Angiogenesis, the formation of new blood vessels, is a requirement for malignant tumor growth and metastasis. In the absence of angiogenesis, local tumor expansion is suppressed at a few millimeters and cells lack routes for distant hematogenous spread. Clinical studies have demonstrated that the degree of angiogenesis is correlated with the malignant potential of several cancers, including breast cancer and malignant melanoma. Moreover, the expression of a specific angiogenesis marker, the endothelial integrin alphaVbeta3, has been shown to correlate with tumor grade. However, studies of tumor angiogenesis such as these have generally relied on invasive procedures, adequate tissue sampling and meticulous estimation of histologic microvessel density. In the present report, we describe a novel approach to detecting angiogenesis in vivo using magnetic resonance imaging (MRI) and a paramagnetic contrast agent targeted to endothelial alphaVbeta3 via the LM609 monoclonal antibody. This approach provided enhanced and detailed imaging of rabbit carcinomas by directly targeting paramagnetic agents to the angiogenic vasculature. In addition, angiogenic 'hot spots' not seen by standard MRI were detected. Our strategy for MR imaging of alphaVbeta3 thus represents a non-invasive means to assess the growth and malignant phenotype of tumors.

Purpose:To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design: Comparisons in vitro and in vivo were carried out between nont hermosensitive liposomes (NTSL) and low temperature^sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42jC for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.The dose of drug required to achieve clinically effective cytotoxicity in tumors often causes severe damage to actively propagating nonmalignant cells, resulting in a variety of undesirable side effects (1). Abnormal and heterogeneous distribution of inefficient vasculature (2), high interstitial fluid pressures (3), and fibrillar collagen in the extracellular matrix (4) are some of the barriers that further complicate effective and uniform drug delivery to tumors. Novel paradigms to overcome these barriers with new drug and device combinations may present fertile ground for continued research.Employing drug delivery strategies, such as liposomal encapsulation, can optimize and enhance the delivery of different agents with lower systemic toxicity and better drug cell internalization compared with free drug (5). A smaller volume of distribution and prolonged clearance time may also be achieved by incorporating lipid-conjugated polyethylene glycol into the liposomal membrane. This polyethylene glycolylation provides a protective barrier against interactions with plasma proteins and the reticuloendothelial system, allowing for enhanced accumulation of the chemotherapeutic agent into tumors (6). Polyethylene glycolylated liposomes containing doxorubicin, or Doxil, have bee...

A real-time interactive MRI system capable of localizing coronary arteries and imaging arrhythmic hearts in real-time is described. Non-2DFT acquisition strategies such as spiral-interleaf, spiral-ring, and circular echo-planar imaging provide short scan times on a conventional scanner. Real-time gridding reconstruction at 8-20 images/s is achieved by distributing the reconstruction on general-purpose UNIX workstations. An X-windows application provides interactive control. A six-interleaf spiral sequence is used for cardiac imaging and can acquire six images/s. A sliding window reconstruction achieves display rates of 16-20 images/s. This allows cardiac images to be acquired in real-time, with minimal motion and flow artifacts, and without breath holding or cardiac gating. Abdominal images are acquired at over 2.5 images/s with spiral-ring or circular echo-planar sequences. Reconstruction rates are 8-10 images/s. Rapid localization in the abdomen is demonstrated with the spiral-ring acquisition, whereas peristaltic motion in the small bowel is well visualized using the circular echo-planar sequence.

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A novel dual-labeled nanoparticle for use in labeling and tracking cells in vivo is described. We report the construction and characterization of these gadolinium-rhodamine nanoparticles. These particles are constructed from lipid monomers with diacetylene bonds that are sonicated and photolyzed to form polymerized nanoparticles. Cells are efficiently labeled with these nanoparticles. We have inoculated labeled tumor cells subcutaneouosly into the flanks of C3H mice and have been able to image these labeled tumor cells via MRI and optical imaging. Furthermore, the labeled tumor cells can be visualized via fluorescent microscopy after tissue biopsy. Our results suggest that these nanoparticles could be used to track cells in vivo. This basic platform can be modified with different fluorophores and targeting agents for studying metastisic cell, stem cell, and immune cell trafficking among other applications.