Recent studies in both rodents and humans suggest that elevated serum phosphorus, in the context of normal renal function, potentiates or exacerbates pathologies associates with cardiovascular disease, bone metabolism, and cancer. Our recent microarray studies identified the potent stimulation of pro-angiogenic genes such as Forkhead box protein C2 (FOXC2), osteopontin, and Vegfα, among others in response to elevated inorganic phosphate (Pi). Increased angiogenesis and neovascularization are important events in tumor growth and the progression to malignancy and FOXC2 has recently been identified as a potential transcriptional regulator of these processes. In this study we addressed the possibility that a high Pi environment would increase the angiogenic potential of cancer cells through a mechanism requiring FOXC2. Our studies utilized lung and breast cancer cell lines in combination with the human umbilical vascular endothelial cell (HUVEC) vessel formation model to better understand the mechanism(s) by which a high Pi environment might alter cancer progression. Exposure of cancer cells to elevated Pi stimulated expression of FOXC2 and conditioned medium from the Pi-stimulated cancer cells stimulated migration and tube formation in the HUVEC model. Mechanistically, we define the requirement of FOXC2 for Pi-induced OPN expression and secretion from cancer cells as necessary for the angiogenic response. These studies reveal for the first time that cancer cells grown in a high Pi environment promote migration of endothelial cells and tube formation and in so doing identify a novel potential therapeutic target to reduce tumor progression.

Image-guided intra-arterial therapies play a key role in the management of hepatic malignancies. However, limited clinical outcomes suggest the need for new multifunctional drug delivery systems to enhance local drug concentration while reducing systemic adverse reactions. Therefore, we developed the albumin-doxorubicin nanoparticle conjugated microbubble (ADMB) to enhance therapeutic efficiency by sonoporation under exposure to ultrasound. ADMB demonstrated a size distribution of 2.33 ± 1.34 µm and a doxorubicin loading efficiency of 82.7%. The echogenicity of ADMBs was sufficiently generated in the 2–9 MHz frequency range and cavitation depended on the strength of the irradiating ultrasound. In the VX2 rabbit tumor model, ADMB enhanced the therapeutic efficiency under ultrasound exposure, compared to free doxorubicin. The intra-arterial administration of ADMBs sufficiently reduced tumor growth by five times, compared to the control group. Changes in the ADC values and viable tumor fraction supported the fact that the antitumor effect of ADMBs were enhanced by evidence of necrosis ratio (over 70%) and survival tumor cell fraction (20%). Liver toxicity was comparable to that of conventional therapies. In conclusion, this study shows that tumor suppression can be sufficiently maximized by combining ultrasound exposure with intra-arterial ADMB administration.

Background: Crossing the blood–brain barrier (BBB) is crucial for drug delivery to the brain and for treatment of brain tumors, such as glioblastoma, the most common of all primary malignant brain tumors. Microbubble (MB) is oscillated and destroyed by controlling ultrasound (US) parameters. This oscillation and destruction of MB can open the BBB transiently, and a drug can be delivered to the brain. Materials and methods: For testing the efficiency of delivery to the brain, we synthesized a US-sensitizing nanoparticle (NP) complex via chemically binding MBs and NPs for the BBB opening, including near-infrared dye-incorporated albumin nanoparticles (NIR-Alb NPs) for fluorescence detection. Results: The human-derived, biocompatible NIR-Alb NPs did not show significant cytotoxicity to 500 μg/mL for 3 days in four human glioma cell lines. In an in vivo animal study, some US parameters were investigated to determine optimal conditions. The optimized US conditions were applied in a U87MG orthotopic mouse model. We found that the fluorescence intensity in the brain was 1.5 times higher than in the control group. Conclusion: Our US-sensitizing NP complex and US technique could become one of the critical technologies for drug delivery to the brain.

Background Interest in an ultrasound‐mediated delivery system for effective T1‐MRI of prostate cancer without adverse effects has steadily increased. Purpose To develop an ultrasound‐responsive dual‐modal ultrasound (US)/T1‐MRI contrast agent for efficient diagnosis of prostate cancer cells overexpressing prostate‐specific membrane antigen (PSMA) and assess their potential. Study Type In vitro. Subjects Two prostate cancer cell lines. Field Strength/Sequence Each study group underwent 3.0T MRI under a TR 400 msec, TE 10 msec, a 240 × 240 matrix, a flip angle 90°, a slice thickness 3 mm, NSA with 4, bandwidth 115 Hz/pixel, and an FOV of 120 × 120 mm. Assessment Microscopes, quantitative and qualitative analyzing instruments, and clinical devices were used for assessing this novel contrast agent and its diagnosis effects. Statistical Tests We used linear regression analyses to determine the longitudinal relaxivity (r1) values of our US/T1‐MRI contrast agent and gadobutrol. Results Microbubble+Fe3+melanin nanoparticle+peptides (MB+Fe3+MNPPs) had a good US contrast effect, like a commercial US agent. The differences of US intensities between them was below 5%. The r1 values of MB+Fe3+MNPPs and gadobutrol were 4.5 and 3.7 s‐1/mM, respectively. More than hundreds of Fe3+MNPPs were located in prostate cancer cells treated with MB+Fe3+MNPPs and US stimulus, but the number of Fe3+MNPPs was below dozens in the other prostate cancer cells expressing less PSMA. The former cells with MB+Fe3+MNPPs and US stimulus only showed the highest T1‐MRI signal because of synergy effects of the peptides targeting the cells and US stimulus for delivery of Fe3+MNPPs to the cells. No cytotoxicity of MB+Fe3+MNPPs was confirmed by using a WST assay. Viability of the cells with the complexes was above 90%. Data Conclusion We synthesized MB+Fe3+MNPPs as a potential US/T1‐MRI contrast agent. This complex was applicable for diagnosing desired prostate cancer cells. Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1610–1616

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