Effect of surfactant on the size and stability of PLGA nanoparticles encapsulating a protein kinase C inhibitor.

Nowadays many drugs with improved therapeutic efficacy are discovered but cannot be utilized due to their low solubility and insufficient bioavailability. An example of such a drug molecule is a protein kinase C inhibitor that influences an enzyme which plays an important role in several signal transduction cascades. The aim of this study was to formulate a stable nanoparticle dispersion of the PKC inhibitor encapsulated into PLGA nanoparticles (NPs). Encapsulation of the PKC inhibitor into PLGA NPs of 100-200 nm diameter should provide a targeted delivery to the inflammation sites. The NPs were prepared via nanoprecipitation and different surfactants were investigated: Fully and partially hydrolyzed poly(vinyl alcohol) (PVA, Mowiol X-88 and X-98), poloxamers (Pluronic F68 and F127) and polysorbates (Tween 20 and 80). From all surfactants tested, only NPs prepared with partially hydrolyzed PVA (Mowiol X-88) provided the desired stability throughout the downstream processes. These NPs were subsequently analyzed regarding their particle size, polydispersity, encapsulation efficiency and loading capacity. Dynamic light scattering results revealed that monodisperse NPs of 150-220 nm were formed, a size range that favors targeted delivery. The drug encapsulation efficiency varied from 31 to 75% with a drug loading of 1.3-2%. Moreover, the long-term stability was studied and the residual amount of PVA of the NP solutions was quantified via nuclear magnetic resonance (NMR) measurements. The shell-less hen's egg model was used to test toxic effects (hemorrhage, vascular lysis, thrombosis, hemolysis and lethality) of the NPs in a more complex biological system under dynamic flow conditions.

A new method to assess ventricular wall stress in patients with heart failure and its relation to heart rate variability.

INTRODUCTION: Heart failure is characterized by an increase in cardiac load, wall stress and autonomic dysfunction. The neurohumoral imbalance arising from adrenergic activation and parasympathetic withdrawal is associated with worse prognosis. We addressed the hypothesis that an increased left ventricular (LV) wall stress as assessed by cardiac magnetic resonance imaging (CMR) in patients with heart failure is related to a depression of heart rate variability (HRV). METHODS: Cardiac function and mass were measured in 37 individuals with suspected cardiomyopathy using CMR imaging. A thick-walled sphere model was used to calculate ventricular wall stress. Time domain analysis of HRV was obtained by long-term Holter ECG. RESULTS: Standard deviation of both normal-to-normal (NN) intervals (SDNN) and average NN intervals over 5 minutes (SDANN-i) were negatively correlated with LV enddiastolic wall stress (r = 0.42, P < 0.01). SDNN and SDANN-i were severely decreased (P < 0.01) in patients with increased enddiastolic LV wall stress > 12 kPa (vs. normal range: < 4 kPa). CONCLUSION: A relation between increased cardiac wall stress and depressed heart rate variability was observed in patients with heart failure. CMR-based measurement of LV volume and mass is appropriate to calculate LV wall stress which should be considered not only as a potential prognostic determinant but also as therapeutic target.

B-type natriuretic peptide and wall stress in dilated human heart.

Background Although B-type natriuretic peptide (BNP) is used as complimentary diagnostic tool in patients with unknown thoracic disorders, many other factors appear to trigger its release. In particular, it remains unresolved to what extent cellular stretch or wall stress of the whole heart contributes to enhanced serum BNP concentration. Wall stress cannot be determined directly, but has to be calculated from wall volume, cavity volume and intraventricular pressure of the heart. The hypothesis was, therefore, addressed that wall stress as determined by cardiac magnetic resonance imaging (CMR) is the major determinant of serum BNP in patients with a varying degree of left ventricular dilatation or dysfunction (LVD). Methods A thick-walled sphere model based on volumetric analysis of the LV using CMR was compared with an echocardiography-based approach to calculate LV wall stress in 39 patients with LVD and 21 controls. Serum BNP was used as in vivo marker of a putatively raised wall stress. Nomograms of isostress lines were established to assess the extent of load reduction that is necessary to restore normal wall stress and related biochemical events. Results Both enddiastolic and endsystolic LV wall stress were correlated with the enddiastolic LV volume (r = 0.54, P < 0.001; r = 0.81, P < 0.001). LV enddiastolic wall stress was related to pulmonary pressure (capillary: r = 0.69, P < 0.001; artery: r = 0.67, P < 0.001). Although LV growth was correlated with the enddiastolic and endsystolic volume (r = 0.73, P < 0.001; r = 0.70, P < 0.001), patients with LVD exhibited increased LV wall stress indicating an inadequately enhanced LV growth. Both enddiastolic (P < 0.05) and endsystolic (P < 0.01) wall stress were increased in patients with increased BNP. In turn, BNP concentration was elevated in individuals with increased enddiastolic wall stress (>8 kPa: 587 +/- 648 pg/ml, P < 0.05; >12 kPa: 715 +/- 661 pg/ml, P < 0.001; normal < or =4 kPa: 124 +/- 203 pg/ml). Analysis of variance revealed LV enddiastolic wall stress as the only independent hemodynamic parameter influencing BNP (P < 0.01). Using nomograms with "isostress" curves, the extent of load reduction required for restoring normal LV wall stress was assessed. Compared with the CMR-based volumetric analysis for wall stress calculation, the echocardiography based approach underestimated LV wall stress particularly of dilated hearts. Conclusions In patients with LVD, serum BNP was increased over the whole range of stress values which were the only hemodynamic predictors. Cellular stretch appears to be a major trigger for BNP release. Biochemical mechanisms need to be explored which appear to operate over this wide range of wall stress values. It is concluded that the diagnostic use of BNP should primarily be directed to assess ventricular wall stress rather than the extent of functional ventricular impairment in LVD.

Relation of B-type natriuretic peptide to left ventricular wall stress as assessed by cardiac magnetic resonance imaging in patients with dilated cardiomyopathy.

Ventricular loading conditions are crucial determinants of cardiac function and prognosis in heart failure. B-type natriuretic peptide (BNP) is mainly stored in the ventricular myocardium and is released in response to an increased ventricular filling pressure. We examined, therefore, the hypothesis that BNP serum concentrations are related to ventricular wall stress. Cardiac magnetic resonance imaging (MRI) was used to assess left ventricular (LV) mass and cardiac function of 29 patients with dilated cardiomyopathy and 5 controls. Left ventricular wall stress was calculated by using a thick-walled sphere model, and BNP was assessed by immunoassay. LV mass (r = 0.73, p < 0.001) and both LV end-diastolic (r = 0.54, p = 0.001) and end-systolic wall stress (r = 0.66, p < 0.001) were positively correlated with end-diastolic volume. LV end-systolic wall stress was negatively related to LV ejection fraction (EF), whereas end-diastolic wall stress was not related to LVEF. BNP concentration correlated positively with LV end-diastolic wall stress (r = 0.50, p = 0.002). Analysis of variance revealed LV end-diastolic wall stress as the only independent hemodynamic parameter influencing BNP (p < 0.001). The present approach using a thick-walled sphere model permits determination of mechanical wall stress in a clinical routine setting using standard cardiac MRI protocols. A correlation of BNP concentration with calculated LV stress was observed in vivo. Measurement of BNP seems to be sufficient to assess cardiac loading conditions. Other relations of BNP with various hemodynamic parameters (e.g., EF) appear to be secondary. Since an increased wall stress is associated with cardiac dilatation, early diagnosis and treatment could potentially prevent worsening of the outcome.