnetic resonance imaging (MRI) shows great promise for biomedical therapeutic applications. Herein, a simple nanophotothermal agent with dopamine multivalent-modified polyaspartic acid chelated superparamagnetic iron oxide (SPIO) and ferric ion (SPIO@PAsp-DAFe/PEG) was developed for MRI-guided near-infrared photothermal therapy (PTT). SPIO@PAsp-DAFe/PEG was random SPIO nanocluster with good water solubility, had a diameter of 57.8 ± 7.8 nm in dynamic light scattering, negatively charged surface (zeta potential = -11 mV), exhibited good stability and outstanding photothermal conversion efficiency (35.4%) and produced superior magnetic resonance enhanced imaging. In the experiment with tumor-bearing mice, the MRI not only monitored the accumulation of SPIO@PAsp-DAFe/PEG nanocomposites enhanced by near-infrared irradiation after intravenous administration but also determined the appropriate time window for PTT. With the use of MRI-guided near-infrared therapy, the SPIO@PAsp-DAFe/PEG nanocomposites provided excellent therapeutic effects, confirming their great potential as effective MRI/PTT therapeutic agents.

T 1-T 2 dual-modal magnetic resonance contrast-enhanced imaging for rat liver fibrosis stage.

The development of an effective method for staging liver fibrosis has always been a hot topic of research in the field of liver fibrosis. In this paper, PEGylated ultrafine superparamagnetic iron oxide nanocrystals (SPIO@PEG) were developed for T 1-T 2 dual-modal contrast-enhanced magnetic resonance imaging (MRI) and combined with Matrix Laboratory (MATLAB)-based image fusion for staging liver fibrosis in the rat model. Firstly, SPIO@PEG was synthesized and characterized with physical and biological properties as a T 1-T 2 dual-mode MRI contrast agent. Secondly, in the subsequent MR imaging of liver fibrosis in rats in vivo, conventional T 1 and T 2-weighted imaging, and T 1 and T 2 mapping of the liver pre- and post-intravenous administration of SPIO@PEG were systematically collected and analyzed. Thirdly, by creative design, we fused the T 1 and T 2 mapping images by MATLAB and quantitively measured each rat's hepatic fibrosis positive pixel ratio (PPR). SPIO@PEG was proved to have an ultrafine core size (4.01 ± 0.16 nm), satisfactory biosafety and T 1-T 2 dual-mode contrast effects under a 3.0 T MR scanner (r 2/r 1 = 3.51). According to the image fusion results, the SPIO@PEG contrast-enhanced PPR shows significant differences among different stages of liver fibrosis (P < 0.05). The combination of T 1-T 2 dual-modal SPIO@PEG and MATLAB-based image fusion technology could be a promising method for diagnosing and staging liver fibrosis in the rat model. PPR could also be used as a non-invasive biomarker to diagnose and discriminate the stages of liver fibrosis.

Application of Triarylboron Substituted with Cyclic Arginine-Glycine-Aspartic Acid Motifs as a Multivalent Two-Photon Fluorescent Probe for Tumor Imaging in Vivo.

Detection of cancer in its early stages is difficult, and this is a major issue that impairs the timely diagnosis and treatment of tumors. Integrin αVß3 is expressed on tumoral endothelial cells, as well as other tumor cells. By functionalizing the triarylboron (TAB) compound with multiple cyclic arginine-glycine-aspartic acid (cRGD) motifs, which specifically bind to integrin αVß3, a multivalent two-photon fluorescent probe TAB-3-cRGD was designed and chemically synthesized. Through cell imaging experiments, we showed that TAB-3-cRGD can selectively bind to integrin αVß3 on the cell surface and can effectively distinguish normal cells from tumor cells overexpressing integrin αVß3. Using a mouse model, we also showed that TAB-3-cRGD could target the tumor site in vivo, offering a promising tool for cancer detection.