Multivariate modeling of encapsulation and release of an ionizable drug from polymer microspheres

In the formulation of polymer microspheres (MSs) loaded with verapamil hydrochloride (VRP), a low molecular weight ionizable drug, by W/O/W emulsification, the pH of the external aqueous phase proved to be a primary determinant of both IE and drug release behavior. Increasing the pH of the external aqueous phase enhanced IE (≈100% at pH 8.4). This was associated with a considerable increase in initial release rate at pH 1.2. Two multivariate methods, factorial analysis (FA) and artificial neural network (ANN), were used to investigate the impact of the combined effect of the external phase pH and other parameters (polymer concentration and initial drug load) on MS characteristics; IE, initial drug release, MS size and yield. FA indicated that the external aqueous phase pH affected all responses, with a particularly strong correlation with IE in addition to a combined synergistic effect with polymer concentration on MS size. ANN showed better internal and external predictive ability of responses compared to FA. The ANN model developed in the study can be successfully used for multivariate modeling of the encapsulation and release of VRP and similar drug salts from hydrophobic polymer MSs prepared by multiple emulsification in addition to other MS characteristics. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4603–4615, 2009     

Surface-grafted polyethylene glycol conformation impacts the transport of PEG-functionalized liposomes through a tumour extracellular matrix model

The effect of surface PEGylation on nanoparticle transport through an extracellular matrix (ECM) is an important determinant for tumor targeting success. Fluorescent stealth liposomes (base lipid DOPC) were prepared incorporating different proportions of PEG-grafted lipids (2.5, 5 and 10% of the total lipid content) for a series of PEG molecular weights (1000, 2000 and 5000 Da). The ECM was modelled using a collagen matrix. The kinetics of PEGylated liposome adhesion to and transport in collagen matrices were tracked using fluorescence correlation spectroscopy (FCS) and confocal microscopy, respectively. Generalized least square regressions were used to determine the temporal correlations between PEG molecular weight, surface density and conformation, and the liposome transport in a collagen hydrogel over 15 hours. PEG conformation determined the interaction of liposomes with the collagen hydrogel and their transport behaviour. Interestingly, liposomes with mushroom PEG conformation accumulated on the interface of the collagen hydrogel, creating a dense liposomal front with short diffusion distances into the hydrogels. On the other hand, liposomes with dense brush PEG conformation interacted to a lesser extent with the collagen hydrogel and diffused to longer distances. In conclusion, a better understanding of PEG surface coating as a modifier of transport in a model ECM matrix has resulted. This knowledge will improve design of future liposomal drug carrier systems.

The effect of surface PEGylation on nanoparticle transport through an extracellular matrix (ECM) is an important determinant for tumor targeting success.     

Gallbladder bile: an experimental study in dogs using MR imaging and proton MR spectroscopy

Magnetic resonance (MR) imaging, proton MR spectroscopy, and biochemical analysis were performed to investigate MR signal intensity (SI) differences between concentrated and dilute gallbladder bile of seven fasting and five sincalide-treated dogs. MR images revealed high SI from bile of fasting dogs and low to medium SI in sincalide-treated dogs when spin-echo (SE) pulse sequences with repetition rates of 0.5 and 2.0 sec were used. Proton MR spectra were similar for fasting and sincalide-treated dogs. In fasting dogs, water content in the bile was slightly lower, and cholesterol, phospholipid, and bile acid concentrations were higher. More than 90% of proton signals in all Fourier transform free induction decay spectra emanated from water molecules, and no lipid proton resonances were detected in Fourier transform SE spectra after tau delays of 7 msec. These results indicate that the differences in SI are caused by alterations in relaxation times of water protons, possibly resulting from the interactions of water protons and macromolecules.     

Perirectal inflammatory disease: CT findings

The findings on computed tomographic (CT) scans were reviewed in 42 patients with perirectal inflammatory disease and suspected perirectal abscesses. CT was reliable for use in distinguishing perirectal abscesses from cellulitis and in localizing both supralevator and infralevator abscesses. CT allowed correct diagnosis of 13 surgically proved perirectal abscesses in ten patients, including three with residual abscesses after surgical drainage. In three patients with supralevator abscesses, the abscess was missed on initial surgical exploration. In patients without abscesses, CT was helpful in evaluating the extent of perirectal inflammation; however, it was not possible to determine its cause. The anatomy on CT scans of the pararectal spaces is reviewed, with emphasis on useful anatomic landmarks in the axial plane for distinguishing supralevator from infralevator abscesses.     

Magnetic resonance imaging and spectroscopy of hepatic iron overload

Experimental animals that had been given excess iron in their diet were studied by magnetic resonance (MR) imaging in vivo and by magnetic resonance (MR) spectroscopy in vitro. Hepatic iron overload in patients with transfusional iron excess was studied by MR imaging, and isolated iron protein fractions were studied in vitro by MR spectroscopy. The spin echo image intensity of livers with iron overload was decreased because of the extreme decreases in T2 compared with normal; T1 was decreased only moderately. The relaxation rates 1/T2 and 1/T1 both showed a linear relationship to hepatic iron levels. Ferritin solutions showed moderate decreases in T2 and mild decreases in T1. The T2 relaxivity of ferritin, which is due to the iron core rather than the apoferritin protein shell, does not appear sufficient to account for the extreme decrease in T2 observed in hepatic iron overload. Low molecular weight cytosol iron is present in lower concentrations than ferritin but potentially has much greater relaxivity and may contribute to the MR findings. These techniques may be useful in other studies of iron metabolism.     

Evaluation of abdominal trauma by computed tomography

Computed tomography (CT) was used in the evaluation of 100 patients suffering abdominal trauma. The type of trauma was blunt in 78 patients, penetrating in eight, and iatrogenic in 14. Forty per cent of cases had normal CT scans, while 60% showed substantial abdominal or retroperitoneal injuries. Surgery, clinical follow-up, and repeated radiologic examinations confirmed the accuracy of CT, and there were no cases in which medical or surgical management was inappropriately guided by CT. A wide variety of injuries was detected, including 19 splenic, eight hepatic, six pancreatic, 13 renal, 13 retroperitoneal or abdominal wall, and one intraperitoneal. CT has major advantages over plain radiography, radionuclide imaging, and angiography in assessment of trauma-induced injuries.     

Intracerebral venous angioma.

Intracerebral venous angioma is a rare congenital vascular malformation of the brain. Three cases are reported, all of which had strikingly similar angiographic findings in the venous phase, viz., a local network of small medullary veins which converge centrally into a single large venous channel which courses transcerebrally to reach the superficial venous system. No gross abnormalities are seen in the arterial phase with the usual techniques. However, magnification delineated enlarged arterial branches supplying the periphery of the malformation in 2 of the 3 cases. A poorly marginated homogeneous blush and early filling of the draining veins were also seen in these 2 patients. The findings in the venous phase agree with those described in previous isolated case reports and appear to be highly suggestive of this rare malformation.     

Activation of the alternative pathway of complement by grain

Ground whole rye and airborne rye dust of comparable size distribution were tested for their ability to activate the complement cascade via the alternative pathway. Precipitin-negative pooled normal human serum was incubated with increasing amounts of the two rye dusts. Electrophoresis of the resultant supernatant fluids demonstrated the conversion of the proactivator of the third component of complement to the gamma-migrating activator of the third component. This activation was completely prevented by pre-treating the serum with the chelator EDTA, while pre-treatment with EGTA allowed suboptimal arc conversion, strongly implying that complement was activated via the alternative pathway. Quantification of the supernatant fluids showed dose-dependent complement consumption as defined by both CH₁₀₀ immunoditfusion and CH₅₀ tube haemolytic techniques. Airborne rye dust showed a greater quantitative potential than ground whole rye for activating the alternative pathway. These results indicate the possibility of the direct action of airborne organic dusts on the induction of inflammatory sequelae in the lungs of both sensitized and unsensitized individuals.