Robert F. Mattrey

Tissue-penetrating delivery of compounds and nanoparticles into tumors

Poor penetration of drugs into tumors is a major obstacle in tumor treatment. We describe a strategy for peptide-mediated delivery of compounds deep into the tumor parenchyma that uses a tumor-homing peptide, iRGD (CRGDK/RGPD/EC). Intravenously injected compounds coupled to iRGD bound to tumor vessels and spread into the extravascular tumor parenchyma, whereas conventional RGD peptides only delivered the cargo to the blood vessels. iRGD homes to tumors through a three-step process: the RGD motif mediates binding to alphav integrins on tumor endothelium and a proteolytic cleavage then exposes a binding motif for neuropilin-1, which mediates penetration into tissue and cells. Conjugation to iRGD significantly improved the sensitivity of tumor-imaging agents and enhanced the activity of an antitumor drug.

Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta

BACKGROUND: The incidence of placenta accreta has increased dramatically over the last three decades, in concert with the increase in the cesarean delivery rate. Optimal management requires accurate prenatal diagnosis. The purpose of this study was to determine the precision and reliability of ultrasonography and magnetic resonance imaging (MRI) in diagnosing placenta accreta. METHODS: A historical cohort study was performed with information gathered from our obstetric, radiologic, and pathology databases. Records from January 2000 to June 2005 were reviewed to identify patients with a diagnosis of placenta previa, low-lying placenta with a prior cesarean delivery, or history of a myomectomy to determine the accuracy of pelvic ultrasonography in the diagnosis of placenta accreta. The records of those considered to be suspicious for placenta accreta and subsequently referred for additional confirmation by MRI were also analyzed. The sonographic and MRI diagnoses were compared with the final pathologic or operative findings or with both. RESULTS: Of the 453 women with placenta previa, previous cesarean delivery and low-lying anterior placenta, or previous myomectomy, 39 had placenta accreta confirmed by pathological examination. Ultrasonography accurately predicted placenta accreta in 30 of 39 of women and correctly ruled out placenta accreta in 398 of 414 without placenta accreta (sensitivity 0.77, specificity 0.96). Forty-two women underwent MRI evaluation because of findings suspicious or inconclusive of placenta accreta by ultrasonography. Magnetic resonance imaging accurately predicted placenta accreta in 23 of 26 cases with placenta accreta and correctly ruled out placenta accreta in 14 of 14 (sensitivity 0.88, specificity 1.0). CONCLUSION: A two-stage protocol for evaluating women at high risk for placenta accreta, which uses ultrasonography first, and then MRI for cases with inconclusive ultrasound features, will optimize diagnostic accuracy. LEVEL OF EVIDENCE: II-3

Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma

Antiangiogenic therapy can produce transient tumor regression in glioblastoma (GBM), but no prolongation in patient survival has been achieved. We have constructed a nanosystem targeted to tumor vasculature that incorporates three elements: (i) a tumor-homing peptide that specifically delivers its payload to the mitochondria of tumor endothelial cells and tumor cells, (ii) conjugation of this homing peptide with a proapoptotic peptide that acts on mitochondria, and (iii) multivalent presentation on iron oxide nanoparticles, which enhances the proapoptotic activity. The iron oxide component of the nanoparticles enabled imaging of GBM tumors in mice. Systemic treatment of GBM-bearing mice with the nanoparticles eradicated most tumors in one GBM mouse model and significantly delayed tumor development in another. Coinjecting the nanoparticles with a tumor-penetrating peptide further enhanced the therapeutic effect. Both models used have proven completely resistant to other therapies, suggesting clinical potential of our nanosystem.

Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver – Update 2012

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Nanoparticle-induced vascular blockade in human prostate cancer

The tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) specifically homes to tumors by binding to fibrin and fibrin-associated clotted plasma proteins in tumor vessels. Previous results show that CREKA-coated superparamagnetic iron oxide particles can cause additional clotting in tumor vessels, which creates more binding sites for the peptide. We have used this self-amplifying homing system to develop theranostic nanoparticles that simultaneously serve as an imaging agent and inhibit tumor growth by obstructing tumor circulation through blood clotting. The CREKA nanoparticles were combined with nanoparticles coated with another tumor-homing peptide, CRKDKC, and nanoparticles with an elongated shape (nanoworms) were used for improved binding efficacy. The efficacy of the CREKA peptide was then increased by replacing some residues with nonproteinogenic counterparts, which increased the stability of the peptide in the circulation. Treatment of mice bearing orthotopic human prostate cancer tumors with the targeted nanoworms caused extensive clotting in tumor vessels, whereas no clotting was observed in the vessels of normal tissues. Optical and magnetic resonance imaging confirmed tumor-specific targeting of the nanoworms, and ultrasound imaging showed reduced blood flow in tumor vessels. Treatment of mice with prostate cancer with multiple doses of the nanoworms induced tumor necrosis and a highly significant reduction in tumor growth.

Therapeutic Enzyme‐Responsive Nanoparticles for Targeted Delivery and Accumulation in Tumors

An enzyme-responsive, paclitaxel-loaded nanoparticle is described and assessed in vivo in a human fibrosarcoma murine xenograft. This work represents a proof-of-concept study demonstrating the utility of enzyme-responsive nanoscale drug carriers capable of targeted accumulation and retention in tumor tissue in response to overexpressed endogenous enzymes.

Structural and functional imaging of bottlenose dolphin (Tursiops truncatus) cranial anatomy

SUMMARY Bottlenose dolphins were submitted to structural (CT) and functional (SPECT/PET) scans to investigate their in vivo anatomy and physiology with respect to structures important to hearing and echolocation. The spatial arrangement of the nasal passage and sinus air spaces to the auditory bullae and phonic lips was studied in two dolphins via CT. Air volume of the sinuses and nasal passages ranged from 267.4 to 380.9 ml. Relationships of air spaces to the auditory bullae and phonic lips support previous hypotheses that air protects the ears from echolocation clicks generated by the dolphin and contributes to dolphin hearing capabilities (e.g. minimum angular resolution, inter-aural intensity differences). Lung air may replenish reductions in sinus and nasal passage air volume via the palatopharyngeal sphincter, thus permitting the echolocation mechanism to operate at depth. To determine the relative extent of regional blood flow within the head of the dolphin, two dolphins were scanned with SPECT after an intravenous dose of 1850 MBq 99mTc-bicisate. A single dolphin received 740 MBq of 18F-2-fluoro-2-deoxyglucose (FDG) to identify the relative metabolic activity of head tissues. Substantial blood flow was noted across the dorsoanterior curvature of the melon and within the posterior region of the lower jaw fats. Metabolism of these tissues relative to others within the head was nominal. It is suggested that blood flow in these fat bodies serves to thermoregulate lipid density of the melon and jaw canal. Sound velocity is inversely related to the temperature of acoustic lipids (decreasing lipid density), and changes in lipid temperature are likely to impact the wave guide properties of the sound projection and reception pathways. Thermoregulation of lipid density may maintain sound velocity gradients of the acoustic lipid complexes, particularly in the outer shell of the melon, which otherwise might vary in response to changing environmental temperatures.

Time Course and Role of Morphine Dose and Concentration in Intrathecal Granuloma Formation in Dogs A Combined Magnetic Resonance Imaging and Histopathology Investigation

Background:Intrathecal morphine infusion leads to intrathecal granulomas. In dogs, the authors examined time course of granuloma formation and the role of concentration in granuloma development. Methods:Dogs were prepared with lumbar intrathecal catheters and vest-mounted pumps. To define the time course of granuloma formation, serial magnetic resonance imaging was performed in animals receiving 10 or 31 days of morphine infusion (12.5 mg/ml at 40 &mgr;l/h). At these times, morphine was removed from the infusate, and further magnetic resonance images were acquired over 14–35 additional days. To assess dose versus concentration, dogs received 28-day infusions of vehicle, 12 mg morphine/day as 12.5 mg/ml at 40 &mgr;l/h, or 1.5 mg/ml at 334 &mgr;l/h (12 mg/day) for 28 days. Additional dogs received 3 mg/day as 12.5 mg/ml at 10 &mgr;l/h. Results:Serial magnetic resonance images in dogs receiving morphine (12.5 mg/ml at 40 &mgr;l/h) revealed pericatheter-enhancing tissues as early as 3 days with a prominent signal by 10 days. Removal of morphine reduced the mass volume within 7 days. At a fixed infusion rate, the incidence of granuloma formation with the continuous intrathecal infusion of morphine ranged from 0 in vehicle-treated dogs to 100% in dogs treated with 12.5 mg/ml at 40 &mgr;l/h (12 mg/day). Infusion of 12 mg/day at 1.5 mg/ml (334 &mgr;l/h) resulted in granuloma in one of four animals. The authors found that infusion of morphine in different concentrations at a fixed rate resulted in a dose-dependent increase in concentration, with the granuloma-producing, dose-yielding lumbar cerebrospinal fluid morphine concentrations around 40 &mgr;g/ml. Conclusions:Serial magnetic resonance imaging showed a rapid formation and regression of the masses initiated by intrathecal morphine infusion. These masses are dependent on local concentration.

The potential role of perfluorochemicals (PFCS) in diagnostic imaging

Although perfluorochemicals (PFCs) are known for their ability to carry oxygen, they are the most versatile and only universal contrast agents with important applications using x-ray, ultrasound, or magnetic resonance (MR). The characteristics that make them unique diagnostic agents are lack of hydrogen atoms, immiscibility with water, low surface tension, compressibility, and long intravascular persistence when emulsified and given i.v. When made radiopaque, they are visible with x-ray computed tomography (CT) and standard radiography. Because the neat liquid is inert it can be ingested, instilled in the lung, or introduced into any hollow organ to image the lumen without untoward effects. The long intravascular persistence allows the imaging of blood vessels and vascularized tissues. Small or deep vessels become visible on Color Doppler Imaging and angiographic images of any vascular tree including the coronaries can be rendered from the serial CT images. As PFCs accumulate within RE cells, specific liver and spleen enhancement is achieved allowing the detection of small tumors within these organs. When injected interstitially, the particles find their way to the draining lymphnodes providing detail of the internal architecture to detect the presence or absence of tumor involvement on both CT and sonography. Using 19F MR, tissue perfusion and tissue pO2 measurements can be achieved. As can be seen, the applications of PFC in diagnosis are vast, unique, and important. These new capabilities will carry radiological tools to new horizons.

Hollow silica and silica-boron nano/microparticles for contrast-enhanced ultrasound to detect small tumors

Diagnosing tumors at an early stage when they are easily curable and may not require systemic chemotherapy remains a challenge to clinicians. In order to improve early cancer detection, gas filled hollow boron-doped silica particles have been developed, which can be used for ultrasound-guided breast conservation therapy. The particles are synthesized using a polystyrene template and subsequently calcinated to create hollow, rigid nanoporous microspheres. The microshells are filled with perfluoropentane vapor. Studies were performed in phantoms to optimize particle concentration, injection dose, and the ultrasound settings such as pulse frequency and mechanical index. In vitro studies have shown that these particles can be continuously imaged by US up to 48 min and their signal lifetime persisted for 5 days. These particles could potentially be given by intravenous injection and, in conjunction with contrast-enhanced ultrasound, be utilized as a screening tool to detect smaller breast cancers before they are detectible by traditional mammography.