Model For Drug Transport Research Articles

Human trophoblast organoids for improved prediction of placental ABC transporter-mediated drug transport

ATP-binding cassette (ABC) transporters, the important transmembrane efflux transporters, play an irreplaceable role in the placenta barrier. The disposition and drug-drug interaction of clinical drugs are also closely related to the functions of ABC transporters. The trophoblast is a unique feature of the placenta, which is crucial for normal placentation and maintenance during pregnancy. ABC transporters are abundantly expressed in placental syncytiotrophoblast, especially P-gp, BCRP, and MRPs. However, due to the lack of appropriate modeling systems, the molecular mechanisms of regulation between ABC transporters and trophoblast remains unclear. In this report, trophoblast organoids were cultured from human placental villi and developed into three-dimension structures with cavities. Trophoblast organoids exhibited transporter expression and localization comparable to that in villous tissue, indicating their physiological relevance for modeling drug transport. Moreover, fluorescent substrates can accumulate in organoids and be selectively inhibited by inhibitors, indicating the efflux function of ABC transporters (P-gp, BCRP, MRP1, and MRP2) in organoids. Two commonly used hypertension drugs and three antipsychotics were chosen to further validate this drug transport model and demonstrate varying degrees of inhibitory effects on ABC transporters. Overall, a new drug transport model mediated by ABC transporter has been successfully established based on human trophoblast organoids, which can be used to study drug transport in the placenta.

Effect of Circadian Rhythm Modulated Blood Flow on Nanoparticle based Targeted Drug Delivery in Virtual In Vivo Arterial Geometries.

A novel integration of nanoparticle-based drug delivery framework with shear-rate dependent blood flow model is presented. The framework is comprised of a unique combination of mechanics-based dispersion model, an asperity model for endothelium surface roughness, and a stochastic nanoparticle-endothelial cell adhesion model. Simulations of MRI based in vivo carotid artery system showcase the effects of vessel geometry on nanoparticle adhesion and retention at the targeted site. Vessel geometry and target site location impact nanoparticle adhesion; curved and bifurcating regions favor local accumulation of drug. It is also shown that aligning drug administration with circadian rhythm and sleep cycle can enhance the efficacy of drug delivery processes. These simulations highlight the potential of the computational modeling for exploring circadian rhythm modulated blood flow for targeted drug delivery while minimizing the in vivo experimentation.

FRAP analysis of peptide diffusion in extracellular matrix mimetic hydrogels as an in vitro model for subcutaneous injection

Subcutaneous (SC) injection is a common route of administration for drug compounds with poor oral bioavailability. However, bioavailability is often variable and incomplete, and there is as yet no standard accepted medium for simulation of the human SC environment. In this work we evaluate a FRAP based method for quantitative determination of local self-diffusion coefficients within extracellular matrix (ECM) mimetic hydrogels, potentially useful as in vitro models for drug transport in the ECM after SC injection. Gels were made consisting of either agarose, cross-linked collagen (COL) and hyaluronic acid (HA) or cross-linked HA. The diffusivities of uncharged FITC-dextran (FD4), the highly charged poly-lysine (PLK20) and poly-glutamic acid (PLE20) as well as the GLP-1 analogue exenatide were determined within the gels using FRAP. The diffusion coefficients in uncharged agarose gels were in the range of free diffusion in PBS. The diffusivity of cationic PLK20 in gels containing anionic HA was substantially decreased due to strong electrostatic interactions. Peptide aggregation could be observed as immobile fractions in experiments with exenatide. We conclude that the FRAP method provides useful information of peptides’ interactions and transport properties in hydrogel networks, giving insight into the mechanisms affecting absorption of drug compounds after subcutaneous injection.

A high-precision view of intercompartmental drug transport via simultaneous, seconds-resolved, in situ measurements in the vein and brain.

The ability to measure specific molecules at multiple sites within the body simultaneously, and with a time resolution of seconds, could greatly advance our understanding of drug transport and elimination. As a proof-of-principle demonstration, here we describe the use of electrochemical aptamer-based (EAB) sensors to measure transport of the antibiotic vancomycin from the plasma (measured in the jugular vein) to the cerebrospinal fluid (measured in the lateral ventricle) of live rats with temporal resolution of a few seconds. In our first efforts, we made measurements solely in the ventricle. Doing so we find that, although the collection of hundreds of concentration values over a single drug lifetime enables high-precision estimates of the parameters describing intracranial transport, due to a mathematical equivalence, the data produce two divergent descriptions of the drug's plasma pharmacokinetics that fit the in-brain observations equally well. The simultaneous collection of intravenous measurements, however, resolves this ambiguity, enabling high-precision (typically of ±5 to ±20% at 95% confidence levels) estimates of the key pharmacokinetic parameters describing transport from the blood to the cerebrospinal fluid in individual animals. The availability of simultaneous, high-density 'in-vein' (plasma) and 'in-brain' (cerebrospinal fluid) measurements provides unique opportunities to explore the assumptions almost universally employed in earlier compartmental models of drug transport, allowing the quantitative assessment of, for example, the pharmacokinetic effects of physiological processes such as the bulk transport of the drug out of the CNS via the dural venous sinuses.

Brownian particles in a soft matter potential: A model for directional drug transport and release in polymer network

Brownian particles in a soft matter potential: A model for directional drug transport and release in polymer network

Mathematical model of oxygen, nutrient, and drug transport in tuberculosis granulomas.

Physiological abnormalities in pulmonary granulomas-pathological hallmarks of tuberculosis (TB)-compromise the transport of oxygen, nutrients, and drugs. In prior studies, we demonstrated mathematically and experimentally that hypoxia and necrosis emerge in the granuloma microenvironment (GME) as a direct result of limited oxygen availability. Building on our initial model of avascular oxygen diffusion, here we explore additional aspects of oxygen transport, including the roles of granuloma vasculature, transcapillary transport, plasma dilution, and interstitial convection, followed by cellular metabolism. Approximate analytical solutions are provided for oxygen and glucose concentration, interstitial fluid velocity, interstitial fluid pressure, and the thickness of the convective zone. These predictions are in agreement with prior experimental results from rabbit TB granulomas and from rat carcinoma models, which share similar transport limitations. Additional drug delivery predictions for anti-TB-agents (rifampicin and clofazimine) strikingly match recent spatially-resolved experimental results from a mouse model of TB. Finally, an approach to improve molecular transport in granulomas by modulating interstitial hydraulic conductivity is tested in silico.

Analysis of reproducibility and robustness of a renal proximal tubule microphysiological system OrganoPlate 3-lane 40 for in vitro studies of drug transport and toxicity.

Microphysiological systems are an emerging area of in vitro drug development, and their independent evaluation is important for wide adoption and use. The primary goal of this study was to test reproducibility and robustness of a renal proximal tubule microphysiological system, OrganoPlate 3-lane 40, as an in vitro model for drug transport and toxicity studies. This microfluidic model was compared with static multiwell cultures and tested using several human renal proximal tubule epithelial cell (RPTEC) types. The model was characterized in terms of the functional transport for various tubule-specific proteins, epithelial permeability of small molecules (cisplatin, tenofovir, and perfluorooctanoic acid) versus large molecules (fluorescent dextrans, 60-150 kDa), and gene expression response to a nephrotoxic xenobiotic. The advantages offered by OrganoPlate 3-lane 40 as compared with multiwell cultures are the presence of media flow, albeit intermittent, and increased throughput compared with other microfluidic models. However, OrganoPlate 3-lane 40 model appeared to offer only limited (eg, MRP-mediated transport) advantages in terms of either gene expression or functional transport when compared with the multiwell plate culture conditions. Although OrganoPlate 3-lane 40 can be used to study cellular uptake and direct toxic effects of small molecules, it may have limited utility for drug transport studies. Overall, this study offers refined experimental protocols and comprehensive comparative data on the function of RPETCs in traditional multiwell culture and microfluidic OrganoPlate 3-lane 40, information that will be invaluable for the prospective end-users of in vitro models of the human proximal tubule.

Drug transport modeling in solid tumors: A computational exploration of spatial heterogeneity of biophysical properties

Inadequate uptake of therapeutic agents by tumor cells is still a major barrier in clinical cancer therapy. Mathematical modeling is a powerful tool to describe and investigate the transport phenomena involved. However, current models for interstitial flow and drug delivery in solid tumors have not yet embedded the existing heterogeneity of tumor biomechanical properties. The purpose of this study is to introduce a novel and more realistic methodology for computational models of solid tumor perfusion and drug delivery accounting for these regional heterogeneities as well as lymphatic drainage effects.Several tumor geometries were studied using an advanced computational fluid dynamics (CFD) modeling approach of intratumor interstitial fluid flow and drug transport. Hereby, the following novelties were implemented: (i) the heterogeneity of tumor-specific hydraulic conductivity and capillary permeability; (ii) the effect of lymphatic drainage on interstitial fluid flow and drug penetration.Tumor size and shape both have a crucial role on the interstitial fluid flow regime as well as drug transport illustrating a direct correlation with interstitial fluid pressure (IFP) and an inverse correlation with drug penetration, except for large tumors having a diameter larger than 50 mm. The results also suggest that the interstitial fluid flow and drug penetration in small tumors depend on tumor shape. A parameter study on the necrotic core size illustrated that the core effect (i.e. fluid flow and drug penetration alteration) was only profound in small tumors. Interestingly, the impact of a necrotic core on drug penetration differs depending on the tumor shape from having no effect in ideally spherical tumors to a clear effect in elliptical tumors with a necrotic core. A realistic presence of lymphatic vessels only slightly affected tumor perfusion, having no substantial effect on drug delivery.In conclusion, our findings illustrated that our novel parametric CFD modeling strategy in combination with accurate profiling of heterogeneous tumor biophysical properties can provide a powerful tool for better insights into tumor perfusion and drug transport, enabling effective therapy planning.

A Two-Species Finite Volume Scalar Model for Modeling the Diffusion of Poly(lactic-co-glycolic acid) into a Coronary Arterial Wall from a Single Half-Embedded Drug Eluting Stent Strut

This paper outlines the methodology and results for a two-species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA)) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two-species (free-drug and bound-drug) mass transport setup, including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of the drug between the free and bound-drug states. The model is solved by a 2D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over previously developed models using the finite-difference and finite element method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying the polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 h (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug.

In Vitro and In Vivo Models for Drug Transport Across the Blood-Testis Barrier.

The blood-testis barrier (BTB) is a selectively permeable membrane barrier formed by adjacent Sertoli cells (SCs) in the seminiferous tubules of the testes that develops intercellular junctional complexes to protect developing germ cells from external pressures. However, due to this inherent defense mechanism, the seminiferous tubule lumen can act as a pharmacological sanctuary site for latent viruses (e.g., Ebola, Zika) and cancers (e.g., leukemia). Therefore, it is critical to identify and evaluate BTB carrier-mediated drug delivery pathways to successfully treat these viruses and cancers. Many drugs are unable to effectively cross cell membranes without assistance from carrier proteins like transporters because they are large, polar, and often carry a charge at physiologic pH. SCs express transporters that selectively permit endogenous compounds, such as carnitine or nucleosides, across the BTB to support normal physiologic activity, although reproductive toxicants can also use these pathways, thereby circumventing the BTB. Certain xenobiotics, including select cancer therapeutics, antivirals, contraceptives, and environmental toxicants, are known to accumulate within the male genital tract and cause testicular toxicity; however, the transport pathways by which these compounds circumvent the BTB are largely unknown. Consequently, there is a need to identify the clinically relevant BTB transport pathways in in vitro and in vivo BTB models that recapitulate human pharmacokinetics and pharmacodynamics for these xenobiotics. This review summarizes the various in vitro and in vivo models of the BTB reported in the literature and highlights the strengths and weaknesses of certain models for drug disposition studies. SIGNIFICANCE STATEMENT: Drug disposition to the testes is influenced by the physical, physiological, and immunological components of the blood-testis barrier (BTB). But many compounds are known to cross the BTB by transporters, resulting in pharmacological and/or toxicological effects in the testes. Therefore, models that assess drug transport across the human BTB must adequately account for these confounding factors. This review identifies and discusses the benefits and limitations of various in vitro and in vivo BTB models for preclinical drug disposition studies.

Enhanced Drug Uptake on Application of Electroporation in a Single-Cell Model.

Electroporation method is a useful tool for delivering drugs into various diseased tissues in the human body. As a result of an applied electric field, drug particles enter the intracellular compartment through the temporarily permeabilized cell membrane. Consequently, electroporation method allows better penetration of the drug into the diseased tissue and improves treatment clinically. In this study, a more generalized model of drug transport in a single cell is proposed. The model is able to capture non-homogeneous drug transport in the cell due to non-uniform cell membrane permeabilization. Several numerical experiments are conducted to understand the effects of electric field and drug permeability on drug uptake into the cell. Through investigation, the appropriate electric field and drug permeability are identified, which lead to sufficient drug uptake into the cell. This model can be used by experimentalists to get information prior to conduct any experiment, and it may help reduce the number of actual experiments that might be conducted otherwise.

The development of a 3D-printed in vitro integrated oro-pharyngeal air-liquid interface cellular throat model for drug transport.

To simulate the deposition of drugs in the oro-pharynx region, several in vitro models are available such as the United States Pharmacopeia-Induction Port (USP-IP) throat and the Virginia Commonwealth University (VCU) models. However, currently, there is no such in vitro model that incorporates a biological barrier to elucidate drug transport across the pharyngeal cells. Cellular models such as in vitro air-liquid interface (ALI) models of human respiratory epithelial cell lines are extensively used to study drug transport. To date, no studies have yet been performed to optimise the ALI culture conditions of the human pharyngeal cell line Detroit 562 and determine whether it could be used for drug transport. Therefore, this study aimed to develop a novel 3D-printed throat model integrated with an ALI cellular model of Detroit 562 cells and optimise the culture conditions to investigate whether the combined model could be used to study drug transport, using Lidocaine as a model drug. Differentiating characteristics specific to airway epithelia were assessed using 3 seeding densities (30,000, 60,000, and 80,000 cells/well (c/w), respectively) over 21days. The results showed that Detroit 562 cells completely differentiates on day 18 of ALI for both 60,000 and 80,000 c/w with significant mucus production, showing response to bacterial and viral stimuli and development of functional tight junctions and Lidocaine transport with no significant differences observed between the ALI models with the 2 cell seeding densities. Results showed the suitability of the Low density (60,000 c/w or 1.8 × 105 cells/cm2) ALI model to study drug transport. Importantly, the developed novel 3D-printed throat model integrated with our optimised in vitro Detroit 562 ALI model showed transport of Lidocaine throat spray. Overall, the study highlights the potential of the novel 3D-printed bio-throat integrated model as a promising in vitro system to investigate the transport of inhalable drug therapies targeted at the oro-pharyngeal region.

The impact of strut profile geometry and malapposition on the haemodynamics and drug-transport behaviour of arteries treated with drug-eluting stents

Purpose Stent malapposition is one of the most significant precursors of stent thrombosis and restenosis. Adverse haemodynamics may play a key role in establishing these diseases, although numerical studies have used idealised drug transport models to show that drug transport from malapposed drug-eluting stent struts can be significant. This paper aims to study whether drug transport from malapposed struts is truly significant. Another aim is to see whether a streamlined strut profile geometry – with a 61% smaller coating but a 32% greater coating-tissue contact area – can mitigate the adverse haemodynamics associated with stent malapposition while enhancing drug uptake. Design/methodology/approach Two- and three-dimensional computational fluid dynamics simulations were used in this study. Unlike past simulations of malapposed drug-eluting stent struts, a qualitatively validated drug-transport model which simulates the non-uniform depletion of drug within the drug coating was implemented. Findings It was shown that even a 10-µm gap between the strut and tissue dramatically reduces drug uptake after 24 h of simulated drug transport. Furthermore, the streamlined strut profile was shown to minimise the adverse haemodynamics of malapposed and well-apposed stent struts alike and enhance drug uptake. Originality/value Unlike prior numerical studies of malapposed stent struts, which did not model the depletion of drug in the drug coating, it was found that stent malapposition yields negligible drug uptake. The proposed semicircular-profiled strut was also shown to be advantageous from a haemodynamic and drug transport perspective.

Mathematical Model of Macromolecular Drug Transport in a Partially Liquefied Vitreous Humor.

The purpose of this study is to investigate the effect of partial liquefaction (due to ageing) of the vitreous humor on the transport of ocular drugs. In our model, the gel part of the vitreous is treated as a Darcy-type porous medium. A spherical region within the porous part of vitreous is in a liquid state which, for computational purposes, is also treated as a porous medium but with a much higher permeability. Using the finite element method, a time-dependent, three-dimensional model has been developed to computationally simulate (using the Petrov-Galerkin method) the transport of intravitreally injected macromolecules where both convection and diffusion are present. From a fluid physics and transport phenomena perspective, the results show many interesting features. For pressure-driven flow across the vitreous, the flow streamlines converge into the liquefied region as the flow seeks the fastest path of travel. Furthermore, as expected, with increased level of liquefaction, the overall flow rate increases for a given pressure drop. We have quantified this effect for various geometrical considerations. The flow convergence into the liquefied region has important implication for convective transport. One effect is the clear diversion of the drug as it reaches the liquefied region. In some instances, the entry point of the drug in the retinal region gets slightly shifted due to liquefaction. While the model has many approximations and assumptions, the focus is illustrating the effect of liquefaction as one of the building blocks toward a fully comprehensive model.

Quantifying uncertainty of a mathematical model of drug transport in tumors

This paper presents a numerical simulation in the two-dimensional for a system of PDE governing drug transport in tumors with random coefficients, which is described as a random field. The continuous stochastic field is approximated by a finite number of random variables via the Karhunen–Loève expansion and transform the stochastic problem into a determinate one with a parameter in high dimension. Then we apply a finite difference scheme and the Euler–Maruyama Integrator in time. The Monte Carlo method is used to compute corresponding simple averages. We compute the error estimate using the Central Limits Theorem (CLT) and the error estimate for the finite difference method. Some numerical results are simulated to illustrate the theoretical analysis. We also propose a comparison between the stochastic and determinate solving processes of our system where we show the efficiency of our adopted method.

Computational Modelling and Big Data Analysis of Flow and Drug Transport in Microfluidic Systems: A Spheroid-on-a-Chip Study.

Microfluidic tumour spheroid-on-a-chip platforms enable control of spheroid size and their microenvironment and offer the capability of high-throughput drug screening, but drug supply to spheroids is a complex process that depends on a combination of mechanical, biochemical, and biophysical factors. To account for these coupled effects, many microfluidic device designs and operating conditions must be considered and optimized in a time- and labour-intensive trial-and-error process. Computational modelling facilitates a systematic exploration of a large design parameter space via in silico simulations, but the majority of in silico models apply only a small set of conditions or parametric levels. Novel approaches to computational modelling are needed to explore large parameter spaces and accelerate the optimization of spheroid-on-a-chip and other organ-on-a-chip designs. Here, we report an efficient computational approach for simulating fluid flow and transport of drugs in a high-throughput arrayed cancer spheroid-on-a-chip platform. Our strategy combines four key factors: i) governing physical equations; ii) parametric sweeping; iii) parallel computing; and iv) extensive dataset analysis, thereby enabling a complete “full-factorial” exploration of the design parameter space in combinatorial fashion. The simulations were conducted in a time-efficient manner without requiring massive computational time. As a case study, we simulated >15,000 microfluidic device designs and flow conditions for a representative multicellular spheroids-on-a-chip arrayed device, thus acquiring a single dataset consisting of ∼10 billion datapoints in ∼95 GBs. To validate our computational model, we performed physical experiments in a representative spheroid-on-a-chip device that showed excellent agreement between experimental and simulated data. This study offers a computational strategy to accelerate the optimization of microfluidic device designs and provide insight on the flow and drug transport in spheroid-on-a-chip and other biomicrofluidic platforms.

Hyperbranched Copolymers Forming Polymersome-like Structures Used for Encapsulation and Controlled Release of α-Tocopherol Succinate (TOS): Drug Transport Modeling.

Trimesic acid (TMA) and ethyelene diamine (ED) were reacted in various molar proportions to yield several branched/hyperbranched copolymers which formed polymersome-like structures, and they were used for encapsulation and release of a model drug, α-tocopherol succinate (TOS). The branched topology of the copolymers was established from spectroscopy, viscometry, and rheological measurements. Hydrodynamic size and transmission electron microscopy revealed the self-aggregated polymersome-like features of the copolymers with a dense core. Zeta potential studies unveiled pH-sensitive features of the aggregates. Both hydrodynamic size and viscosity were found to decrease with more branching, whereas the encapsulation efficiency displayed a drastic increase from 68 to 89.5% from the least branched (30%) to mostly branched grade (68%). The hydrophobic drug was primarily accommodated within the macromolecular voids inside the core and was released slowly following the diffusion mechanism. An indigenous model was established to explain the release kinetics from such a pH-sensitive and highly branched core-shell matrix which yielded a unique parameter called effective diffusivity or ED that took account of those parameters affecting the release rate. The copolymers were found to be biologically viable through a series of in vitro tests, thus inviting in vivo trials for future experimentation.

Vein‐to‐brain: Simultaneous, seconds‐resolved measurements of intracranial and intravenous drug levels provide a highly time‐resolved picture of drug transport

Drug action, particularly for centrally-active compounds, is critically dependent upon the transport of molecules across physiological barriers to reach the site of action. The ability to measure specific molecules simultaneously at multiple sites within the body and with seconds time resolution could revolutionize our understanding of drug transport, metabolism, and elimination. It could, for example, improve our understanding of the blood-brain and blood-cerebral spinal fluid barriers that protect the central nervous system by regulating the transfer of molecules to and from these central compartments. As a proof-of-principle demonstration of this, here we describe the use of electrochemical aptamer-based (EAB) sensors to measure transport of the antibiotic vancomycin (a drug that is subject to negligible metabolism or biotransformation) from the plasma to the cerebrospinal fluid of live rats with 7 s temporal resolution. Doing so, we show that, while the collection of hundreds of concentration values over a single drug lifetime enables high-precision estimates of the parameters describing transport, ambiguity is introduced by a mathematical equivalence that produces two divergent pharmacokinetics parameter sets that fit the data equally well. The inclusion of simultaneous, intravenous measurements, however, resolves this equivalence, enabling high-precision (±5 to ±20% at 95% confidence levels) estimates of the pharmacokinetic parameters describing inter-compartmental transport in individual animals. The availability of simultaneous “in-brain” and “in-vein” measurements also provides an opportunity to relax the assumptions almost universally employed in prior compartmental models of drug transport, allowing us to quantitatively address (rather than simply assume), for example, whether the targeted drug is potentially metabolized in brain tissue or actively transported into or out of the ventricles. In sum, the present work highlight the potential of EAB sensors for the tracking intercompartmental molecular transport in the living body, which would not only increase our ability to understand -and therefore modulate- such transport, but could be used as a powerful preclinical tool during drug development to screen drug candidates more effectively in vivo. Such an advance would allow swifter, more accurate, exploration of the clinical impact of novel drug candidates, opening the door for better dosing regimens, as well as streamlining and increasing cost effectiveness of novel drug development.

Taylor dispersion in non-Darcy porous media with bulk chemical reaction: a model for drug transport in impeded blood vessels

The present article discusses the solute transport process in steady laminar blood flow through a non-Darcy porous medium, as a model for drug movement in blood vessels containing deposits. The Darcy–Brinkman–Forchheimer drag force formulation is adopted to mimic a sparsely packed porous domain, and the vessel is approximated as an impermeable cylindrical conduit. The conservation equations are implemented in an axisymmetric system (R, Z) with suitable boundary conditions, assuming constant tortuosity and porosity of the medium. Newtonian flow is assumed, which is physically realistic for large vessels at high shear rates. The velocity field is expanded asymptotically, and the concentration field decomposed. Advection and dispersion coefficient expressions are rigorously derived. Extensive visualization of the influence of effective Péclet number, Forchheimer number, reaction parameter on velocity, asymptotic dispersion coefficient, mean concentration, and transverse concentration at different axial locations and times is provided. Increasing reaction parameter and Forchheimer number both decrease the dispersion coefficient, although the latter exhibits a linear decay. The maximum mean concentration is enhanced with greater Forchheimer numbers, although the centre of the solute cloud is displaced in the backward direction. Peak mean concentration is suppressed with the reaction parameter, although the centroid of the solute cloud remains unchanged. Peak mean concentration deteriorates over time since the dispersion process is largely controlled by diffusion at the large time, and therefore the breakthrough curve is more dispersed. A similar trend is computed with increasing Péclet number (large Péclet numbers imply diffusion-controlled transport). The computations provide some insight into a drug (pharmacological agents) reacting linearly with blood.

Closed-loop trans-skull ultrasound hyperthermia leads to improved drug delivery from thermosensitive drugs and promotes changes in vascular transport dynamics in brain tumors.

Effective drug delivery in brain tumors remains a major challenge in oncology. Although local hyperthermia and stimuli-responsive delivery systems, such as thermosensitive liposomes, represent promising strategies to locally enhance drug delivery in solid tumors and improve outcomes, their application in intracranial malignancies remains unexplored. We hypothesized that the combined abilities of closed-loop trans-skull Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS) hyperthermia with those of thermosensitive drugs can alleviate challenges in drug delivery and improve survival in gliomas.Methods: To conduct our investigations, we first designed a closed loop MR-guided Focused Ultrasound (MRgFUS) system for localized trans-skull hyperthermia (ΔT < 0.5 °C) in rodents and established safety thresholds in healthy mice. To assess the abilities of the developed system and proposed therapeutic strategy for FUS-triggered chemotherapy release we employed thermosensitive liposomal Dox (TSL-Dox) and tested it in two different glioma tumor models (F98 in rats and GL261 in mice). To quantify Dox delivery and changes in the transvascular transport dynamics in the tumor microenvironment we combined fluorescent microscopy, dynamic contrast enhanced MRI (DCE-MRI), and physiologically based pharmacokinetic (PBPK) modeling. Lastly, to assess the therapeutic efficacy of the system and of the proposed therapeutic strategy we performed a survival study in the GL261 glioma bearing mice.Results: The developed closed-loop trans-skull MRgFUS-hyperthermia system that operated at 1.7 MHz, a frequency that maximized the brain (FUS-focus) to skull temperature ratio in mice, was able to attain and maintain the desired focal temperature within a narrow range. Histological evidence (H&E and Nissl) suggests that focal temperature at 41.5 ± 0.5 °C for 10 min is below the threshold for tissue damage. Quantitative analysis of doxorubicin delivery from TSLs with MRgFUS-hyperthermia demonstrated 3.5-fold improvement in cellular uptake in GL261 glioma mouse tumors (p < 0.001) and 5-fold increase in delivery in F98 glioma rat tumors (p < 0.05), as compared to controls (TSL-Dox-only). Moreover, PBPK modeling of drug transport that was calibrated using the experimental data indicated that thermal stress could lead to significant improvement in the transvascular transport (2.3-fold increase in the vessel diffusion coefficient; P < 0.001), in addition to promoting targeted Dox release. Prospective experimental investigations with DCE-MRI during FUS-hyperthermia, supported these findings and provided evidence that moderate thermal stress (≈41 °C for up to 10 min) can promote acute changes in the vascular transport dynamics in the brain tumor microenvironment (Ktrans value for control vs. FUS was 0.0097 and 0.0148 min-1, respectively; p = 0.026). Crucially, survival analysis demonstrated significant improvement in the survival in the TSL-Dox-FUS group as compared to TSL-Dox-only group (p < 0.05), providing supporting evidence on the therapeutic potential of the proposed strategy.Conclusions: Our investigations demonstrated that spatially controlled thermal stress can be attained and sustained in the mouse brain, using a trans-skull closed-loop MRgFUS system, and used to promote the effective delivery of chemotherapy in gliomas from thermosensitive drugs. This system also allowed us to conduct mechanistic investigations that resulted in the refinement of our understanding on the role of thermal stress in augmenting mass and drug transport in brain tumors. Overall, our study established a new paradigm for effective drug delivery in brain tumors based on closed-loop ultrasound-mediated thermal stress and thermosensitive drugs.