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Transport processes involved in direct drug delivery in combination with focusedultrasound-and-microbubble (FUS-MB)-induced blood-brain barrier disruption (BBBD). Red dashed line indicates the disrupted BBB, and the enhanced transvascular transport processes are highlighted in green.
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Focused ultrasound (FUS) coupled with microbubbles (MB) has been found as 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 the combination therapy of liposomes and FUS-MB induced BBB disruption (BBBD) is investigated based on a multip...
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... and πi are the osmotic pressures of blood and interstitial fluid, respectively. Figure 1 shows the transport processes of non-encapsulated doxorubicin delivered via bolus injection. The doxorubicin concentration (í µí° ¶í µí° ¶) in the intravascular space (IVS) can be described by í µí° ¶í µí° ¶ í µí°¼í µí°¼í µí°¼í µí°¼í µí°¼í µí°¼ = í µí°·í µí°·í µí°·í µí°·í µí°·í µí°·í µí°·í µí°· í µí±í µí± í µí°¹í µí°¹,í µí±í µí± í µí°·í µí°· −í µí±í µí± í µí°¹í µí°¹,í µí±í µí± í µí±¡í µí±¡ ...
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... BBB was disrupted simultaneously with the liposome injection in the baseline study. The delivery outcomes were compared to those of treatments in which BBBD was induced at 30, 60 and 90 min after the chemotherapy started, as shown in Figure 10. Given that the BBBD has no effect on liposome pharmacokinetics and release dynamics, identical time courses of í µí° ¶í µí° ¶ í µí°¿í µí°¿,í µí°¼í µí°¼í µí°¼í µí°¼í µí°¼í µí°¼ and í µí° ¶í µí° ¶ í µí°¹í µí°¹,í µí°¼í µí°¼í µí°¼í µí°¼í µí°¼í µí°¼ were found in each treatment. ...
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... was the same in normal tissue, since all the drug came from tumour ECS by convection and diffusion. The transvascular flux in treatments with different sonication timings is shown in Figure 11. Results showed that the transvascular flux of liposomes was reduced by postponing the BBBD. ...
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... showed that the transvascular flux of liposomes was reduced by postponing the BBBD. However, since the enhanced í µí±í µí± í µí°¿í µí°¿ dropped quickly to its normal level, changing the BBBD timing had no obvious impact on the liposome ECS concentration in tumour tissue, as shown in Figure 10B. This was different from free doxorubicin-its transvascular flux jumped to a higher peak during BBBD; however, it must be noted that there was no exchange of free doxorubicin between blood and tumour tissue before the BBBD occurred. ...
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... was different from free doxorubicin-its transvascular flux jumped to a higher peak during BBBD; however, it must be noted that there was no exchange of free doxorubicin between blood and tumour tissue before the BBBD occurred. As a result, the transvascular flux over the entire treatment period was low, and the free doxorubicin accumulation in tumour tissue was therefore reduced, as shown in Figure 10E. Pharmaceutics 2020, 12, 69 ...
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... doxorubicin concentration in treatments with different sonication durations are shown in Figure 12. Given that BBBD has no impact on liposome transport within blood, the encapsulated doxorubicin presented the same time course for IVS concentration in different treatments. ...
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... contrast, the drug concentrations in tumour and normal tissue ECS were increased by prolonging the FUS sonication. The impacts of sonication duration on the drug transvascular flux are given in Figure 13 as a function of time. Results showed that the IVS-ECS exchange of liposomal doxorubicin began to decline after the treatment started. ...
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... more liposomes were able to accumulate in the tumour ECS, as shown in Figure 12B. A sharp fall was observed after the sonication ended, because of the fast recovery of BBBD to liposomes [32]. ...
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... is because the BBBD-enhanced í µí±í µí± í µí°¹í µí°¹ remained at a higher level for free doxorubicin transport back to the blood. As a result, the improved drug release from liposomes was assumed to be the main reason for the effective free drug accumulation in tumour ECS shown in Figure 12E. Table 7 compares the delivery outcomes of treatments with different sonication durations. ...
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... order to examine the impact of enhanced liposome transvascular permeability on the delivery outcomes, the sonication duration was prolonged up to 45 min. Although the loss of free doxorubicin by capillary drainage was slightly raised, as shown in Figure 13, the modelling results showed that keeping the BBB open for a longer time effectively improved the accumulation of both the liposomeencapsulated and free doxorubicin, which could lead to better therapy. However, it is important to note that the enhancement of drug transvascular permeability is very limited when FUS is applied in isolation [31]. ...
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Citations
... Using a syngeneic mouse model where FUS was combined with the administration of doxorubicin showed increased concentrations of drug in the GBM tumor and improved survival [115]. Similar effects were obtained with FUS in combination with liposomal doxorubicin [116][117][118][119]. Improved extravasation of doxorubicin by FUS was confirmed by intravital multiphoton imaging of doxorubicin [120]. ...
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While focused ultrasound (FUS) is non-invasive, the ultrasound energy is attenuated by the skull which results in differences in energy efficiency among patients. In this study, we investigated the effect of skull variables on the energy efficiency of FUS. The thickness and density of the skull and proportion of the trabecular bone were selected as factors that could affect ultrasound energy transmittance. Sixteen 3D-printed skull models were designed and fabricated to reflect the three factors. The energy of each phantom was measured using an ultrasonic sound field energy measurement system. The thickness and proportion of trabecular bone affected the attenuation of transmitted energy. There was no difference in the density of the trabecular bone. In clinical data, the trabecular bone ratio showed a significantly greater correlation with dose/delivered energy than that of thickness and the skull density ratio. Currently, for clinical non-thermal FUS, the data are not sufficient, but we believe that the results of this study will be helpful in selecting patients and appropriate parameters for FUS treatment.
BACKGROUND AND OBJECTIVES
Previous mechanisms of opening the blood–brain barrier (BBB) created a hypertonic environment. Focused ultrasound (FUS) has recently been introduced as a means of controlled BBB opening. Here, we performed a scoping review to assess the advances in drug delivery across the BBB for treatment of brain tumors to identify advances and literature gaps.
METHODS
A review of current literature was conducted through a MEDLINE search inclusive of articles on FUS, BBB, and brain tumor barrier, including human, modeling, and animal studies written in English. Using the Rayyan platform, 2 reviewers (J.P and C.Y) identified 967 publications. 224 were chosen to review after a title screen. Ultimately 98 were reviewed. The scoping review was designed to address the following questions: (1) What FUS technology improvements have been made to augment drug delivery for brain tumors? (2) What drug delivery improvements have occurred to ensure better uptake in the target tissue for brain tumors?
RESULTS
Microbubbles (MB) with FUS are used for BBB opening (BBBO) through cavitation to increase its permeability. Drug delivery into the central nervous system can be combined with MB to enhance transport of therapeutic agents to target brain tissue resulting in suppression of tumor growth and prolonging survival rate, as well as reducing systemic toxicity and degradation rate. There is accumulating evidence demonstrating that drug delivery through BBBO with FUS-MB improves drug concentrations and provides a better impact on tumor growth and survival rates, compared with drug-only treatments.
CONCLUSION
Here, we review the role of FUS in BBBO. Identified gaps in the literature include impact of tumor microenvironment and extracellular space, improved understanding and control of MB and drug delivery, further work on ideal pharmacologics for delivery, and clinical use.
Computational modeling enables researchers to study and understand various complex biological phenomena in anticancer drug delivery systems (DDSs), especially nano‐sized DDSs (NSDDSs). The combination of NSDDSs and therapeutic ultrasound (TUS), that is, focused ultrasound and low‐intensity pulsed ultrasound, has made significant progress in recent years, opening many opportunities for cancer treatment. Multiple parameters require tuning and optimization to develop effective DDSs, such as NSDDSs, in which mathematical modeling can prove advantageous. In silico computational modeling of ultrasound‐responsive DDS typically involves a complex framework of acoustic interactions, heat transfer, drug release from nanoparticles, fluid flow, mass transport, and pharmacodynamic governing equations. Owing to the rapid development of computational tools, modeling the different phenomena in multi‐scale complex problems involved in drug delivery to tumors has become possible. In the present study, we present an in‐depth review of recent advances in the mathematical modeling of TUS‐mediated DDSs for cancer treatment. A detailed discussion is also provided on applying these computational models to improve the clinical translation for applications in cancer treatment.
This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
