Transvascular Transport Research Articles

Mathematical modeling of 18F-Fluoromisonidazole (18F-FMISO) radiopharmaceutical transport in vascularized solid tumors

18F-Fluoromisonidazole (18F-FMISO) is a highly promising positron emission tomography radiopharmaceutical for identifying hypoxic regions in solid tumors. This research employs spatiotemporal multi-scale mathematical modeling to explore how different levels of angiogenesis influence the transport of radiopharmaceuticals within tumors. In this study, two tumor geometries with heterogeneous and uniform distributions of capillary networks were employed to incorporate varying degrees of microvascular density. The synthetic image of the heterogeneous and vascularized tumor was generated by simulating the angiogenesis process. The proposed multi-scale spatiotemporal model accounts for intricate physiological and biochemical factors within the tumor microenvironment, such as the transvascular transport of the radiopharmaceutical agent, its movement into the interstitial space by diffusion and convection mechanisms, and ultimately its uptake by tumor cells. Results showed that both quantitative and semi-quantitative metrics of 18F-FMISO uptake differ spatially and temporally at different stages during tumor growth. The presence of a high microvascular density in uniformly vascularized tumor increases cellular uptake, as it allows for more efficient release and rapid distribution of radiopharmaceutical molecules. This results in enhanced uptake compared to the heterogeneous vascularized tumor. In both heterogeneous and uniform distribution of microvessels in tumors, the diffusion transport mechanism has a more pronounced than convection. The findings of this study shed light on the transport phenomena behind 18F-FMISO radiopharmaceutical distribution and its delivery in the tumor microenvironment, aiding oncologists in their routine decision-making processes.

Spatiotemporal modeling of nano-delivered chemotherapeutics for synergistic microwave ablation cancer therapy

Background and objectiveThe effectiveness of current microwave ablation (MWA) therapies is limited. Administration of thermosensitive liposomes (TSLs) which release drugs in response to heat has presented a significant potential for enhancing the efficacy of thermal ablation treatment, and the benefits of targeted drug delivery. However, a complete knowledge of the mechanobiological processes underlying the drug release process, especially the intravascular drug release mechanism and its distribution in response to MWA needs to be improved. Multiscale computational-based modeling frameworks, integrating different biophysical phenomena, have recently emerged as promising tools to decipher the mechanobiological events in combo therapies. The present study aims to develop a novel multiscale computational model of TSLs delivery following MWA implantation. MethodsDue to the complex interplay between the heating procedure and the drug concentration maps, a computational model is developed to determine the intravascular release of doxorubicin from TSL, its transvascular transport into the interstitium, transport in the interstitium, and cell uptake. Computational models can estimate the interplays among liposome and drug properties, tumor perfusion, and heating regimen to examine the impact of essential parameters and to optimize a targeted drug delivery platform. ResultsResults indicated that the synergy of TSLs with MWA allows more localized drug delivery with lower side effects. The drug release rate and tumor permeability play crucial roles in the efficacy of TSLs during MWA treatment. The computational model predicted an unencapsulated drug lime around the ablated zone, which can destroy more cancer cells compared to MWA alone by 40%. Administration of TSLs with a high release rate capacity can improve the percentage of killed cancer cells by 24%. Since the heating duration in MWA is less than 15 min, the presented combination therapy showed better performance for highly permeable tumors. ConclusionThis study highlights the potential of the proposed computational framework to address complex and realistic scenarios in cancer treatment, which can serve as the future research foundation, including advancements in nanomedicine and optimizing the pair of TSL and MWA for both preclinical and clinical studies. The present model could be as a valuable tool for patient-specific calibration of essential parameters.

Simulation of transvascular transport of nanoparticles in tumor microenvironments for drug delivery applications

Nanomedicine is a promising approach for tumor therapy but penetration is challenged by complex tumor microenvironments. The purpose of this study is to design nanoparticles and analyze their transport in two abnormal microenvironments through a 2-D simulation. Employing a Computational Fluid Dynamics (CFD) approach, tumor vascular-interstitial models were initially simulated, and the impact of nanoparticles on the velocity profile and pressure gradient within the tumor microenvironment was observed. Through meticulous mesh analysis, it was determined that optimal outcomes were achieved using a quadrilateral meshing method for pancreatic tumor and a quad/tri meshing method for hepatic tumor. Results showed an increase in vessel diameter correlated with elevated blood flow velocity, reaching a maximum of 1.40 × 10^−3 m/s with an expanding cell gap. The simulation results for pressure distribution show that as vessel diameter increases, the velocity of nanoparticles in blood increases and decreases the pressure of blood. Intriguingly, distinct fluid flow patterns in pancreatic and hepatic tumors, emphasize how microenvironmental differences, specifically cell pore size, profoundly impact therapeutic agent transport, with implications for drug delivery strategies in cancer therapy. These simulation-based insights enable researchers to anticipate nanofluid behavior in realistic settings. Future work, incorporating immune cells, will enhance the understanding of nanoparticle efficiency in cancer therapy.

Design of in vitro biomimetic experimental system and simulation analysis for transvascular transport of nano-preparation

Recently, the enhanced penetration and retention (EPR) effect of nano-preparations has been questioned. Whether the vascular endothelial cell gap (VECG) is the main transport pathway of nano-preparations has become a hot issue at present. Therefore, we propose an in vitro biomimetic experimental system that demonstrates the transvascular transport of nano-preparation. Based on the tumor growth process, the experimental system was used to simulate the change process of abnormal factors (vascular endothelial cell gap and interstitial fluid pressure (IFP)) in the tumor microenvironment. The influence of change in the abnormal factors on the enhanced penetration and retention effect of nano-preparation was explored, and simulation verification was performed. The results show that when the interstitial fluid pressure is close to the vascular fluid pressure (VFP), the transport of nano-preparation is obstructed, resulting in the disappearance of enhanced penetration and retention effect of the nano-preparation. This indicates that the pressure gradient between vascular fluid pressure and interstitial fluid pressure determines whether the enhanced penetration and retention effect of nano-preparations can exist.

Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.

Polysaccharide-based nanocarriers for efficient transvascular drug delivery

Polysaccharide-based nanocarriers (PBNs) are the focus of extensive investigation because of their biocompatibility, low cost, wide availability, and chemical versatility, which allow a wide range of anticancer agents to be loaded within the nanocarriers. Similar to other nanocarriers, most PBNs are designed to extravasate out of tumor vessels, depending on the enhanced permeability and retention (EPR) effect. However, the EPR effect is compromised in some tumors due to the heterogeneity of tumor structures. Transvascular transport efficacy is decreased by complex blood vessels and condensed tumor stroma. The limited extravasation impedes efficient drug delivery into tumor parenchyma, and thus affects the subsequent tumor accumulation, which hinders the therapeutic effect of PBNs. Therefore, overcoming the biological barriers that restrict extravasation from tumor vessels is of great importance in PBN design. Many strategies have been developed to enhance the EPR effect that involve nanocarrier property regulation and tumor structure remodeling. Moreover, some researchers have proposed active transcytosis pathways that are complementary to the paracellular EPR effect to increase the transvascular extravasation efficiency of PBNs. In this review, we summarize the recent advances in the design of PBNs with enhanced transvascular transport to enable optimization of PBNs in the extravasation of the drug delivery process. We also discuss the obstacles and challenges that need to be addressed to clarify the transendothemial mechanism of PBNs and the potential interactions between extravasation and other drug delivery steps.

A mathematical model of intratumoral infusion, particle distribution and heat transfer in cancer tumors: In-silico investigation of magnetic nanoparticle hyperthermia

Tumor cells can be killed by rising the tumor temperature above 42 °C and keeping it for sufficiently longer durations by exploiting magnetic nanoparticles and alternative magnetic fields, which is known as magnetic nanoparticle hyperthermia. In-vivo experiments are often complex and difficult to perform to evaluate therapeutic efficacy. Hence, mathematical models and computer simulations are widely used as methods of investigation. Although different aspects of the treatment modality have been covered in the literature, a comprehensive model to consider the infusion of nanoparticles into the tumor, diffusion and distribution of the particles followed by heat transfer analysis to predict temperature elevation are lacking. This study presents a mathematical model to simulate clinical procedure by addressing the injection process, post-injection distribution and bio-heat transfer in the tumors considering in-vivo physiological aspects such as tumor heterogeneity and transvascular transport. The proposed model is implemented in COMSOL Multiphysics software to predict the fluid flow, particle distribution and temperature elevation in the tumor. Interstitial fluid flow is solved and utilized in predicting particle distribution through a convection-diffusion model. The obtained concentration profiles were used to calculate the nanoparticle heat generation in the tissues under an alternating magnetic field and the corresponding temperature distribution was predicted. The results demonstrate that the smaller particles diffuse faster and result in a higher temperature rise in the tumors. The numerical simulations also indicate that the ideal case of confined uniform distribution of nanoparticles inside the tumor only leads to the inaccurate prediction of the tumor temperatures and the efficiency of the treatment. In addition, it is observed that single-site injection at the tumor center does not achieve a therapeutic temperature in the entire tumor. This indicates that alternative techniques or multiple-site injections need to be investigated to achieve a therapeutic effect in large tumors.

Accelerated vascular ageing and retention of LDL in type 2 diabetes

Background and Aims : Patients with Type 2 Diabetes (T2D) are disproportionately affected by atherosclerosis compared with non-diabetics. We previously reported that the interstitial fluid-to serum ratio (IF:S) for atherogenic lipoproteins is reduced in T2D. Further measures related to pathophysiological functions of atherogenic lipoproteins in serum and IF may unveil novel insights in transvascular transport of cholesterol in atherosclerosis.

A mathematical model for understanding nanoparticle biodistribution after intratumoral injection in cancer tumors

To exploit the benefits of a multifunctional nanomaterial as theranostics, drug carriers, and adjuvant therapeutics, tissue parameters affecting in-vivo transport, intratumoral diffusion, need to be understood properly. Literature has reported different regions of tumor such as necrotic core, viable tumor which are surrounded by healthy tissue. Transvascular exchange of the fluid and solute plays a crucial role in nanoparticle retention in the tumors. Modeling fluid and solute transport phenomenon in tissue considering in-vivo tumor architecture is essential. In this study, the influence of necrotic core presence, transvascular transport, nanoparticle size, and vascular normalization have been investigated to better understand the nanoparticle distribution in tumors. A three-dimensional numerical model has been developed to study the interstitial fluid flow and nanoparticle distribution in tumors considering the reported in-vivo scenario. The effects of nanoparticle size, intratumoral single-site, and multi-site injection methods, and vascular normalization on the distribution were investigated. In-silico investigations were carried out with respective parameters of tumor and healthy tissues using finite element based COMSOL Multiphysics 5.6® software. Interstitial fluid pressure, velocity, and nanoparticle concentration in interstitial space were predicted by solving the developed models. It was found that the interstitial fluid pressure is elevated and uniform throughout the tumor region, inhibiting the convective transport of the nanoparticles. Post-injection distribution patterns of nanoparticles revealed that the smaller nanoparticles show faster diffusion and rapid clearance from the tissues, while larger particles are retained for longer periods. The multi-site infusion method is more efficacious than the single-site method, gives better distribution patterns in the tumor. Vascular normalization does not affect the distribution of larger particles while it has shown a profound effect on the 10 nm particle distribution. Considering necrotic core and transvascular transport is inevitable in modeling to replicate the in-vivo scenario in in-silico investigations. Based on the results obtained, it is found that very fine particles of the size 10 nm will lead to lower therapeutic concentrations due to vascular clearance, despite faster diffusion rates. Particle sizes larger than 30 nm will not diffuse into the tumor due to lower diffusion coefficients and retained at the injected site. This study proposes 15 nm–30 nm as the suitable size for hyperthermia considerations.

Mathematical modeling of intraplaque neovascularization and hemorrhage in a carotid atherosclerotic plaque

BackgroundGrowing experimental evidence has identified neovascularization from the adventitial vasa vasorum and induced intraplaque hemorrhage (IPH) as critical indicators during the development of vulnerable atherosclerotic plaques. In this study, we propose a mathematical model incorporating intraplaque angiogenesis and hemodynamic calculation of the microcirculation, to obtain the quantitative evaluation of the influences of intraplaque neovascularization and hemorrhage on vulnerable plaque development. A two-dimensional nine-point model of angiogenic microvasculature is generated based on the histology of a patient’s carotid plaque. The intraplaque angiogenesis model includes three key cells (endothelial cells, smooth muscle cells, and macrophages) and three key chemical factors (vascular endothelial growth factors, extracellular matrix, and matrix metalloproteinase), which densities and concentrations are described by a series of reaction–diffusion equations. The hemodynamic calculation by coupling the intravascular blood flow, the extravascular plasma flow, and the transvascular transport is carried out on the generated angiogenic microvessel network. We then define the IPH area by using the plasma concentration in the interstitial tissue, as well as the extravascular transport across the capillary wall.ResultsThe simulational results reproduce a series of pathophysiological phenomena during the atherosclerotic plaque progression. It is found that the high microvessel density region at the shoulder areas and the extravascular flow across the leaky wall of the neovasculature contribute to the IPH observed widely in vulnerable plaques. The simulational results are validated by both the in vivo MR imaging data and in vitro experimental observations and show significant consistency in quantity ground. Moreover, the sensitivity analysis of model parameters reveals that the IPH area and extent can be reduced significantly by decreasing the MVD and the wall permeability of the neovasculature.ConclusionsThe current quantitative model could help us to better understand the roles of microvascular and intraplaque hemorrhage during the carotid plaque progression.

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.

Simulation study of the effects of interstitial fluid pressure and blood flow velocity on transvascular transport of nanoparticles in tumor microenvironment

Background and objectiveAlthough nanoparticle preparations have great potential in the treatment of tumors, nanoparticle preparations have not achieved the desired therapeutic effect. The reason is that the abnormal tumor microenvironment prevents nanoparticles from effective concentrating and reaching tumor area. Therefore, it's very necessary to better understand the effect of the abnormal tumor microenvironment on the transvascular transport of nanoparticles to overcome this critical problem. MethodsIn this paper, a tumor abnormal vascular-interstitial model was established, and the transvascular transport process of nanoparticles was simulated in the model by computational fluid dynamics (CFD) modeling. ResultsThe simulation results showed that the transport efficiency of nanoparticles decreased with increasing interstitial fluid pressure (IFP), and nanoparticles could not cross the blood vessel wall when the IFP approached the blood vessel wall pressure. Interestingly, the transport efficiency of nanoparticles first increased with blood flow velocity, and then decreased with blood flow velocity. ConclusionsThe results showed that with the continuous malignant development of tumors, the ability of nanoparticles to passively diffuse has almost disappeared. The enhanced permeability and retention (EPR) effect of the nanoparticles disappeared with the disappearance of the pressure gradient inside the tumor. These results provided guidance for future research on the vascular transport pathways and mechanisms of nanoparticles.

Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour: A Pilot Numerical Simulation Study.

Focused ultrasound (FUS) coupled with microbubbles (MB) has been found to be a promising approach to disrupt the blood-brain barrier (BBB). However, how this disruption affects drug transport remains unclear. In this study, drug transport in combination therapy of liposomes and FUS-MB-induced BBB disruption (BBBD) was investigated based on a multiphysics model. A realistic 3D brain tumour model extracted from MR images was applied. The results demonstrated the advantage of liposomes compared to free doxorubicin injection in further improving treatment when the BBB is opened under the same delivery conditions using burst sonication. This improvement was mainly due to the BBBD-enhanced transvascular transport of free doxorubicin and the sustainable supply of the drug by long-circulating liposomes. Treatment efficacy can be improved in different ways. Disrupting the BBB simultaneously with liposome bolus injection enables more free drug molecules to cross the vessel wall, while prolonging the BBBD duration could accelerate liposome transvascular transport for more effective drug release. However, the drug release rate needs to be well controlled to balance the trade-off among drug release, transvascular exchange and elimination. The results obtained in this study could provide suggestions for the future optimisation of this FUS-MB–liposome combination therapy against brain cancer.

BSCI-09. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN METASTASES WITH FOCUSED ULTRASOUND-INDUCED BLOOD-TUMOR BARRIER DISRUPTION

Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in HER2-positive breast cancer brain metastases at cellular resolution: the non-targeted chemotherapeutic doxorubicin and the antibody-drug conjugate ado- trastuzumab emtansine (T-DM1). Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy we demonstrate multifold increases in the extravasation of both agents (7-fold and 2-fold for doxorubicin and T-DM1, respectively) and we provide evidence of increased drug penetration (>100μm vs. < 20μm and 42±7μm vs. 12±4μm for doxorubicin and T-DM1, respectively) after application of FUS as compared to control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via increase in hydraulic conductivity. Combination of experimental data and PBPK modeling suggests that FUS in combination with microbubbles increases the endothelial cell transmembrane transport and uptake. PBPK modelling indicates selective increase in transvascular transport of the non- targeted small chemotherapeutic doxorubicin through small vessel-wall pores size with a narrow range (Diameter: 10-50nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of novel therapeutic strategies against brain metastases.

Influence of the preparation “Prodevit-tetra” and “Nanovit” on endogenous intoxication of cows during the dry period

It is well known that medium-sized molecules (MSM) affect the tone of smooth muscle structures of organs and the transvascular transport system. MSM also can pass through placental barrier and intoxicate fetus, resulting in multiple organ damage. The goal of the work was to determine the level of endogenous intoxication in cow’s organism on the last trimester of pregnancy and under the influence of the “Prodovit-tetra” and “Nanovit” preparations, as well as calving process and after it. Experiment was conducted in LLC “Agroprodservice invest” of Ternopil oblast on the cows of Ukrainian black-and-white dairy breed. Biochemical studies conducted in the laboratory of veterinary obstetrics and gynecology of the Ternopil Research Station of the Institute of Veterinary Medicine of the NAAS. One control and two experimental groups of animals were used for this experiment. Cows of the first experimental group received 15.0 ml of “Prodevit-tetra” preparation intramuscularly on the 35–25 day before calving. Blood was taken from the observed animals before and after administration of the medicines. The level of endogenous intoxication of the cow’s organism were determined by the concentration of MSM in their blood and prooxidant/antioxidant index. Concentration of MSM in the blood of cows after administration of “Prodevit-tetra” reduced by 41.0% and after administration of “Nanovit” containing metal nanoparticles – by 61.0% that promoted increase of prooxidant/antioxidant index by 1.7 and 2.3 times (Р ≤ 0.001) compered to initial indicators and indicated the positive effect of preparations on the cow’s organism. Application of the “Nanovit” preparation showed better result, therefore we can recommend it to be used in scheme to reduce intoxication of the cows during the dry period and to prevent postnatal pathology. The results of the experiment suggest that multivitamin complex “Nanovit” could be used for reducing of intoxication in the body of cows during dry period and to prevent postnatal pathology. In the future, we will study effect of the “Nanovit” preparation on the humoral immunity of cows in dry period and after calving and possibility of “Nanovit” usage in the system of prevention of obstetric pathology as well.

Intravenous infusion of mesenchymal stem cells improves impaired cognitive function in a cerebral small vessel disease model

Cerebral small vessel disease (CSVD) is not only a cause of vascular dementia (VD) but also a contributing factor to Alzheimer's disease (AD). The essential pathological feature of CSVD is the disruption of blood–brain barrier (BBB). Dysfunction of BBB due to degeneration of both endothelial cells and pericytes in capillaries leads to neuronal damage and progressive brain atrophy. Moreover, deterioration of amyloid-β (Aβ) clearance due to the failure of the transvascular BBB transport system results in accumulation of Aβ in the brain. Intravenous infusion of mesenchymal stem cells (MSCs) elicits functional recovery in experimental models including stroke and spinal cord injury. One effect of MSCs is to restore disrupted BBB through remodeling of microvasculature. Using spontaneously hypertensive rats (stroke-prone) with impaired cognitive function as a CSVD model, we have shown that infused MSCs has a therapeutic effect for cognitive function. Restoration of BBB function via remodeling of microvasculature and inhibition of Aβ accumulation could inhibit progressive brain atrophy and lead to restore cognitive dysfunction. Gene expression analysis indicated that infused MSCs activates both transforming growth factor-β and angiopoietin 1 signaling pathways and promotes the remodeling of microvasculature. Thus, infused MSCs may represent a novel therapy for both VD and AD.

Glucose transporter 1-mediated vascular translocation of nanomedicines enhances accumulation and efficacy in solid tumors

Nanomedicine modification with ligands directed to receptors on tumor blood vessels has the potential for selectively enhancing nanomedicine accumulation in malignant tissues by overcoming the vascular barrier of tumors. Nevertheless, the development of broadly applicable ligand approaches capable of promoting the transvascular transport of nanomedicines in a wide spectrum of tumors has been elusive so far. By considering the indispensable and persistent glycolytic fueling of tumors, we developed glucose-installed polymeric micelles loading cisplatin (Gluc-CDDP/m) targeting the glucose transporter 1 (GLUT1), which is overexpressed in most tumors and present on vascular endothelial cells, toward improving the delivery efficiency and therapeutic efficacy. The design of the glucose ligands on Gluc-CDDP/m was engineered to control the conjugation via the carbon 6 of the glucose moieties, as well as the ligand density on the poly (ethylene glycol) (PEG) shell of the micelles. The series of micelles was then studied in vitro and in vivo against GLUT1-high human squamous cell carcinoma of the head and neck OSC-19 cells and GLUT1-low human glioblastoma-astrocytoma U87MG cells. Our results showed that precisely tuning the micelles to have glucose ligands on 25% of their PEG chains increased the efficacy against the tumors by significantly enhancing the tumor accumulation, even in GLUT1-low U87MG tumors. The enhancement of the intratumoral levels of these micelles was hindered by concomitant administration of glucose, or the GLUT1 inhibitor STF-31, confirming a GLUT1/glucose-mediated increment of the accumulation. Intravital confocal laser scanning microscopy imaging of tumor tissues further demonstrated the rapid extravasation and penetration of Gluc-CDDP/m in OSC-19 tumors compared to non-targeted CDDP/m. These findings indicate GLUT1-targeting as a promising approach for overcoming the vascular barrier and boosting the delivery of nanomedicine in tumors.

Therapeutic Remodeling of the Tumor Microenvironment Enhances Nanoparticle Delivery.

A major challenge in the development of cancer nanomedicine is the inability for nanomaterials to efficiently penetrate and deliver therapeutic agents into solid tumors. Previous studies have shown that tumor vasculature and extracellular matrix regulate the transvascular and interstitial transport of nanoparticles, both critical for successfully delivering nanomedicine into solid tumors. Within the malignant tumor microenvironment, blood vessels are morphologically abnormal and functionally exhibit substantial permeability. Furthermore, the tumor extracellular matrix (ECM), unlike that of the normal tissue parenchyma, is densely packed with collagen. These pathophysiological properties greatly impede intratumoral delivery of nanomaterials. By using an antivascular endothelial growth factor receptor antibody, DC101, and an antitransforming growth factor β1 (TGF‐β1) antibody, normalization of the tumor vasculature and ECM is achieved, respectively, in a syngeneic murine glioma model. This normalization effect results in a more organized vascular network, improves tissue perfusion, and reduces collagen density, all of which contribute to enhanced nanoparticle delivery and distribution within tumors. These findings suggest that combined vascular and ECM normalization strategies can be used to remodel the tumor microenvironment and improve nanomedicine delivery into solid tumors, which has significant implications for developing more effective combinational therapeutic strategies using cancer nanomedicine.

CADD-32. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN TUMORS WITH FOCUSED ULTRASOUND-INDUCED TRANSIENT BLOOD-TUMOR BARRIER DISRUPTION

Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in HER2-positive breast cancer brain metastases at cellular resolution: doxorubicin, a non-targeted low molecular weight chemotherapeutic, and ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy we demonstrate significant increases in the extravasation of both agents (7-fold and 2-fold for doxorubicin and T-DM1, respectively) and we provide evidence of increased drug penetration (>100µm vs. <20µm and 42 ± 7µm vs. 12 ± 4µm for doxorubicin and T-DM1, respectively) after application of FUS as compared to control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via an increase in hydraulic conductivity. Combination of experimental data and PBPK modeling suggests that FUS in combination with microbubbles increases the endothelial cell transmembrane transport and uptake. PBPK modeling indicates a selective increase in transvascular transport of doxorubicin through small vessel-wall pores size with a narrow range (Diameter: 10-50nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of novel strategies to treat brain metastases.

Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood–tumor barrier disruption

Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in breast cancer brain metastases at cellular resolution: doxorubicin, a nontargeted chemotherapeutic, and ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy, we demonstrate significant increases in the extravasation of both agents (sevenfold and twofold for doxorubicin and T-DM1, respectively), and we provide evidence of increased drug penetration (>100 vs. <20 µm and 42 ± 7 vs. 12 ± 4 µm for doxorubicin and T-DM1, respectively) after the application of FUS compared with control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via an increase in hydraulic conductivity. Experimental data demonstrate that FUS in combination with microbubbles enhances significantly the endothelial cell uptake of the small chemotherapeutic agent. Quantification with PBPK modeling reveals an increase in transmembrane transport by more than two orders of magnitude. PBPK modeling indicates a selective increase in transvascular transport of doxorubicin through small vessel wall pores with a narrow range of sizes (diameter, 10-50 nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of strategies to treat brain metastases.