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Register a new userMathematical modeling of shear-activated targeted nanoparticle drug delivery for the treatment of aortic diseases
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The human aorta is a high-risk area for vascular diseases, which are commonly restored by thoracic endovascular aortic repair. In this paper, we report a promising shear-activated targeted nanoparticle drug delivery strategy to assist in the treatment of coarctation of the aorta and aortic aneurysm. Idealized three-dimensional geometric models of coarctation of the aorta and aortic aneurysm are designed, respectively. The unique hemodynamic environment of the diseased aorta is used to improve nanoparticle drug delivery. Micro-carriers with nanoparticle drugs would be targeting activated to release nanoparticle drugs by local abnormal shear stress rate (SSR). Coarctation of the aorta provides a high SSR hemodynamic environment, while the aortic aneurysm is exposed to low SSR. Results show that the upstream near-wall area of the diseased location is an ideal injection point for the micro-carriers, which could be activated by the abnormal SSR. Released nanoparticle drugs would be successfully targeted delivered to the aortic diseased wall. Besides, coarctation of the aorta would prevent blood flow to the descending aorta, while the effect of the aortic aneurysm on the blood flow distribution is negligible. This study preliminary demonstrates the feasibility of shear-activated targeted nanoparticle drug delivery in the treatment of aortic diseases and provides a theoretical basis for developing novel therapy.
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Drug delivery systems represent a promising strategy to treat cancer and to overcome the side effects of chemotherapy. In particular, polymeric nanocontainers have attracted major interest because of their structural and morphological advantages and the variety of polymers that can be used, allowing the synthesis of materials capable of responding to the biochemical alterations of the tumour microenvironment. While experimental methodologies can provide much insight, the generation of experimental data across a wide parameter space is usually prohibitively time consuming and/or expensive. To better understand the influence of varying design parameters on the drug release profile and drug kinetics involved, appropriately-designed mathematical models are of great benefit. Here, we developed a novel mathematical model to describe drug transport within, and release from, a hollow nanocontainer consisting of a core and a pH-responsive polymeric shell. The two-layer mathematical model fully accounts for drug dissolution, diffusion and interaction with polymer. We generated experimental drug release profiles using daunorubicin and [Cu(TPMA)(Phenantroline)](ClO_4)_2 as model drugs, for which the nanocontainers exhibited excellent encapsulation ability. The in vitro drug release behaviour was studied under different conditions, where the system proved capable of responding to the selected pH stimuli by releasing a larger amount of drug in an acidic than in the physiological environments. By comparing the results of the mathematical model with our experimental data, we were able to identify the model parameter values that best-fit the data and demonstrate that the model is capable of describing the phenomena at hand. The proposed methodology can be used to describe and predict the release profiles for a variety of drug delivery systems.
Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1beta. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications.
Background: Chronic rhinosinusitis (CRS) is a prevalent and disruptive disease. Medical management including nasal steroid sprays is the primary treatment modality. Computational fluid dynamics (CFD) has been used to characterize sinonasal airflow and intranasal drug delivery; however, variation in simulation methods indicates a need for large scale CFD model validation. Methods: Anatomic reconstructions of pre and post-operative CT scans of 3 functional endoscopic sinus surgery patients were created in Mimics(TM). Fluid analysis and drug particle deposition modeling were conducted using CFD methods with Fluent(TM) in 18 cases. Models were 3D printed and in vitro studies were performed using Tc99-labeled Nasacort(TM). Gamma scintigraphy signals and CFD-modeled spray mass were post-processed in a superimposed grid and compared. Statistical analysis using overlap coefficients (OCs) evaluated similarities between computational and experimental distributions and Kendalls tau rank correlation coefficient was employed to test independence. Results: OCs revealed strong agreement in percent deposition and grid profiles between CFD models and experimental results (mean [range] for sagittal, axial, and coronal grids were 0.69 [0.57], 0.61 [0.49], and 0.78 [0.44], respectively). Kendalls tau values showed strong agreement (average 0.73) between distributions, which were statistically significant (p < 0.05) apart from a single coronal grid in one model and two sagittal grids of another. Conclusions: CFD modeling demonstrates statistical agreement with in vitro experimental results. This validation study is one of the largest of its kind and supports the applicability of CFD in accurately modeling nasal spray drug delivery and using computational methods to investigate means of improving clinical drug delivery.
The aortic vessel tree is composed of the aorta and its branching arteries, and plays a key role in supplying the whole body with blood. Aortic diseases, like aneurysms or dissections, can lead to an aortic rupture, whose treatment with open surgery is highly risky. Therefore, patients commonly undergo drug treatment under constant monitoring, which requires regular inspections of the vessels through imaging. The standard imaging modality for diagnosis and monitoring is computed tomography (CT), which can provide a detailed picture of the aorta and its branching vessels if combined with a contrast agent, resulting in a CT angiography (CTA). Optimally, the whole aortic vessel tree geometry from consecutive CTAs, are overlaid and compared. This allows to not only detect changes in the aorta, but also more peripheral vessel tree changes, caused by the primary pathology or newly developed. When performed manually, this reconstruction requires slice by slice contouring, which could easily take a whole day for a single aortic vessel tree and, hence, is not feasible in clinical practice. Automatic or semi-automatic vessel tree segmentation algorithms, on the other hand, can complete this task in a fraction of the manual execution time and run in parallel to the clinical routine of the clinicians. In this paper, we systematically review computing techniques for the automatic and semi-automatic segmentation of the aortic vessel tree. The review concludes with an in-depth discussion on how close these state-of-the-art approaches are to an application in clinical practice and how active this research field is, taking into account the number of publications, datasets and challenges.
Purpose: In this study, procedures were developed to achieve efficient reversible conversion of a clinical linear accelerator (LINAC) and deliver electron FLASH (eFLASH) or conventional beams to the treatment room isocenter. Material & Methods: The LINAC was converted to deliver eFLASH beam within 20 minutes by retracting the x-ray target from the beams path, positioning the carousel on an empty port, and selecting 10 MV photon beam energy in the treatment console. Dose per pulse and average dose rate were measured in a solid water phantom at different depths with Gafchromic film and OSLD. A pulse controller counted the pulses via scattered radiation signal and gated the delivery for preset pulse count. A fast photomultiplier tube-based Cherenkov detector measured per pulse beam output at 2 ns sampling rate. After conversion back to clinical mode, conventional beam output, flatness, symmetry, field size and energy were measured for all clinically commissioned energies. Results: Dose per pulse of 0.86 +/- 0.01 Gy (310 +/- 7 Gy/s average dose rate) were achieved at isocenter. The dose from simultaneous irradiation of film and OSLD were within 1%. The PMT showed the LINAC required about 5 pulses before the output stabilized and its long-term stability was within 3% for measurements performed at 3 minutes intervals. The dose, flatness, symmetry, and photon energy were unchanged from baseline and within tolerance (1%, 3%, 2%, and 0.1% respectively) after reverting to conventional beams. Conclusion: 10 MeV FLASH beams were achieved at the isocenter of the treatment room. The beam output was reproducible but requires further investigation of the ramp up time in the first 5 pulses, equivalent to <100 cGy. The eFLASH beam can irradiate both small and large subjects in minimally modified clinical settings and dose rates can be further increased by reducing the source to surface distance.
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