The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

A harmonic oscillator consisting of a neodymium magnet attached inside a spring is driven through resonance. Eddy currents, induced in pipes surrounding the magnet, result in a damping of the motion of the magnet. Our experiment makes precise measurements of the motion and damping of the magnet as we vary pipe composition, length, thickness, radius, and position. A theoretical analysis combining the standard differential equation for a damped, driven harmonic oscillator and Faraday’s law of electromagnetic induction gives excellent agreement with the experimental results. This analysis allows for the calculation of electromagnetic damping for any pipe configuration which is coaxial with the magnet’s motion and provides strong evidence for the eddy current damping analysis of the common demonstration of dropping a magnet down a conducting tube.

Qualitative and quantitative properties of the finite part, H(f), of the Shannon entropy of a continuous waveform f(t) in the continuum limit are derived in order to illuminate its use for waveform characterization. Simple upper and lower bounds on H(f), based on features of f(t), are defined. Quantitative criteria for a priori estimation of the average-case variation of H(f) and log E(f), where E(f) is the signal energy of f(t) are also derived. These provide relative sensitivity estimates that could be used to prospectively choose optimal imaging strategies in real-time ultrasonic imaging machines, where system bandwidth is often pushed to its limits. To demonstrate the utility of these sensitivity relations for this application, a study designed to assess the feasibility of identification of angiogenic neovasculature targeted with perfluorocarbon nanoparticles that specifically bind to alpha(v)beta3-integrin expression in tumors was performed. The outcome of this study agrees with the prospective sensitivity estimates that were used for the two receivers. Moreover, these data demonstrate the ability of entropy-based signal receivers when used in conjunction with targeted nanoparticles to elucidate the presence of alpha(v)beta3 integrins in primordial neovasculature, particularly in acoustically unfavorable environments.

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Echocardiography requires imaging of the heart with sound propagating at varying angles relative to the predominant direction of the myofibers. The degree of anisotropy of attenuation can significantly influence ultrasonic imaging and tissue characterization measurements in vivo. This study quantifies the anisotropy of attenuation of freshly excised myocardium at frequencies typical of echocardiographic imaging. Results show a significantly larger anisotropy than previously reported in specimens of locally unidirectional myofibers. Through-transmission radio frequency-based measurements were performed on specimens from 12 ovine and 12 bovine hearts. Although ovine hearts are closer in size to human, the larger size of bovine hearts offers the potential for specimens in which myofibers are more nearly unidirectionally aligned. The attenuation coefficient increased approximately linearly with frequency. The mean slope of attenuation with frequency was 3-4 times larger for propagation parallel than for perpendicular to the myofibers. At perpendicular insonification, slopes between ovine and bovine myocardium were approximately equal. However, attenuation in bovine specimens was larger for angles approaching parallel. The difference in results for parallel appears consistent with what might be expected from increased myofiber curvature associated with smaller lamb hearts. Quantitative knowledge of anisotropy of attenuation may be useful in understanding mechanisms underlying the interaction of ultrasound with myocardium.

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The objective of this study was to quantify the anisotropy of ultrasonic velocity in freshly excised myocardial tissue and to examine the effects of formalin-fixation. Through-transmission radiofrequency-based measurements were performed on ovine and bovine myocardial specimens from 24 different hearts. A total of 81 specimens were obtained from specific locations within each heart to investigate the possibility of regional differences in anisotropy of velocity in the left ventricular wall and septum. No regional differences were observed for either lamb or cow myocardial specimens. In addition, no specific species-dependent differences were observed between ovine and bovine myocardium. Average values of velocity at room temperature for perpendicular and parallel insonification were 1556.9 ± 0.6 m/s and 1565.2 ± 0.7 m/s (mean ± standard error), respectively, for bovine myocardium (N = 45) and 1556.3 ± 0.6 m/s and 1564.7 ± 0.7 m/s for ovine myocardium (N = 36). Immediately after measurements of freshly excised myocardium, ovine specimens were fixed in formalin for at least one month and then measurements were repeated. Formalin-fixation appears to increase the overall velocity at all angles of insonification and to increase the magnitude of anisotropy of velocity.