Selective targeting of tumor and stromal cells by a nanocarrier system displaying lipidated cathepsin B inhibitor.

Cathepsin B (CtsB) is a lysosomal cysteine proteinase that is specifically translocated to the extracellular milieu during cancer progression. The development of a lipidated CtsB inhibitor incorporated into the envelope of a liposomal nanocarrier (LNC-NS-629) is described. Ex vivo and in vivo studies confirmed selective targeting and internalization of LNC-NS-629 by tumor and stromal cells, thus validating CtsB targeting as a highly promising approach to cancer diagnosis and treatment.

The use of a combination of different MR methods to study swelling of hydrophilic xanthan matrix tablets at different pHs.

Modified-release matrix tablets have been extensively used by the pharmaceutical industry as one of the most successful oral drug-delivery systems. The key element in drug release from hydrophilic matrix tablets is the gel layer that regulates the penetration of water and controls drug dissolution and diffusion. Magnetic resonance imaging (MRI) is a powerful, non-invasive technique that can help improve our understanding of the gel layer formed on swellable, polymer-matrix tablets, as well as the layer's properties and its influence on the drug release. The aim was to investigate the effects of pH and ionic strength on swelling and to study the influence of structural changes in xanthan gel on drug release. For this purpose a combination of different MRI methods for accurate determination of penetration, swelling and erosion fronts was used. The position of the penetration and swelling fronts were the same, independently of the different xanthan gel structures formed under different conditions of pH and ionic strength. The position of the erosion front, on the other hand, is strongly dependent on pH and ionic strength, as reflected in different thicknesses of the gel layers.

A mathematical model for the dissolution of non-occlusive blood clots in fast tangential blood flow.

Our aim was to study the effect of an axially directed blood plasma flow on the dissolution rate of cylindrical non-occlusive blood clots in an in vitro flow system and to derive a mathematical model for the process. The model was based on the hypothesis that clot dissolution dynamics is proportional not only to the biochemical proteolysis of fibrin but also to the power of the flowing blood plasma dissipated along the clot. The predicted rate of thrombolysis is then proportional to the square of the average blood plasma velocity for laminar flow and to the third power of the average velocity for turbulent flow. To verify the model, the time dependence of the clot cross-sectional area was measured by dynamic magnetic resonance microscopy during fast (turbulent) and slow (laminar) flow of plasma through an axially directed channel along the clot. The flowing plasma contained a magnetic resonance imaging contrast agent (Gd-DTPA) and a thrombolytic agent (recombinant tissue-type plasminogen activator). The experimental data fitted well to the model, and confirmed the predicted increase in the dissolution rate when blood flow changed from a laminar to a turbulent flow regime.

Modelling the effect of laminar axially directed blood flow on the dissolution of non-occlusive blood clots.

Axially directed blood plasma flow can significantly accelerate thrombolysis of non-occlusive blood clots. Viscous forces caused by shearing of blood play an essential role in this process, in addition to biochemical fibrinolytic reactions. An analytical mathematical model based on the hypothesis that clot dissolution dynamics is proportional to the power of the flowing blood plasma dissipated along the clot is presented. The model assumes cylindrical non-occlusive blood clots with the flow channel in the centre, in which the flow is assumed to be laminar and flow rate constant at all times during dissolution. Effects of sudden constriction on the flow and its impact on the dissolution rate are also considered. The model was verified experimentally by dynamic magnetic resonance (MR) microscopy of artificial blood clots dissolving in an in vitro circulation system, containing plasma with a magnetic resonance imaging contrast agent and recombinant tissue-type plasminogen activator (rt-PA). Sequences of dynamically acquired 3D low resolution MR images of entire clots and 2D high resolution MR images of clots in the axial cross-section were used to evaluate the dissolution model by fitting it to the experimental data. The experimental data fitted well to the model and confirmed our hypothesis.

Lysability of arterial thrombi assessed by magnetic resonance imaging.

BACKGROUND: Intravascular thrombi change in time due to retraction and organization, which is reflected in the appearance of magnetic resonance images of clots. We have hypothesized that MRI has the potential to improve patient selection for thrombolytic treatment. The aim of our study was to analyze occlusive arterial thrombi with MRI, and to correlate the MRI parameters with the therapeutic outcome in patients with occlusive atherothrombotic disease of the superficial femoral artery who were treated with catheter-directed thrombolysis by streptokinase. PATIENTS AND METHODS: We included 13 patients with subacute (2 weeks to 3 months old) occlusive arterial thrombi and 4 patients with chronic (more than 6 months old) arterial occlusions. We measured the MRI signal intensity on gradient echo images of 98 axial slices of the subacute occlusive thrombi and in 45 slices of 4 chronic thrombi. Following MRI, the patients with subacute history were treated with catheter-directed thrombolysis. RESULTS: Thrombolysis was successful in 11/13 patients. The normalized MRI signal intensity was significantly higher in the unsuccessfully treated thrombi than in the successfully treated thrombi (1.10 +/- 0.08 vs. 0.72 +/- 0.17, p < 0.003), but the subacute and chronic thrombi did not differ in signal intensity. CONCLUSIONS: High signal intensity of arterial thrombi on gradient echo MRI might predict resistance to thrombolytic therapy.

Dynamics of the pinned modulation wave in incommensurate bis (4-chlorophenyl) sulfone (BCPS).

We show that both the anomalously huge resonance-frequency dependence of the (35)Cl nuclear quadrupole resonance (NQR) spin-lattice relaxation time in BCPS, reported here for the first time, and its anomalous temperature dependence can be explained by large-scale fluctuations of the pinned modulation wave instead of small-scale fluctuations (phasons and amplitudons). The results were obtained by measuring the laboratory (T(1Q)) and rotating frame (T(1Q,rho)) (35)Cl relaxation times. This is the first time that an effective resonance frequency dependence of the spin-lattice relaxation rate was measured in pure NQR.

Magnetic resonance imaging of alternating electric currents.

Electric Current Density Imaging (CDI) is a new modality of magnetic resonance imaging that enables electric current distribution imaging in conductive samples containing water. So far, two CDI techniques have been in use: DC-CDI operating at zero frequency and RF-CDI operating at the RF Larmor frequency. In this paper we present a new CDI technique, which extends the CDI frequency range to alternating electric currents (AC-CDI). First, a theoretical model for the electric current response to the alternating voltage is presented. Later, this model is used for the frequency analysis of the AC-CDI sequence. Additionally, the effect of off-resonance spins and imperfect refocusing RF pulses on the stability of the AC-CDI sequence and the echo formation is studied. The new theory is verified by experiments on a model system and compared to the other two methods: DC-CDI and RF-CDI. Finally, an application of the AC-CDI sequence to biological systems is demonstrated by an experiment on a wood twig in which an increase of approximately 30% was obtained at AC as compared to DC electric current.