Control of targeting ligand display by pH-responsive polymers on gold nanoparticles mediates selective entry into cancer cells.

Selective targeting of cells for intracellular delivery of therapeutics represents a major challenge for pharmaceutical intervention in disease. Here we show pH-triggered receptor-mediated endocytosis of nanoparticles via surface ligand exposure. Gold nanoparticles were decorated with two polymers: a 2 kDa PEG with a terminal folate targeting ligand, and a di-block copolymer including a pH-responsive and a hydrophilic block. At the normal serum pH of 7.4, the pH-responsive block (apparent pKa of 7.1) displayed a hydrophilic extended conformation, shielding the PEG-folate ligands, which inhibited cellular uptake of the nanoparticles. Under pH conditions resembling those of the extracellular matrix around solid tumours (pH 6.5), protonation of the pH-responsive polymer triggered a coil-to-globule polymer chain contraction, exposing folate residues on the PEG chains. In line with this, endocytosis of folate-decorated polymer-coated gold nanoparticles in cancer cells overexpressing folate receptor was significantly increased at pH 6.5, compared with pH 7.4. Thus, the tumour acidic environment and high folate receptor expression were effectively exploited to activate cell binding and endocytosis of these nanoparticles. These data provide proof-of-concept for strategies enabling extracellular pH stimuli to selectively enhance cellular uptake of drug delivery vectors and their associated therapeutic cargo.

Experimental and CFD flow studies in an intracranial aneurysm model with Newtonian and non-Newtonian fluids.

BACKGROUND: According to the clinical data, flow conditions play a major role in the genesis of intracranial aneurysms. The disorder of the flow structure is the cause of damage of the inner layer of the vessel wall, which leads to the development of cerebral aneurysms. Knowledge of the alteration of the flow field in the aneurysm region is important for treatment. OBJECTIVE: The aim is to study quantitatively the flow structure in an patient-specific aneurysm model of the internal carotid artery using both experimental and computational fluid dynamics (CFD) methods with Newtonian and non-Newtonian fluids. METHODS: A patient-specific geometry of aneurysm of the internal carotid artery was used. Patient data was segmented and smoothed to obtain geometrical model. An elastic true-to-scale silicone model was created with stereolithography. For initial investigation of the blood flow, the flow was visualized by adding particles into the silicone model. The precise flow velocity measurements were done using 1D Laser Doppler Anemometer with a spatial resolution of 50 µ m and a temporal resolution of 1 ms. The local velocity measurements were done at a distance of 4 mm to each other. A fluid with non-Newtonian properties was used in the experiment. The CFD simulations for unsteady-state problem were done using constructed hexahedral mesh for Newtonian and non-Newtonian fluids. RESULTS: Using 1D laser Doppler Anemometer the minimum velocity magnitude at the end of systole -0.01 m/s was obtained in the aneurysm dome while the maximum velocity 1 m/s was at the center of the outlet segment. On central cross section of the aneurysm the maximum velocity value is only 20% of the average inlet velocity. The average velocity on the cross-section is only 11% of the inlet axial velocity. Using the CFD simulation the wall shear stresses for Newtonian and non-Newtonian fluid at the end of systolic phase (t= 0.25 s) were computed. The wall shear stress varies from 3.52 mPa (minimum value) to 10.21 Pa (maximum value) for the Newtonian fluid. For the non-Newtonian fluid the wall shear stress minimum is 2.94 mPa; the maximum is 9.14 Pa. The lowest value of the wall shear stress for both fluids was obtained at the dome of the aneurysm while the highest wall shear stress was at the beginning of the outlet segment. The vortex in the aneurysm region is unstable during the cardiac cycle. The clockwise rotation of the streamlines at the inlet segment for Newtonian and non-Newtonian fluid is shown. CONCLUSION: The results of the present study are in agreement with the hemodynamics theory of aneurysm genesis. Low value of wall shear stress is observed at the aneurysm dome which can cause a rupture of an aneurysm.

Flow analyses of microvascular bifurcation using laser Doppler anemometry.

INTRODUCTION: Vascular surgery affects, among other factors, vessel geometry and might result in significant flow changes. For this reason a basic understanding of flow behavior at bifurcations plays an important role for microsurgeons. The aim of the present work was to establish an experimental model that enables rheological analyses of microvascular techniques. METHODS: Laser Doppler anemometer (LDA) measurements in a total of four cross-sections of a true-to-scale silicone model were performed. The model was installed in a circulatory experimental setup that simulates the physiologic human blood flow. The flow velocity data measured with the LDA system was processed and analyzed with an image-processing system. RESULTS: The flow curve at each cross-section was recorded for sevem cycles. A physiologic flow separation at bifurcational level was seen. Maximal and minimal horizontal velocities of all measurement points were between 0.32 and -0.15 m/s. No signs of turbulentlike flow were seen in the cross-sections distal to the bifurcation. A total, centrally located backflow in the diastolic phases in all four cross-sections was registered, resembling an oscillatorylike flow. CONCLUSIONS: The LDA analysis represents a valid experimental method for rheological evaluation of microvessels. Due to its unique high spatial and temporal resolution, it represents a worthwhile alternative to other flow investigations.