Genipin-crosslinked albumin nanoparticles containing neratinib and silibinin: A dual-death therapy for triple negative breast cancer.

Triple negative breast cancer (TNBC) cells resist chemotherapy by hijacking apoptosis. Alternative cell death forms like ferroptosis offer new treatment options. A combined therapy using neratinib (NTB; ferroptosis inducer) and silibinin (SLB; apoptosis inducer) via albumin-based nanocarriers (N-S Alb NPs) was explored to target TNBC. N-S Alb NPs had optimal size (134.26 ± 10.23 nm), PDI (0.224 ± 0.01), and % entrapment efficiency (∼80 % for NTB and ∼87 % for SLB). Transmission electron microscopy confirmed their spherical shape. In vitro release studies showed sustained drug release without hemolysis risk. N-S Alb NPs had higher cellular uptake and cytotoxicity than individual drugs or their mixture. IC50 values for N-S Alb NPs were significantly reduced in MDA-MB-231 (∼2.23-fold) and 4T1 (∼1.85-fold) cell lines and apoptosis index were significantly higher in MDA-MB-231 (∼1.31-fold) and 4T1 cell line (∼1.35-fold) than the physical mixture of both drugs (NTB + SLB). N-S Alb NPs generated more reactive oxygen species (ROS) and caused mitochondrial membrane depolarization, indicating increased cell death. They also exhibited better ferroptosis induction by reducing glutathione (GSH), increasing Fe2+ activity and MDA levels in TNBC cells. Thus, N-S Alb NPs had the ability to promote "mixed" type cell death, showed promise in enhancing the payload capabilities and targeting in TNBC.

Effect of foam insertion in aneurysm sac on flow structures in parent lumen: relating vortex structures with disturbed shear.

Numerous studies suggest that disturbed shear, causing endothelium dysfunction, can be related to neighboring vortex structures. With this motivation, this study presents a methodology to characterize the vortex structures. Precisely, we use mapping and characterization of vortex structures' changes to relate it with the hemodynamic indicators of disturbed shear. Topological features of vortex core lines (VCLs) are used to quantify the changes in vortex structures. We use the Sujudi-Haimes algorithm to extract the VCLs from the flow simulation results. The idea of relating vortex structures with disturbed shear is demonstrated for cerebral arteries with aneurysms virtually treated by inserting foam in the sac. To get physiologically realistic flow fields, we simulate blood flow in two patient-specific geometries before and after foam insertion, with realistic velocity waveform imposed at the inlet, using the Carreau-Yasuda model to mimic the shear-thinning behavior. With homogenous porous medium assumption, flow through the foam is modeled using the Forchheimer-Brinkman extended Darcy model. Results show that foam insertion increases the number of VCLs in the parent lumen. The average length of VCL increases by 168.9% and 55.6% in both geometries. For both geometries under consideration, results demonstrate that the region with increased disturbed shear lies in the same arterial segment exhibiting an increase in the number of oblique VCLs. Based on the findings, we conjecture that an increase in oblique VCLs is related to increased disturbed shear at the neighboring portion of the arterial wall.

Assessment and visualization of hemodynamic loading in aneurysm sac and neck: Effect of foam insertion.

Shape memory polymer (SMP) foam is often proposed as the future alternative of coils in aneurysm treatment devices. Present work numerically investigates the unsteady, three-dimensional simulation of blood flow in a cerebral aneurysm filled with SMP foam. Simulations are conducted on patient-specific geometries with realistic blood velocity waveform imposed at the inlet while SMP foam is treated as a porous medium. The present study introduces a "loading risk map" that helps to visualize the hemodynamic effect of foam insertion on the aneurysm sac and neck. The loading risk maps suggest that while the SMP foam subdues the flow and wall shear pulsations in the aneurysm sac, the pressure distribution is minimally affected. The maps suggest that while the downstream lip is the most risk-prone site for both geometries, downstream vascular anatomy significantly influences foam efficiency in reducing pressure and wall shear stress loading.

Inorganic clay nanocomposite system for improved cholinesterase inhibition and brain pharmacokinetics of donepezil.

Objective: Brain drug delivery for effective treatment of neurodegenerative disorders is limited due to the selective permeability of blood brain barrier (BBB). During the past few years, development of novel delivery system has attracted considerable attention of formulation scientists to overcome the permeability limitation caused by BBB.Significance: Based on the outcomes of this study and taking into consideration of the unique characteristics of laponite, it can be further explored to deliver many other central nervous system acting drugs.Methods: In the present study, laponite (LAP) nanocomposites were exploited for the improved brain delivery of donepezil (DZ) following encapsulation approach due to their nano-size and positive charge at pH <9.Result: The size of prepared nanocomposites was 53.7 ± 4.0 to 137.7 ± 11.0 nm. The drug was released in a sustained manner till 120 h in phosphate buffer saline (pH 7.4) and acid phthalate buffer (pH 4.0). LAPDZ formulations inhibited acetylcholinesterase approximately by 82%, significantly higher (p < 0.05) than plain DZ (30%). Swiss albino mice exhibited enhanced brain uptake of LAPDZ administered via intravenous route. Promising pharmacokinetic parameters were observed in animals treated with LAPDZ. LAPDZ formulation showed half-life (t1/2), volume of distribution (Vd) and clearance (Cl) as 5.53 ± 0.40 h-1, 0.129 ± 0.02 L, 0.015 ± 0.002 L/h, respectively. While DZ solution showed the same parameters as 1.06 ± 0.12 h-1, 0.168 ± 0.01 L, 0.106 ± 0.013 L/h, respectively. The brain uptake of LAPDZ formulation was improved with quintuplet t1/2.Conclusion: Based on the results of present study, it is proposed that the formulated nanocomposite would result in improved patient compliance with therapeutic effect at lower doses.

Blood brain barrier: An overview on strategies in drug delivery, realistic in vitro modeling and in vivo live tracking.

Blood brain barrier (BBB) is a group of astrocytes, neurons and endothelial cells, which makes restricted passage of various biological or chemical entities to the brain tissue. It gives protection to brain at one hand, but at the other hand it has very selective permeability for bio-actives and other foreign materials and is one of the major challenges for the drug delivery. Nanocarriers are promising to cross BBB utilizing alternative route of administration such as intranasal and intra-carotid drug delivery which bypasses BBB. In future more optimized drug delivery system can be achieved by compiling the best routes with the best carriers. Single photon emission tomography (SPECT) and different brain-on-a-chip in vitro models are being very reliable to study live in vivo tracking of BBB and its pathophysiology, respectively. In the current review we have tried to exploit mechanistically all these to understand and manage the various BBB disruptions in diseased condition along with crossing the hurdles occurring in drug or gene delivery across BBB.