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The degree of tumor removal at surgery is a major factor in predicting outcome for ovarian cancer. A single multimodality agent that can be used with magnetic resonance (MR) for staging and pre-surgical planning, and with optical imaging to aid surgical removal of tumors, would present a new paradigm for ovarian cancer. We assessed whether a dual-mode, dual-Gadolinium (DM-Dual-Gd-ICG) contrast agent can be used to visualize ovarian tumors in the peritoneal cavity by multimodal MR and near infra-red imaging (NIR). Intraperitoneal ovarian tumors (Hey-A8 or OVCAR3) in mice enhanced on MR two days after intravenous DM-Dual Gd-ICG injection compared to controls (SNR, CNR, p

Nanoparticle-assisted laser-induced photothermal therapy (PTT) is a promising method for cancer treatment; yet, visualization of nanoparticle uptake and photothermal response remain a critical challenge. Here, we report a magnetic resonance imaging-active nanomatryoshka (Gd 2 O 3 -NM), a multilayered (Au core/Gd 2 O 3 shell/Au shell) sub-100 nm nanoparticle capable of combining T 1 MRI contrast with PTT. This bifunctional nanoparticle demonstrates an r 1 of 1.28 × 10 8 mM -1 s -1 , an MRI contrast enhancement per nanoparticle sufficient for T 1 imaging in addition to tumor ablation. Gd 2 O 3 -NM also shows excellent stability in an acidic environment, retaining 99% of the internal Gd(3). This report details the synthesis and characterization of a promising system for combined theranostic nanoparticle tracking and PTT., (© The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences.)

A water-soluble octanuclear cluster, [Fe 8 ], was studied with regard to its properties as a potential contrast enhancing agent in magnetic resonance imaging (MRI) in magnetic fields of 1.3, 7.2 and 11.9 T and was shown to have transverse relaxivities r 2  = 4.01, 10.09 and 15.83 mM s -1 , respectively. A related hydrophobic [Fe 8 ] cluster conjugated with 5 kDa hyaluronic acid (HA) was characterized by 57 Fe-Mössbauer and MALDI-TOF mass spectroscopy, and was evaluated in aqueous solutions in vitro with regard to its contrast enhancing properties [r 2  = 3.65 mM s -1 (1.3 T), 26.20 mM s -1 (7.2 T) and 52.18 mM s -1 (11.9 T)], its in vitro cellular cytotoxicity towards A-549 cells and COS-7 cells and its in vivo enhancement of T 2 -weighted images (4.7 T) of a human breast cancer xenografted on a nude mouse. The physiologically compatible [Fe 8 ]-HA conjugate was i.v. injected to the tumor-bearing mouse, resulting in observable, heterogeneous signal change within the tumor, evident 15 min after injection and persisting for approximately 30 min. Both molecular [Fe 8 ] and its HA-conjugate show a strong magnetic field dependence on r 2 , rendering them promising platforms for the further development of T 2 MRI contrast agents in high and ultrahigh magnetic fields., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Engineering a compact, near-infrared plasmonic nanostructure with integrated image-enhancing agents for combined imaging and therapy is an important nanomedical challenge. Recently, we showed that Au@SiO 2 @Au nanomatryoshkas (NM) are a highly promising nanostructure for hosting either T 1 MRI or fluorescent contrast agents with a photothermal therapeutic response in a compact geometry. Here, we show that a near-infrared-resonant NM can provide simultaneous contrast enhancement for both T 1 magnetic resonance imaging (MRI) and fluorescence optical imaging (FOI) by encapsulating both types of contrast agents in the internal silica layer between the Au core and shell. We also show that this method of T 1 enhancement is even more effective for Fe(III), a potentially safer contrast agent compared to Gd(III). Fe-NM-based contrast agents are found to have relaxivities 2× greater than those found in the widely used gadolinium chelate, Gd(III) DOTA, providing a practical alternative that would eliminate Gd(III) patient exposure entirely. This dual-modality nanostructure can enable not only tissue visualization with MRI but also fluorescence-based nanoparticle tracking for quantifying nanoparticle distributions in vivo, in addition to a near-infrared photothermal therapeutic response.

Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumorigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programmes by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anticancer metabolism therapy development in future.

Purpose: The understanding of the role of genetic alterations in Wilms tumor development could be greatly advanced using a genetically engineered mouse models that can replicate the development and progression of this disease in human patients and can be monitored using non-invasive structural and molecular imaging optimized for renal tumors., Procedures: Repetitive dual-contrast computed tomography (CT; intravenous and intraperitoneal contrast), T2-weighted magnetic resonance imaging (MRI), and delayed 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET) were utilized for characterization of Igf2 biallelic expression/Wt1 knockout mouse model of Wilms tumor. For CT imaging, Ioversol 678 mg/ml in 200 μl was administered i.p. followed by 100 μl injected intravenously at 20 and 15 min prior to imaging, respectively. Static PET imaging studies were acquired at 1, 2, and 3 h after i.v. administration of (18)F-FDG (400 μCi). Coronal and sagittal T1-weighted images (TE/TR 8.5/620 ms) were acquired before and immediately after i.v. injection of 0.4 ml/kg gadopentetate dimeglumine followed by T2-weighted images (TE/TR 60/300 ms). Tumor tissue samples were characterized by histopathology and immunohistochemistry for Glut1, FASN, Ki67, and CD34. In addition, six Wt1-Igf2 mice were treated with a mitogen-activated protein kinase (MEK) inhibitor U0126 (50 μmol/kg i.p.) every 4 days for 6 weeks. (18)F-FDG PET/CT imaging was repeated at different days after initiation of therapy with U0126. The percent change of initial tumor volume and SUV was compared to non-treated historic control animals., Results: Overall, the best tumor-to-adjacent kidney contrast as well as soft tissue contrast for other abdominal organs was achieved using T2-weighted MRI. Delayed (18)F-FDG PET (3-h post (18)F-FDG administration) and dual-contrast CT (intravenous and intraperitoneal contrast) provided a more accurate anatomic and metabolic characterization of Wilms tumors in Wt1-Igf2 mice during early development and progression of renal tumors. Over the 8-month period, 46 Wt1-Igf2 mice and 8 littermate control mice were studied. Renal tumors were identified in 54.3 % of Wt1-Igf2 mice between post-natal 50-100 days. In 35.6 % of Wt1-Igf2 mice, tumors were localized in the right kidney; in 24 %, in the left kidney, while 40.4 % of Wt1-Igf2 mice had bilateral kidney tumors. Metastatic lesions were identified in 15.4 % of Wt1-Igf2 mice. Increased levels of Glut1 and IGF1R expression, high Ki67 labeling index, and a dense network of CD34+ microvessels in renal tumors was consistent with increased (18)F-FDG accumulation. Treatment with a MEK 1/2 inhibitor U0126 did not cause the inhibition of tumor growth as compared to untreated animals. However, after the first three to four doses (~2 weeks of treatment), a decrease in (18)F-FDG SUV was observed, as compared to pre-treatment levels (p < 0.05, paired Student t test), which constitutes a metabolic response. Six weeks later, despite continuing therapy, the (18)F-FDG SUV increased again to previous levels., Conclusions: The optimized dual contrast PET/CT imaging with early post i.v. and i.p. contrast CT and 3 h delayed PET imaging after (18)F-FDG administration provides a sensitive and reliable method for detecting early tumor lesions in this endogenous mouse model of Wilms tumor and for monitoring their growth in response to targeted therapies. Therapy with MEK inhibitor U0126 produces only a transient inhibition of tumor glycolytic activity but does not inhibit tumor growth, which is due to continuing IGF2-induced signaling from IGF1R through the PI3K-AKT-mTOR pathway.

Although polymeric magnetic resonance imaging (MRI) agents have significantly improved relaxivity and prolonged circulation time in vivo compared with current imaging agents, the potential for long-term toxicity prevents their translation into the clinic. The aim of this study was to develop a new biodegradable, nonionic polymeric blood pool MRI contrast agent with efficient clearance from the body. We synthesized PHPG-DTPA, which possesses two potentially degradable sites in vivo: protein amide bonds of the polymer backbone susceptible to enzymatic degradation and hydrolytically labile ester bonds in the side chains. After chelation with Gd(3+), PHPG-DTPA-Gd displayed an R(1) relaxivity of 15.72 mm(-1)⋅sec(-1) (3.7 times higher than that of Magnevist(T)). In vitro, DTPA was completely released from PHPG polymer within 48 h when incubated in mouse plasma. In vivo, PHPG-DTPA-Gd was cleared via renal route as shown by micro-single photon emission computed tomography of mice after intravenous injection of (111)In-labeled PHPG-DTPA-Gd. MRI of nude rats bearing C6 glioblastoma showed significant enhancement of the tumor periphery after intravenous injection of PHPG-DTPA-Gd. Furthermore, mouse brain angiography was clearly delineated up to 2 h after injection of PHPG-DTPA-Gd. PHPG-DTPA-Gd's biodegradability, efficient clearance, and significantly increased relaxivity make it a promising polymeric blood pool MRI contrast agent., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Hypoxia-inducible factor 1 (HIF-1) promotes cancer cell survival and tumor progression. The specific role played by HIF-1 and tumor-stromal interactions toward determining tumor resistance to radiation treatment remains undefined. We applied a multimodality preclinical imaging platform to mechanistically characterize tumor response to radiation, with a focus on HIF-1-dependent resistance pathways., Methods: C6 glioma and HN5 human squamous carcinoma cells were stably transfected with a dual HIF-1 signaling reporter construct (dxHRE-tk/eGFP-cmvRed2XPRT). Reporter cells were serially interrogated in vitro before and after irradiation as monolayer and multicellular spheroid cultures and as subcutaneous xenografts in nu/nu mice., Results: In vitro, single-dose irradiation of C6 and HN5 reporter cells modestly impacted HIF-1 signaling in normoxic monolayers and inhibited HIF-1 signaling in maturing spheroids. In contrast, irradiation of C6 or HN5 reporter xenografts with 8 Gy in vivo elicited marked upregulation of HIF-1 signaling and downstream proangiogenic signaling at 48 hours which preceded recovery of tumor growth. In situ ultrasound imaging and dynamic contrast-enhanced (DCE) MRI indicated that HIF-1 signaling followed acute disruption of stromal vascular function. High-resolution positron emission tomography and dual-contrast DCE-MRI of immobilized dorsal skin window tumors confirmed postradiotherapy HIF-1 signaling to spatiotemporally coincide with impaired stromal vascular function. Targeted disruption of HIF-1 signaling established this pathway to be a determinant of tumor radioresistance., Conclusions: Our results illustrate that tumor radioresistance is mediated by a capacity to compensate for stromal vascular disruption through HIF-1-dependent proangiogenic signaling and that clinically relevant vascular imaging techniques can spatially define mechanisms associated with tumor irradiation.

Purpose: Novel therapeutic approaches for complex karyotype soft tissue sarcoma (STS) are crucially needed. Consequently, we assessed the efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with chemotherapy, on local and metastatic growth of human STS xenografts in vivo., Experimental Design: TRAIL was evaluated alone and combined with low-dose doxorubicin in two human STS severe combined immunodeficient mouse xenograft models using fibrosarcoma (HT1080; wild-type p53) and leiomyosarcoma (SKLMS1; mutated p53), testing for effects on local growth, metastasis, and overall survival. Magnetic resonance imaging was used to evaluate local growth and bioluminescence was used to longitudinally assess lung metastases. Tissues were evaluated through immunohistocemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining for treatment effects on tumor cell proliferation, apoptosis, angiogenesis, angiogenic factors, and TRAIL receptor expression. Quantitative real-time polymerase chain reaction (QRTPCR) angiogenesis array was used to assess therapy-induced gene expression changes., Results: TRAIL/doxorubicin combination induced marked STS local and metastatic growth inhibition in a p53-independent manner. Significantly increased (P < 0.001) host survival was also demonstrable. Combined therapy induced significant apoptosis, decreased tumor cell proliferation, and increased TRAIL receptor (DR4 and DR5) expression in all treated tumors. Moreover, decreased microvessel density was observed, possibly secondary to increased expression of the antiangiogenic factor CXCL10 and decreased proangiogenic interleukin-8 cytokine in response to TRAIL/doxorubicin combination, as was also observed in vitro., Conclusions: Given the urgent need for better systemic approaches to STS, clinical trials evaluating TRAIL in combination with low-dose chemotherapy are potentially warranted., (Copyright 2010 AACR.)

Background: Liposomal-based gadolinium (Gd) nanoparticles have elicited significant interest for use as blood pool and molecular magnetic resonance imaging (MRI) contrast agents. Previous generations of liposomal MR agents contained gadolinium-chelates either within the interior of liposomes (core-encapsulated gadolinium liposomes) or presented on the surface of liposomes (surface-conjugated gadolinium liposomes). We hypothesized that a liposomal agent that contained both core-encapsulated gadolinium and surface-conjugated gadolinium, defined herein as dual-mode gadolinium (Dual-Gd) liposomes, would result in a significant improvement in nanoparticle-based T1 relaxivity over the previous generations of liposomal agents. In this study, we have developed and tested, both in vitro and in vivo, such a dual-mode liposomal-based gadolinium contrast agent., Methodology/principal Findings: THREE TYPES OF LIPOSOMAL AGENTS WERE FABRICATED: core-encapsulated, surface-conjugated and dual-mode gadolinium liposomes. In vitro physico-chemical characterizations of the agents were performed to determine particle size and elemental composition. Gadolinium-based and nanoparticle-based T1 relaxivities of various agents were determined in bovine plasma. Subsequently, the agents were tested in vivo for contrast-enhanced magnetic resonance angiography (CE-MRA) studies. Characterization of the agents demonstrated the highest gadolinium atoms per nanoparticle for Dual-Gd liposomes. In vitro, surface-conjugated gadolinium liposomes demonstrated the highest T1 relaxivity on a gadolinium-basis. However, Dual-Gd liposomes demonstrated the highest T1 relaxivity on a nanoparticle-basis. In vivo, Dual-Gd liposomes resulted in the highest signal-to-noise ratio (SNR) and contrast-to-noise ratio in CE-MRA studies., Conclusions/significance: The dual-mode gadolinium liposomal contrast agent demonstrated higher particle-based T1 relaxivity, both in vitro and in vivo, compared to either the core-encapsulated or the surface-conjugated liposomal agent. The dual-mode gadolinium liposomes could enable reduced particle dose for use in CE-MRA and increased contrast sensitivity for use in molecular imaging.

Hypoxia inducible factor-1 (HIF-1) promotes tumor cell adaptation to microenvironmental stress. HIF-1 is up-regulated in irradiated tumors and serves as a promising target for radiosensitization. We initially confirmed that the orally bioavailable HIF-1 inhibitor PX-478 reduces HIF-1 protein levels and signaling in vitro in a dose-dependent manner and provides direct radiosensitization of hypoxic cancer cells in clonogenic survival assays using C6 glioma, HN5 and UMSCCa10 squamous cells, and Panc-1 pancreatic adenocarcinoma cell lines. However, PX-478 yields striking in vivo tumor sensitization to single-dose irradiation, which cannot be explained by incremental improvement in direct tumor cell killing. We show that PX-478 prevents postradiation HIF-1 signaling and abrogates downstream stromal adaptation in C6 and HN5 reporter xenografts as measured by serial ultrasound, vascular magnetic resonance imaging, and hypoxia response element-specific micro-positron emission tomography imaging. The primacy of indirect PX-478 in vivo effects was corroborated by our findings that (a) either concurrent or early postradiation sequencing of PX-478 provides roughly equivalent sensitization and (b) constitutive vascular endothelial growth factor expression maintains refractory tumor vessel function and progression following combined radiation and PX-478. These results confirm that disruption of postradiation adaptive HIF-1 signaling by PX-478 imparts increased therapeutic efficacy through blockade of HIF-1-dependent reconstitution of tumor stromal function. Successful translation of targeted HIF-1 radiosensitization to the clinical setting will require specific consideration of tumor microenvironmental effects and mechanisms.

Environmental ultraviolet (UV) exposure exacts a significant toll annually in terms of overall morbidity and undesirable esthetic effects of skin aging. In order to establish the molecular and pathologic basis of this process, the murine model of ultraviolet B (UVB)-induced aging has long been used with reproducibility and success. Although morphometric and histological endpoints have been useful tools to describe this model historically, they fail to allow for the real time monitoring of the aging process, and do not fully account for effects of the in vivo environment on cutaneous strata with aging. The objective of the present study was to evaluate the ability of high-resolution magnetic resonance imaging (MRI) to characterize the murine model of photoaging throughout the aging process. Six-week-old male nu/nu mice were exposed to narrow-band UVB at 30 min intervals five times weekly for 10 weeks, resulting in a characteristic photoaged morphometric result. MRI scans were performed using a 7 tesla (7 T) small animal imaging platform at pre-exposure baseline at 4 and 10 weeks. Histological analysis of full-thickness biopsies taken in 10 week photoaged mice was correlated with MRI findings, and was compared against control animals receiving no ultraviolet radiation. MRI studies revealed a statistically significant prominent evolution of epidermal hyperplasia at 4 weeks versus baseline and at 10 weeks compared to 4 week values (0.172 +/- 0.017 mm versus undetectable, P < or = 0.05; 0.258 +/- 0.007 versus 0.172 +/- 0.017 mm, P < or = 0.05, respectively). A parallel trend of dermal hyperplasia which approached statistical significance was likewise noted at 10 weeks compared to baseline values (0.420 +/- 0.073 versus 0.295 +/- 0.078 mm, P = 0.06). Histology confirmed the progressive epidermal hyperplastic change characterized by MRI findings. This study validates the novel use of high-resolution MRI for study of the murine photoaging model and establishes its potential to describe progressive cutaneous pathology in such an experimental setting.

Pharmacokinetic parameters corresponding to perfused microvascular volume determined from dynamic contrast-enhanced (DCE) MRI data were compared to immunohistochemical measures of microvascular density (MVD) and perfused microvascular density. DCE MRI data from human mammary tumors (MDA-MB-435) implanted in nude mice using low (Gd-DTPA, MW approximately equal 0.6 kDa), medium (Gadomer-17, MW(eff) approximately equal 35 kDa), and high (PG-Gd-DTPA, MW approximately equal 220 kDa) molecular weight contrast agents were analyzed with single- and dual-tracer pharmacokinetic models. MVD values were determined by two manual counting methods, "hot spot" and summed region of interest (SROI). Pharmacokinetic parameters determined using the single-tracer model (Gd-DTPA [n = 15] and Gadomer-17 [n = 13]) did not correlate with MVD measures using either manual counting method. For dual-tracer studies (Gadomer-17/Gd-DTPA [n = 15] and PG-Gd-DTPA/Gd-DTPA [n = 13]), pharmacokinetic parameters demonstrated a statistically significant correlation with MVD determined by the SROI method, but not the "hot spot" method. Ten mice successfully underwent intravital FITC-labeled lectin perfusion with the hemisphere of highest lectin labeling correlating with pharmacokinetic parameter values in 9 of 10 tumors (single-tracer Gd-DTPA [n = 2], single-tracer Gadomer-17 [n = 3], and dual-tracer Gadomer-17/Gd-DTPA [n = 5]). This study demonstrates that dual-tracer DCE MRI studies yield pharmacokinetic parameters that correlate with immunohistochemical measures of MVD.

NPRL2 is one of the novel candidate tumor suppressor genes identified in the human chromosome 3p21.3 region. The NPRL2 has shown potent tumor suppression activity in vitro and in vivo and has been suggested to be involved in DNA mismatch repair, cell cycle checkpoint signaling, and regulation of the apoptotic pathway. In this study, we analyzed the endogenous expression of the NPRL2 protein and the cellular response to cisplatin in 40 non-small-cell lung cancer cell lines and found that expression of NPRL2 was significantly and reciprocally correlated to cisplatin sensitivity, with a Spearman correlation coefficient of -0.677 (P < 0.00001). Exogenously introduced expression of NPRL2 by N-[1-(2,3-dioleoyloxyl)propyl]-NNN-trimethylammoniummethyl sulfate:cholesterol nanoparticle-mediated gene transfer significantly resensitized the response to cisplatin, yielding a 40% greater inhibition of tumor cell viability and resulting in a 2- to 3-fold increase in induction of apoptosis by activation of multiple caspases in NPRL2-transfected cells compared with untransfected cells at an equal dose of cisplatin. Furthermore, a systemic treatment with a combination of NPRL2 nanoparticles and cisplatin in a human H322 lung cancer orthotopic mouse model significantly enhanced the therapeutic efficacy of cisplatin and overcame cisplatin-induced resistance (P < 0.005). These findings implicate the potential of NPRL2 as a biomarker for predicting cisplatin response in lung cancer patients and as a molecular therapeutic agent for enhancing response and resensitizing nonresponders to cisplatin treatment.

Time domain multiplexing (TDM) is presented as a viable approach to increasing the sensitivity and efficiency of magnetic resonance spectroscopic (MRS) experiments through multi-channel signal acquisition. By switching very rapidly between coils of a receive phased array, TDM receiver extensions allow the acquisition of multiple, independent spectra through a single channel magnetic resonance console. A TDM receiver extension designed for imaging and spectroscopy is described, and the impact of this hardware extension on the processing and quantitation of MRS data is addressed. The primary complication involves the use of fixed bandwidth RF band-pass filters that can not be adjusted to match the spectral width of the desired MRS experiment.MRS sequences whose bandwidths are narrower than the bandwidth provided by TDM band-pass filters can be acquired through TDM with minimal loss of SNR as long as two constraints are met. The first constraint requires that the entire bandwidth of the band-pass filters be sampled at or more rapidly than the Nyquist rate associated with their bandwidth, to prevent extra noise from aliasing into the final spectrum. The second requirement is that spectral resolution be held constant to that of the desired experiment. Results from a two-channel multiplexed MRS experiment, conducted according to these guidelines, illustrate that TDM can be used to allow acquisition of multi-channel MRS experiments through single channel console systems with a minimal loss in SNR.

SMASH (SiMultaneous Acquisition of Spatial Harmonics) is a technique which can be used to acquire multiple lines of k-space in parallel, by using spatial information from a radiofrequency coil array to perform some of the encoding normally produced by gradients. Using SMASH, imaging speed can be increased up to a maximum acceleration factor equal to the number of coil array elements. This work is a feasibility study which examines the use of SMASH with specialized coil array and data reception hardware to achieve previously unattainable accelerations. An eight element linear SMASH array was designed to operate in conjunction with a time domain multiplexing system to examine the effectiveness of SMASH imaging with as much as eightfold acceleration factors. Time domain multiplexing allowed the multiple independent array elements to be sampled through a standard single-channel receiver. SMASH-reconstructed images using this system were compared with reference images, and signal to noise ratio and reconstruction artifact power were measured as a function of acceleration factor. Results of the imaging experiments showed an almost constant SNR for SMASH acceleration factors of up to eight. Artifact power remained low within this range of acceleration factors. This study demonstrates that efficient SMASH imaging at high acceleration factors is feasible using appropriate hardware, and that time domain multiplexing is a convenient strategy to provide the multiple channels required for rapid imaging with large arrays.