Drug Concentration Distribution Research Articles

Model development using hybrid method for prediction of drug release from biomaterial matrix

A comprehensive multi-scale computational strategy was developed in this study based on mass transfer and machine learning for simulation of drug concentration distribution in a biomaterial matrix. The controlled release was modeled and validated via the hybrid model. Mass transfer equations along with kinetics models were solved numerically and the results were then used for machine learning models. We investigated the performance of three regression models, namely Decision Tree (DT), Random Forest (RF), and Extra Tree (ET) in predicting medicine concentration (C) based on r and z data. Hyper-parameter optimization is conducted using Glowworm Swarm Optimization (GSO). Results revealed high predictive accuracy across all models, with ET demonstrating superior performance, achieving a coefficient of determination value (R2) of 0.99854, an RMSE of 1.1446E-05, and a maximum error of 6.49087E-05. DT and RF also exhibit notable performance, with coefficients of determination equal to 0.99571 and 0.99655, respectively. These results highlight the effectiveness of ensemble tree-based methods in accurately predicting chemical concentrations, with Extra Tree (ET) Regression emerging as the most promising model for this specific dataset.

Medication adherence framework: A population-based pharmacokinetic approach and its application in antimalarial treatment assessments.

We reported here on the development of a pharmacometric framework to assess patient adherence, by using two population-based approaches - the percentile and the Bayesian method. Three different dosing strategies were investigated in patients prescribed a total of three doses; (1) non-observed therapy, (2) directly observed administration of the first dose, and (3) directly observed administration of the first two doses. The percentile approach used population-based simulations to derive optimal concentration percentile cutoff values from the distribution of simulated drug concentrations at a specific time. This was done for each adherence scenario and compared to full adherence. The Bayesian approach calculated the posterior probability of each adherence scenario at a given drug concentration. The predictive performance (i.e., Youden index, receiver operating characteristic [ROC] curve) of both approaches were highly influenced by sample collection time (early was better) and interindividual variability (smaller was better). The complexity of the structural model and the half-life had a minimal impact on the predictive performance of these methods. The impact of the assay limitation (LOQ) on the predictive performance was relatively small if the fraction of LOQ data was less than 20%. Overall, the percentile method performed similar or better for adherence predictions compared to the Bayesian approach, with the latter showing slightly better results when investigating the adherence to the last dose only. The percentile approach showed acceptable adherence predictions (area under ROC curve > 0.74) when sampling the antimalarial drugs piperaquine at day 7 postdose and lumefantrine at day 3 postdose (i.e., 12 h after the last dose). This could be a highly useful approach when evaluating programmatic implementations of preventive and curative antimalarial treatment programs in endemic areas.

Multi-physics simulations for investigating the effect of electrode conditions on transscleral ocular iontophoresis for particulate drug delivery into ocular tissues.

Transscleral ocular iontophoresis has been proposed to deliver charged particulate drugs to ocular tissues effectively by transmitting a weak electrical current through the sclera. The electric fields formed are influenced by the electrode conditions, thus affecting the amount of particulate drugs delivered to the ocular tissues via iontophoresis. Computational simulation is widely used to simulate drug concentrations in the eye; therefore, reflecting the characteristics of the drugs in living tissues to the simulations is important for a more precise estimation of drug concentration. In this study, we investigated the effect of electrode conditions (location and size) on the efficacy of transscleral iontophoresis. We first determined the simulation parameters based on the comparison of the amount of drug in the sclera in the simulation and in vivo experimental results. The injection of the negatively charged nanoparticles into the cul-de-sac of the lower eyelid was simulated. The active electrode (cathode) was attached to the skin immediately above the injection site, while the return electrode (anode) was placed over the eyebrow. The drug concentration distribution in the eye, based on either the location or size of each electrode, was evaluated using the finite element method with the estimated simulation parameters. Our results indicate that drug permeability varies depending on the location and the size of the electrodes. Our findings demonstrate that the determination of optimal electrode conditions is necessary to enhance the effectiveness of transscleral iontophoresis. The online version contains supplementary material available at 10.1007/s13534-024-00359-2.

Zero-order Release of Metformin in Polyacrylamide Hydrogel

Water-soluble polymers with a three-dimensional crosslinked network structure, known as a hydrogel, has widespread applications in clinical and experimental medicine as drug carriers. Upon entering the targeted area for treatment, hydrogel loaded with drugs releases them through both diffusion and self-degradation mechanisms. In this study, the drug release process in polyacrylamide hydrogel uniformly loaded with metformin hydrochloride is investigated. To achieve a uniform drug release rate from the hydrogel, we establish a statistical model of drug release from polyacrylamide hydrogel using response surface methodology based on experimental design technique. The established statistical model can predict drug release behavior at a low cost within the design domain. The relationship between initial drug concentration and drug release rate in metformin-loaded polyacrylamide hydrogel has been investigated. A zero-order drug release effect in hydrogels is achieved through an optimized design of the initial distribution of drug concentration of a five-layered drug-containing hydrogel. This study has significant implications for the realization of drug molecule transport and sustained release in vivo.

Image-Based Modeling of Drug Delivery during Intraperitoneal Chemotherapy in a Heterogeneous Tumor Nodule.

Intraperitoneal (IP) chemotherapy is a promising treatment approach for patients diagnosed with peritoneal carcinomatosis, allowing the direct delivery of therapeutic agents to the tumor site within the abdominal cavity. Nevertheless, limited drug penetration into the tumor remains a primary drawback of this method. The process of delivering drugs to the tumor entails numerous complications, primarily stemming from the specific pathophysiology of the tumor. Investigating drug delivery during IP chemotherapy and studying the parameters affecting it are challenging due to the limitations of experimental studies. In contrast, mathematical modeling, with its capabilities such as enabling single-parameter studies, and cost and time efficiency, emerges as a potent tool for this purpose. In this study, we developed a numerical model to investigate IP chemotherapy by incorporating an actual image of a tumor with heterogeneous vasculature. The tumor's geometry is reconstructed using image processing techniques. The model also incorporates drug binding and uptake by cancer cells. After 60 min of IP treatment with Doxorubicin, the area under the curve (AUC) of the average free drug concentration versus time curve, serving as an indicator of drug availability to the tumor, reached 295.18 mol·m-3·s-1. Additionally, the half-width parameter W1/2, which reflects drug penetration into the tumor, ranged from 0.11 to 0.14 mm. Furthermore, the treatment resulted in a fraction of killed cells reaching 20.4% by the end of the procedure. Analyzing the spatial distribution of interstitial fluid velocity, pressure, and drug concentration in the tumor revealed that the heterogeneous distribution of tumor vasculature influences the drug delivery process. Our findings underscore the significance of considering the specific vascular network of a tumor when modeling intraperitoneal chemotherapy. The proposed methodology holds promise for application in patient-specific studies.

Controlling release from encapsulated drug-loaded devices: insights from modeling the dissolution front propagation.

Dissolution of drug from its solid form to a dissolved form is an important consideration in the design and optimization of drug delivery devices, particularly owing to the abundance of emerging compounds that are extremely poorly soluble. When the solid dosage form is encapsulated, for example by the porous walls of an implant, the impact of the encapsulant drug transport properties is a further confounding issue. In such a case, dissolution and diffusion work in tandem to control the release of drug. However, the interplay between these two competing processes in the context of drug delivery is not as well understood as it is for other mass transfer problems, particularly for practical controlled-release considerations such as an encapsulant layer around the drug delivery device. To address this gap, this work presents a mathematical model that describes controlled release from a drug-loaded device surrounded by a passive porous layer. A solution for the drug concentration distribution is derived using the method of eigenfunction expansion. The model is able to track the dissolution front propagation, and predict the drug release curve during the dissolution process. The utility of the model is demonstrated through comparison against experimental data representing drug release from a cylindrical drug-loaded orthopedic fixation pin, where the model is shown to capture the data very well. Analysis presented here reveals how the various geometrical and physicochemical parameters influence drug dissolution and, ultimately, the drug release profile. It is found that the non-dimensional initial concentration plays a key role in determining whether the problem is diffusion-limited or dissolution-limited, whereas the nature of the problem is largely independent of other parameters including diffusion coefficient and encapsulant thickness. We expect the model will prove to be a useful tool for those designing encapsulated drug delivery devices, in terms of optimizing the design of the device to achieve a desired drug release profile.

Accurate numerical integration of highly stiff pharmacokinetics models using continuous block implicit hybrid one-step collocation methods

The differential equations of pharmacokinetic models, obtained from the formulation based on the Fick's perfusion principle and law of conservation of mass action, deals with absorption, distribution, and elimination of drugs by the body systems. In the formulation, the ordinary differential equations obtained may result into highly stiff systems whereby suitable implicit methods have to be employed to solve accurately drug concentration in the body systems, owing to the complex nature of the exact solutions, if they exist. Further, because of the large and increasing interest in the problems of drug kinetics, it is necessary to apply considerably accurate implicit numerical methods in evaluating and in applying them to specific cases. These solutions are to help determine the distribution of drug concentration in different compartments (parts) of the human body network systems as a fundamental step to help in understanding and improving treatments. This is necessary since drug concentration in each compartment is different from one another because of the differences in drug affinity to tissues. From the study, the solution curves obtained show that drug level in the gastrointestinal tract decreases with the passage of time, while drug concentration in the blood increases from zero and reaches its maximum level and then decreases steadily again. We further, compared the model curves with some experimental data plots published in scientific papers. The results obtained from the study can be used extensively for various drug diffusion problems arising in pharmaceutical studies. The presented results widen the applicability of the continuous block implicit hybrid one-step collocation methods to diffusion process which have good number of applications in the drug control, drug dosage and other related problems in pharmaceutical and biomedical industries.

Drug sustained release from degradable drug-loaded in-situ hydrogels in the posterior eye: A mechanistic model and analytical method

Biodegradable in-situ hydrogels as drug release carriers injected into the eye can treat Neovascular age-related macular degeneration (NV-AMD). Obviously, the biodegradation behavior of hydrogels affects the drug diffusion process in the eye, which can influence the drug concentration distribution and development in the macula. Herein, the intraocular diffusion process of the drugs which are released from the biodegradable hydrogel was studied by using finite element method, with the effect of the biodegradation behavior of hydrogels on the drug release process was considered. The effects of the initial average mesh size, rate constant of biodegradation, and position of hydrogels on the drug release process were analyzed. The results showed that the biodegradation behavior of hydrogels decreases the drug release rate by gradually expanding the mesh size, prolonging the duration of drug treatment in the macula. The biodegradable hydrogels’ position, initial mesh size, and biodegradation rate constant also affect drug delivery. Different locations of hydrogels denote different distances between the drug and macula, which affects the diffusion time and further influence the macular drug concentration. The initial mesh size alters the initial drug release rate, which affects the duration of hydrogels’ drug release process and drug concentration and duration in the macula. The hydrogel degradation rate affects the development of its mesh size, which affects the drug diffusion in hydrogels, and further affects the drug concentration in the macular region.

Modeling and Analysis of Nanoparticle with Non-Uniform Drug Concentration Distribution: How to Approach a Programmed Delivery?

Modeling and Analysis of Nanoparticle with Non-Uniform Drug Concentration Distribution: How to Approach a Programmed Delivery?

Drug diffusion and release from a bioerodible spherical capsule

Controlled release of a drug contained in a spherical polymer capsule is of significant interest in many fields of medicine. There is growing interest in tailoring the erosion properties of the drug to help control and optimize the drug release process. Theoretical understanding of the nature of drug release from a bioerodible capsule is, therefore, important for designing effective drug delivery systems. While drug release from a fixed-radius capsule is relatively easier to model, the shrinking nature of a bioerodible capsule due to surface erosion presents several difficulties in theoretical modeling. This work presents a closed-form solution for the drug concentration distribution and drug delivery characteristics from a spherical capsule undergoing linear surface erosion. This problem is solved by a transformation that converts the moving boundary problem into a fixed boundary problem. For uniform initial drug distribution, the solution is shown to depend on a single non-dimensional parameter. The theoretical model is used to develop an understanding of the impact of varying the drug diffusion coefficient and rate of erosion on drug delivery characteristics. It is found that, in general, the nature of drug release in a bioerodible sphere is determined by a delicate balance between two simultaneously occurring processes – erosion and diffusion. This work improves the theoretical understanding of diffusion in drug delivery systems by accounting for the practical erosion phenomena, and may contribute towards the design and optimization of drug delivery systems.

Analysis of topical dosing and administration effects on ocular drug delivery in a human eyeball model using computational fluid dynamics

Predicting the spatial and temporal drug concentration distributions in the eyes is essential for quantitative analysis of the therapeutic effect and overdose issue via different topical administration strategies. To address such needs, an experimentally validated computational fluid dynamics (CFD) based virtual human eye model with physiologically realistic multiple ophthalmic compartments was developed to study the effect of administration frequency and interval on drug concentration distributions. Timolol was selected as the topical dosing drug for the numerical investigation of how administration strategy can influence drug transport and concentration distribution over time in the human eye. Administration frequencies employed in this study are 1–4 times per day, and the administration time intervals are Δt = 900 s, 1800 s, and 3600 s. Numerical results indicate that the administration frequency can significantly affect the temporal timolol concentration distributions in the ophthalmic compartments. More administrations per day can prolong the mediations at relatively high levels in all compartments. CFD simulation results also show that shorter administration intervals can help the medication maintain a relatively higher concentration during the initial hours. Longer administration intervals can provide a more stable medication concentration during the entire dosing time. Furthermore, numerical parametric analysis in this study indicates that the elimination rate in the aqueous humor plays a dominant role in affecting the drug concentrations in multiple ophthalmic compartments. However, it still needs additional clinical data to identify how much drugs can be transported into the cardiac and/or respiratory systems via blood circulation for side effect assessment.

Spectrophotometric Methodologies Applied for Determination of Pharmaceuticals

Background: The development of innovative approaches in drug analysis is a challenging task for medicine, pharmacy, and engineering sciences. For instance, the requirement of proper dosage forms in releasing active ingredients is crucial. It is essential to analyze drugs in biological liquids for early diagnosis and treatment purposes. Drug analysis is also of great importance to control the quality of pharmaceutical products, test their efficacy, and develop novel drug formulation. The present review is aimed to highlight the most recent spectrophotometric approaches applied to analyze various classes of drugs in biological media and/or dosage forms. Methods: Direct and derivative UV/UV-Vis spectrophotometry and a combination of various techniques with spectrophotometry, such as injection analysis and chemometrics, have most widely been applied in the analysis of dosage forms. In addition, emerging technologies, such as UV imaging allows to obtain the distribution of drug concentration in time-resolved 2D images based on UV light absorption, utilization of nanotechnology, self-assembled nanomaterials, and aptamer-based nanoparticles have gained interests to investigate drug assays and to quantify the proper drug release. Results: Due to their high versatility, ease of application, low cost, and fast response, spectrophotometric methods are one of the most preferable methods providing high accuracy and precision with a wide linear range in drug analysis. Conclusion: Selected examples demonstrating the applicability of spectrophotometric methods in pharmaceutical assays in this review might contribute to the overall importance of the analytical test used in modern pharmaceutical analysis.

Rapid Determination of Pemetrexed Concentration and Distribution in Human Breast Cancer Cells (McF-7) Based on UHPLC-MS/MS

Cell is the basic unit of structure and function of all living bodies. The study of intracellular drug concentration distribution is helpful to understand the drug efficacy of target site. Pemetrexed is a new multitarget folate antagonist with pyrrolidine group as its core structure. An ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was developed for rapid quantification of pemetrexed concentration in human breast cancer cells (MCF-7). Sample pretreatment was completed by protein precipitation using methanol. The optimized chromatographic separation was achieved on a ZORBAX SB-C18 column (2.1 × 150 mm, 3.5 μm). The column was equilibrated with initial mobile phase and eluted under gradient phases containing 0.1% formic acid in water (phase A) and in acetonitrile (phase B). The gradient program started at 5% B, increased to 95% B in 2 min, and then held at 95% B for 1.5 min. The linear range of pemetrexed in cells and nucleus was 2.0–200.0 ng/mL, while in the medium sample it was 50.0–5000.0 ng/ml, and the correlation coefficients were all greater than 0.99. The recovery was 47.50–67.55% (2.0–200.0 ng/mL) and 82.72–97.15% (50.0–5000.0 ng/mL), and the matrix effect was 98.10–100.62% (2.0–200.0 ng/mL) and 89.78–97.65% (50.0–5000.0 ng/mL). Interday precision and intraday precision (RSD%) were less than 15.0% (for LLOQ, less than 20%), and accuracy (RE%) was within ±15%; the deviation of stability was within ±15%, all meeting the requirements of biological sample analysis. The results of intracellular samples showed that the concentration of pemetrexed reached its peak at 3 h after administration. The concentration of pemetrexed in the nucleus continued to increase 2 h after administration and may have reached the maximum concentration at 6 h.

Determination of the distribution of drug concentration and tissue optical properties for ALA-mediated anal photodynamic therapy.

PDT efficacy depends on the availability and dynamic interactions of photosensitizer, light, and oxygen. Tissue optical properties influence the delivered light dose and impact PDT outcome. In-vivo measurements of tissue optical properties and photosensitizer concentration enable determination of explicit and implicit dose factors affecting PDT and helps to understand the underlying biophysical mechanism of PDT. In this study, we measure tissue optical properties (absorption μa (λ) and scattering μs' (λ) coefficients) and PpIX concentration in tissue simulating liquid phantoms with a geometry that resembles anal canal. In-vivo light fluence rate and photosensitizer fluorescence of 405nm excitation light source were acquired using a dual-motor continuous wave transmittance spectroscopy system. We characterized the tissue optical properties correction factor of fluorescence signal using a series of tissue simulating phantoms with known PpIX concentrations and with absorption coefficient between 0.1 - 0.9 cm-1 and reduced scattering coefficient between 5 - 40 cm-1. The results demonstrated that our spectroscopy system could determine the distribution of tissue optical properties and PPIX concentration during anal PDT.

In Vivo Experimental and Analytical Studies for Bevacizumab Diffusion Coefficient Measurement in the Rabbit Vitreous Humor.

In order to measure the effective diffusion coefficient of Bevacizumab (Avastin, Genentech) in the vitreous humor, a new technique is developed based on the "contour method" and in vivo optical coherence tomography measurements. After injection of Bevacizumab-fluorescein conjugated compound solution into the rabbit eye, the contours of drug concentration distribution at the subsurface of injection were tracked over time. The 2D contours were extrapolated to 3D contours using reasonable assumptions and a numerically integrated analytical model was developed for the theoretical contours for the irregularly shaped drug distribution in the experimental result. By floating the diffusion coefficient, different theoretical contours were constructed and the least-squares best fit to the experimental contours was performed at each time point to get the best fit solution. The approach generated consistent diffusion coefficient values based on the experiments on four rabbit eyes over a period of 3 h each, which gave , and the corresponding theoretical contours matched well with the experimental contours. The quantitative measurement of concentration using optical coherence tomography and fluorescein labeling gives a new approach for the "noncontact" in vivo drug distribution measurement within vitreous.

Characterization method for calculating diffusion coefficient of drug from polylactic acid (PLA) microneedles into the skin

Microneedles are designed for piercing the stratum corneum and delivering drugs into the epidermis and dermis layers of the skin. Their micrometric dimension causes minor or negligible stimulations to sensory nerve fibers in the dermis layer of the skin, making drug administration through microneedles less painful compared to conventional hypodermic needle injection. With the advancement of microneedle related research, an increasing number of drugs are using microneedle-mediated drug delivery in the topical area of the skin, including localized delivery of some highly toxic drugs. It is essential to understand drug diffusion from microneedles to skin to avoid unwanted spread of toxic drugs in non-infected areas.This work aims to 1) deliver into the skin tissue fluorescent rhodamine B as a model drug from coated polylactic acid (PLA) microneedles and dissolvable microneedles; 2) detect and depict the concentration distribution of the model drug from two types of microneedles into the skin tissue respectively; 3) determine a reliable diffusion coefficient of the model drug based on a constant source diffusion model and a limited source diffusion model for dissolvable microneedles and coated PLA microneedles, respectively. Dissolvable microneedles and coated PLA microneedles were designed and fabricated by a novel methodology combining 3D printing, chemical etching, micro-molding and drop coating. Rhodamine B was chosen as the model drug to enable fluorescent detection. Two types of microneedles were mounted to a single patch and inserted into porcine skin to deliver the model drug. After microneedle removal, confocal microscopy was used to monitor the fluorescence intensity of rhodamine B in the skin tissue. Based on an intensity-concentration calibration and two diffusion models, the diffusion coefficients of rhodamine B from the constant source (dissolvable microneedles) and limited source (coated PLA microneedles) to the dermis layer of porcine skin were inferred to be from 3.1×10−8 to 3.6×10−8 cm2/s. This characterization method is expected to offer medical personnel a quantitative understanding of the diffusion process related to microneedle-mediated transdermal drug delivery.

An Inverse Problem Solution Scheme for Solving the Optimization Problem of Drug-Controlled Release from Multilaminated Devices.

The optimization problem of drug release based on the multilaminated drug-controlled release devices has been solved in this paper under the inverse problem solution scheme. From the viewpoint of inverse problem, the solution of optimization problem can be regarded as the solution problem of a Fredholm integral equation of first kind. The solution of the Fredholm integral equation of first kind is a well-known ill-posed problem. In order to solve the severe ill-posedness, a modified regularization method is presented based on the Tikhonov regularization method and the truncated singular value decomposition method. The convergence analysis of the modified regularization method is also given. The optimization results of the initial drug concentration distribution obtained by the modified regularization method demonstrate that the inverse problem solution scheme proposed in this paper has the advantages of the numerical accuracy and antinoise property.

Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study

BackgroundInterleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm’s influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival. MethodsThree chronomodulation schedules (5:00–13:00, 13:00–21:00, and 21:00–5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI). ResultsThirty patients were enrolled and completed treatment. Two patients were treated at 5:00–13:00, 15 at 13:00–21:00, and 13 at 21:00–5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2–107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1–2), MSKCC score (0–2 vs. ≥ 3), IMDC risk score (0–2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule. ConclusionIL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.

Numerical investigation of drug transport from blood vessels to tumour tissue using a Tumour-Vasculature-on-a-Chip

Delivery of adequate amount of anticancer drugs to tumour sites is critical to achieve effective therapeutic treatment, but it remains challenging to observe drug transport and investigate the spatial distribution of the drug in tumour microenvironment experimentally. In this study, we investigated the drug transport from a blood vessel to a tumour tissue, and explored the effect of tumour size, tumour numbers and positioning on drug concentration distribution using a numerical method in combination with a microfluidic Tumour-Vasculature-on-a-Chip (TVOC) model. The TVOC model is composed of a blood vessel channel, and a tumour channel sandwiched with a porous membrane. A species transport model based on computational fluid dynamics was adopted to investigate drug transport. The numerical simulation was firstly validated using experimental data, and then used to analyse the spatial-temporal structure of the flow, and to investigate the effect of tumour size and positioning on drug transport and drug concentration heterogeneity. We found the drug concentration surrounding the tumour was highly heterogeneous, with the most downstream point the most difficult for drugs to transport and the nearest point to the blood vessel the easiest. Moreover, tumour size and positioning contributed significantly to this drug concentration heterogeneity on tumour surface, which was dramatically augmented in large and downstream-positioned tumours. These studies established the relationship between solid tumour size/positioning and drug concentration heterogeneity in the tumour microenvironment, which could help to understand heterogeneous drug distribution in tumour microenvironment.

Hemodynamic Effects on Particle Targeting in the Arterial Bifurcation for Different Magnet Positions.

The present study investigated the possibilities and feasibility of drug targeting for an arterial bifurcation lesion to influence the host healing response. A micrometer sized iron particle was used only to model the magnetic carrier in the experimental investigation (not intended for clinical use), to demonstrate the feasibility of the particle targeting at the lesion site and facilitate the new experimental investigations using coated superparamagnetic iron oxide nanoparticles. Magnetic fields were generated by a single permanent external magnet (ferrite magnet). Artery bifurcation exerts severe impacts on drug distribution, both in the main vessel and the branches, practically inducing an uneven drug concentration distribution in the bifurcation lesion area. There are permanently positioned magnets in the vicinity of the bifurcation near the diseased area. The generated magnetic field induced deviation of the injected ferromagnetic particles and were captured onto the vessel wall of the test section. To increase the particle accumulation in the targeted region and consequently avoid the polypharmacology (interaction of the injected drug particles with multiple target sites), it is critical to understand flow hemodynamics and the correlation between flow structure, magnetic field gradient, and spatial position.