A comprehensive review on modeling aspects of infusion-based drug delivery in the brain.

Brain disorders represent an ever-increasing health challenge worldwide. While conventional drug therapies are less effective due to the presence of the blood-brain barrier, infusion-based methods of drug delivery to the brain represent a promising option. Since these methods are mechanically controlled and involve multiple physical phases ranging from the neural and molecular scales to the brain scale, highly efficient and precise delivery procedures can significantly benefit from a comprehensive understanding of drug-brain and device-brain interactions. Behind these interactions are principles of biophysics and biomechanics that can be described and captured using mathematical models. Although biomechanics and biophysics have received considerable attention, a comprehensive mechanistic model for modeling infusion-based drug delivery in the brain has yet to be developed. Therefore, this article reviews the state-of-the-art mechanistic studies that can support the development of next-generation models for infusion-based brain drug delivery from the perspective of fluid mechanics, solid mechanics, and mathematical modeling. The supporting techniques and database are also summarized to provide further insights. Finally, the challenges are highlighted and perspectives on future research directions are provided. STATEMENT OF SIGNIFICANCE: Despite the immense potential of infusion-based drug delivery methods for bypassing the blood-brain barrier and efficiently delivering drugs to the brain, achieving optimal drug distribution remains a significant challenge. This is primarily due to our limited understanding of the complex interactions between drugs and the brain that are governed by principles of biophysics and biomechanics, and can be described using mathematical models. This article provides a comprehensive review of state-of-the-art mechanistic studies that can help to unravel the mechanism of drug transport in the brain across the scales, which underpins the development of next-generation models for infusion-based brain drug delivery. More broadly, this review will serve as a starting point for developing more effective treatments for brain diseases and mechanistic models that can be used to study other soft tissue and biomaterials.

Image-based predictive modelling frameworks for personalised drug delivery in cancer therapy.

Personalised drug delivery enables a tailored treatment plan for each patient compared to conventional drug delivery, where a generic strategy is commonly employed. It can not only achieve precise treatment to improve effectiveness but also reduce the risk of adverse effects to improve patients' quality of life. Drug delivery involves multiple interconnected physiological and physicochemical processes, which span a wide range of time and length scales. How to consider the impact of individual differences on these processes becomes critical. Multiphysics models are an open system that allows well-controlled studies on the individual and combined effects of influencing factors on drug delivery outcomes while accommodating the patient-specific in vivo environment, which is not economically feasible through experimental means. Extensive modelling frameworks have been developed to reveal the underlying mechanisms of drug delivery and optimise effective delivery plans. This review provides an overview of currently available models, their integration with advanced medical imaging modalities, and code packages for personalised drug delivery. The potential to incorporate new technologies (i.e., machine learning) in this field is also addressed for development.

Radiopharmaceutical transport in solid tumors via a 3-dimensional image-based spatiotemporal model.

Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA)-targeted radiopharmaceutical therapy is a clinically approved treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Even though common practice reluctantly follows "one size fits all" approach, medical community believes there is significant room for deeper understanding and personalization of radiopharmaceutical therapies. To pursue this aim, we present a 3-dimensional spatiotemporal radiopharmaceutical delivery model based on clinical imaging data to simulate pharmacokinetic of 177Lu-PSMA within the prostate tumors. The model includes interstitial flow, radiopharmaceutical transport in tissues, receptor cycles, association/dissociation with ligands, synthesis of PSMA receptors, receptor recycling, internalization of radiopharmaceuticals, and degradation of receptors and drugs. The model was studied for a range of values for injection amount (100-1000 nmol), receptor density (10-500 nmol•l-1), and recycling rate of receptors (10-4 to 10-1 min-1). Furthermore, injection type, different convection-diffusion-reaction mechanisms, characteristic time scales, and length scales are discussed. The study found that increasing receptor density, ligand amount, and labeled ligands improved radiopharmaceutical uptake in the tumor. A high receptor recycling rate (0.1 min-1) increased radiopharmaceutical concentration by promoting repeated binding to tumor cell receptors. Continuous infusion results in higher radiopharmaceutical concentrations within tumors compared to bolus administration. These insights are crucial for advancing targeted therapy for prostate cancer by understanding the mechanism of radiopharmaceutical distribution in tumors. Furthermore, measures of characteristic length and advection time scale were computed. The presented spatiotemporal tumor transport model can analyze different physiological parameters affecting 177Lu-PSMA delivery.

Mathematical modelling of microneedle-mediated transdermal delivery of drug nanocarriers into skin tissue and circulatory system.

Microneedle-mediated transdermal delivery using nanocarriers can successfully overcome the barrier of the stratum corneum and protect drugs from elimination in skin tissues. However, the effectiveness of drug delivery to different layers of skin tissues and the circulatory system varies considerably, subject to the properties of the drug delivery system and delivery regime. How to maximise delivery outcomes remains unclear. In this study, mathematical modelling is employed to investigate this transdermal delivery under various conditions, using the skin model that is reconstructed based on the realistic skin anatomical structure. Treatment efficacy is evaluated in terms of drug exposure over time. The modelling results demonstrate the complex dependence of drug accumulation and distribution on the nanocarrier properties, microneedle properties and environment in different skin layers and blood. Specifically, delivery outcomes in the entire skin and blood can be improved by increasing the loading dose and reducing microneedle spacing. However, several parameters need to be optimised with respect to the specific location of the target site in the tissue for better treatment; these include the drug release rate, nanocarrier diffusivity in microneedle and skin tissue, nanocarrier transvascular permeability, nanocarrier partition coefficient between tissue and microneedle, microneedle length, wind speed and relative humidity. The delivery is less sensitive to the diffusivity and physical degradation rate of free drugs in microneedle, and their partition coefficient between tissue and microneedle. Results obtained from this study can be used to improve the design of the microneedle-nanocarrier combined drug delivery system and delivery regime.

Mathematical Optimisation of Magnetic Nanoparticle Diffusion in the Brain White Matter.

Magnetic nanoparticles (MNPs) are a promising drug delivery system to treat brain diseases, as the particle transport trajectory can be manipulated by an external magnetic field. However, due to the complex microstructure of brain tissues, particularly the arrangement of nerve fibres in the white matter (WM), how to achieve desired drug distribution patterns, e.g., uniform distribution, is largely unknown. In this study, by adopting a mathematical model capable of capturing the diffusion trajectories of MNPs, we conducted a pilot study to investigate the effects of key parameters in the MNP delivery on the particle diffusion behaviours in the brain WM microstructures. The results show that (i) a uniform distribution of MNPs can be achieved in anisotropic tissues by adjusting the particle size and magnetic field; (ii) particle size plays a key role in determining MNPs' diffusion behaviours. The magnitude of MNP equivalent diffusivity is reversely correlated to the particle size. The MNPs with a dimension greater than 90 nm cannot reach a uniform distribution in the brain WM even in an external magnitude field; (iii) axon tortuosity may lead to transversely anisotropic MNP transport in the brain WM; however, this effect can be mitigated by applying an external magnetic field perpendicular to the local axon track. This study not only advances understanding to answer the question of how to optimise MNP delivery, but also demonstrates the potential of mathematical modelling to help achieve desired drug distributions in biological tissues with a complex microstructure.

Linking fluid-axons interactions to the macroscopic fluid transport properties of the brain.

Many brain disorders, including Alzheimer's Disease and Parkinson's Disease, and drug delivery procedures are linked to fluid transport in the brain; yet, while neurons are extremely soft and can be easily deformed, how the microscale channel flow interacts with the neuronal structures (especially axons) deformation and how these interactions affect the macroscale tissue function and transport properties is poorly understood. Misrepresenting these relationships may lead to the erroneous prediction of e.g. disease spread, drug delivery, and nerve injury in the brain. However, understanding fluid-neuron interactions is an outstanding challenge because the behaviours of both phases are not only dynamic but also occur at an extremely small length scale (the width of the flow channel is ∼100 nm), which cannot be captured by state-of-the-art experimental techniques. Here, by explicitly simulating the dynamics of the flow and axons at the microstructural level, we, for the first time, establish the link between micromechanical tissue response to the physical laws governing the macroscopic transport property of the brain white matter. We found that interactions between axons and the interstitial flow are very strong, thus playing an essential role in the brain fluid/mass transport. Furthermore, we proposed the first anisotropic pressure-dependent permeability tensor informed by microstructural dynamics for more accurate brain modelling at the macroscale, and analysed the effect of the variation of the microstructural parameters that influence such tensor. These findings will shed light on some unsolved issues linked to brain functions and medical treatments relying on intracerebral transport, and the mathematical model provides a framework to more realistically model the brain and design brain-tissue-like biomaterials. STATEMENT OF SIGNIFICANCE: This study reveals how neurons interact with the fluid flowing around them and how these microscale interactions affect macroscale transport behaviour of the brain tissue. The findings provide unprecedented insights into some unsolved issues linked to brain functions and medical treatments relying on intracerebral fluid transport. Furthermore, we, for the first time, established a microstructure-informed permeability tensor as a function of local hydraulic pressure and pressure gradient for the brain tissue, which inherently captures the dynamic transport property of the brain. This study is a cornerstone to advance the predicting accuracy of brain tissue transport property and neural tissue engineering.

In-situ vaccination using dual responsive organelle targeted nanoreactors.

The poor translation of nanomedicines from bench to bedside can be attributed to (i) lack of a delivery system with precise drug compositions with no batch-to-batch variations, (ii) off-target or undesirable release of payload, and (iii) lack of a method to monitor the fate of the specific drug of interest, which often has to be modified with a fluorescent tag or replaced with a model drug which can be tracked. To overcome these translation hurdles, we developed dual responsive organelle targeted nanoreactors (DRONEs) with precise drug composition, site specific payload release and which enable accurate in-vivo monitoring. DRONEs consist of a polyprodrug inner core composed of a dual responsive backbone containing a photosensitizer (Protoporphyrin IX) grafted with functionalized polyethylene glycol (PEG) outer shell to prolong blood circulation and a tumour homing pro-apoptotic peptide (CGKRKD[KLAKLAK]2) (THP). DRONEs can significantly reduce the tumour burden in an orthotopic glioblastoma model due to its BBB penetrating and tumour homing capabilities. DRONEs exhibit good safety profile and biocompatibility along with a reliable route of elimination. DRONEs showed great potential as an in-situ vaccine which can not only eliminate the tumour but also trigger an adaptive immune response which would provide long-term anti-tumoural immunity.

Convection-Enhanced Delivery of Antiangiogenic Drugs and Liposomal Cytotoxic Drugs to Heterogeneous Brain Tumor for Combination Therapy.

Although convection-enhanced delivery can successfully bypass the blood-brain barrier, its clinical performance remains disappointing. This is primarily attributed to the heterogeneous intratumoral environment, particularly the tumor microvasculature. This study investigates the combined convection-enhanced delivery of antiangiogenic drugs and liposomal cytotoxic drugs in a heterogeneous brain tumor environment using a transport-based mathematical model. The patient-specific 3D brain tumor geometry and the tumor's heterogeneous tissue properties, including microvascular density, porosity and cell density, are extracted from dynamic contrast-enhanced magnetic resonance imaging data. Results show that antiangiogenic drugs can effectively reduce the tumor microvascular density. This change in tissue structure would inhibit the fluid loss from the blood to prevent drug concentration from dilution, and also reduce the drug loss by blood drainage. The comparisons between different dosing regimens demonstrate that the co-infusion of liposomal cytotoxic drugs and antiangiogenic drugs has the advantages of homogenizing drug distribution, increasing drug accumulation, and enlarging the volume where tumor cells can be effectively killed. The delivery outcomes are susceptible to the location of the infusion site. This combination treatment can be improved by infusing drugs at higher microvascular density sites. In contrast, infusion at a site with high cell density would lower the treatment effectiveness of the whole brain tumor. Results obtained from this study can deepen the understanding of this combination therapy and provide a reference for treatment design and optimization that can further improve survival and patient quality of life.

On the microstructurally driven heterogeneous response of brain white matter to drug infusion pressure.

Delivering therapeutic agents into the brain via convection-enhanced delivery (CED), a mechanically controlled infusion method, provides an efficient approach to bypass the blood-brain barrier and deliver drugs directly to the targeted focus in the brain. Mathematical methods based on Darcy's law have been widely adopted to predict drug distribution in the brain to improve the accuracy and reduce the side effects of this technique. However, most of the current studies assume that the hydraulic permeability and porosity of brain tissue are homogeneous and constant during the infusion process, which is less accurate due to the deformability of the axonal structures and the extracellular matrix in brain white matter. To solve this problem, a multiscale model was established in this study, which takes into account the pressure-driven deformation of brain microstructure to quantify the change of local permeability and porosity. The simulation results were corroborated using experiments measuring hydraulic permeability in ovine brain samples. Results show that both hydraulic pressure and drug concentration in the brain would be significantly underestimated by classical Darcy's law, thus highlighting the great importance of the present multiscale model in providing a better understanding of how drugs transport inside the brain and how brain tissue responds to the infusion pressure. This new method can assist the development of both new drugs for brain diseases and preoperative evaluation techniques for CED surgery, thus helping to improve the efficiency and precision of treatments for brain diseases.

Role of Tissue Hydraulic Permeability in Convection-Enhanced Delivery of Nanoparticle-Encapsulated Chemotherapy Drugs to Brain Tumour.

PURPOSE: Tissue hydraulic permeability of brain tumours can vary considerably depending on the tissue microstructure, compositions in interstitium and tumour cells. Its effects on drug transport and accumulation remain poorly understood. METHODS: Mathematical modelling is applied to predict the drug delivery outcomes in tumours with different tissue permeability upon convection-enhanced delivery. The modelling is based on a 3-D realistic tumour model that is extracted from patient magnetic resonance images. RESULTS: Modelling results show that infusing drugs into a permeable tumour can facilitate a more favourable hydraulic environment for drug transport. The infused drugs will exhibit a relatively uniform distribution and cover a larger tumour volume for effective cell killing. Cross-comparisons show the delivery outcomes are more sensitive to the changes in tissue hydraulic permeability and blood pressure than the fluid flow from the brain ventricle. Quantitative analyses demonstrate that increasing the fluid gain from both the blood and brain ventricle can further improve the interstitial fluid flow, and thereby enhance the delivery outcomes. Furthermore, similar responses to the changes in tissue hydraulic permeability can be found for different types of drugs. CONCLUSIONS: Tissue hydraulic permeability as an intrinsic property can influence drug accumulation and distribution. Results from this study can deepen the understanding of the interplays between drug and tissues that are involved in the drug delivery processes in chemotherapy.

Effect of Particle Size and Surface Charge on Nanoparticles Diffusion in the Brain White Matter.

PURPOSE: Brain disorders have become a serious problem for healthcare worldwide. Nanoparticle-based drugs are one of the emerging therapies and have shown great promise to treat brain diseases. Modifications on particle size and surface charge are two efficient ways to increase the transport efficiency of nanoparticles through brain-blood barrier; however, partly due to the high complexity of brain microstructure and limited visibility of Nanoparticles (NPs), our understanding of how these two modifications can affect the transport of NPs in the brain is insufficient. METHODS: In this study, a framework, which contains a stochastic geometric model of brain white matter (WM) and a mathematical particle tracing model, was developed to investigate the relationship between particle size/surface charge of the NPs and their effective diffusion coefficients (D) in WM. RESULTS: The predictive capabilities of this method have been validated using published experimental tests. For negatively charged NPs, both particle size and surface charge are positively correlated with D before reaching a size threshold. When Zeta potential (Zp) is less negative than -10 mV, the difference between NPs' D in WM and pure interstitial fluid (IF) is limited. CONCLUSION: A deeper understanding on the relationships between particle size/surface charge of NPs and their D in WM has been obtained. The results from this study and the developed modelling framework provide important tools for the development of nano-drugs and nano-carriers to cure brain diseases.

Mathematical modelling of nanoparticle-mediated topical drug delivery to skin tissue.

Nanoparticles have been extensively studied to improve drug delivery outcomes, however, their use in topical delivery remains controversial. Although the feasibility to cross the human skin barrier has been demonstrated in experiments, the risk of low drug concentration in deep tissue still limits the application. In this study, mathematical modelling is employed to examine the performance of nanoparticle-mediated topical delivery for sending drugs into the deep skin tissue. The pharmacokinetic effect is evaluated based on the drug exposure over time. As compared to the delivery using plain drugs, nanoparticle-mediated topical delivery has the potential to significantly improve the drug exposure in deep skin tissue. Modelling predictions denote that the importance of sufficient long-term drug-skin contact in achieving effective drug deposition in the deep skin tissue. The delivery outcomes are highly sensitive to the release rate. Accelerating the release from nanoparticles in stratum corneum is able to improve the drug exposure in stratum corneum and viable epidermis while resulting in the reductions in dermis and blood. The release rate in stratum corneum and viable epidermis should be well-designed below a threshold for generating effective drug accumulation in dermis and blood. A more localised drug accumulation can be achieved in the capillary-rich region of dermis by increasing the local release rate. The release rate in dermis needs to be optimised to increase the drug exposure in the dermis region where there are fewer blood and lymphatics capillaries. Results from this study can be used to improve the regimen of topical delivery for localised treatment.

Convection enhanced delivery of light responsive antigen capturing oxygen generators for chemo-phototherapy triggered adaptive immunity.

In recent years, combination therapy has emerged as the cornerstone of clinical practice in treating glioblastoma multiforme. However, their ability to trigger and leverage the body's adaptive immunity has rarely been studied. Tumour heterogeneity, the presence of the blood-brain barrier, and an immunosuppressive tumor microenvironment play a crucial role in the 90% local tumor recurrence post-treatment. Herein, we report an improved combination therapy approach capable of stimulating an immune response that utilizes Light responsive antigen-capturing oxygen generators (LAGs). The engineered LAGs loaded with a non-genotoxic molecule, Nutlin-3a, and a photosensitizer, Protoporphyrin IX, can release the payload on-demand when exposed to light of a specific wavelength. The in-situ oxygen generation capability of LAGs enables tumor oxygenation enhancement, thereby alleviating the tumor hypoxia and enhancing the efficacy of chemo-photodynamic therapy. Furthermore, by modulating the surface properties of LAGs, we demonstrated that the tumor-derived protein antigens released can be captured and retained in-situ, which improves antigen uptake and presentation by the antigen-presenting cells. Dual drug-loaded LAGs (DD-LAGs) upregulated the expression of cell surface CD83 maturation and CD86 costimulatory markers on monocyte-derived-dendritic cells, suggesting intrinsic immune adjuvancy. In the presence of 3D printed hypoxic U87 spheroids (h-U87), DD-LAGs induced cancer cell death, upregulated IL-1ß, and downregulated IL-10 resulting in CD3+, helper CD4+, and cytotoxic CD8+ proliferation. Finally, we have investigated convection-enhanced delivery as a potential route of administration for DD-LAGs. Our work presents a novel strategy to induce tumor cell death both during and post-treatment, thereby reducing the possibility of recurrence.

Enhanced penetration of pro-apoptotic and anti-angiogenic micellar nanoprobe in 3D multicellular spheroids for chemophototherapy.

Light irradiation is considered an ideal non-invasive stimulus that enables precise tumour treatment with flexible, facile, and spatiotemporal control. Photodynamic therapy (PDT) is an important clinically relevant therapeutic modality that has proven to compensate for the reduced therapeutic efficacy of conventional chemotherapy. However, oxygen consumption during PDT can result in an inadequate oxygen supply which reduces photodynamic efficacy. In our quest to circumvent the limitations of chemotherapy and photodynamic therapy, we have engineered a robust and smart "all-in-one" nanoparticle-based drug delivery system capable of overcoming biological barriers and leveraging on several synergistic cancer cell killing mechanisms. The fabricated Targeted Micellar Nanoprobe (TMNP) had exceptionally high encapsulation efficiencies of a hydrophobic drug simvastatin (SV) and a photosensitizer protoporphyrin IX (PpIX) due to the ℼ-ℼ stacking of the aromatic groups of SV and PpIX and strong hydrophobic interactions with the alkyl chains of the carrier. In-vitro results demonstrated that TMNP exhibited excellent colloidal stability, biocompatibility and drug retaining capability in physiological condition. Under light irradiation, TMNP causes the accelerated generation of reactive oxygen species (ROS) which subsequently damages the mitochondria. On further evaluation of the mechanisms behind the superior anti-cancer effect of TMNP, we concluded that TMNP causes synergistic apoptosis and necrosis along with cell cycle arrest at the G1-S phase and elicits anti-angiogenic effects. Taking into consideration that these promising results on 2D monolayer cell cultures might not translate into similar results in animal models, we developed 3D multicellular tumour spheroids (MCs) as an intermediate step to bridge the gap between 2-D cell experiments and in-vivo studies. TMNPs showed enhanced penetration and growth inhibition on MCs. In addition, the modelling of the transport of TMNP in the tumour exhibited the improved effective delivery volume. Overall, TMNPs could potentially be used for image-guided delivery of the therapeutic payloads for precise cancer treatment.

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.

Convection enhanced delivery of anti-angiogenic and cytotoxic agents in combination therapy against brain tumour.

Convection enhanced delivery is an effective alternative to routine delivery methods to overcome the blood brain barrier. However, its treatment efficacy remains disappointing in clinic owing to the rapid drug elimination in tumour tissue. In this study, multiphysics modelling is employed to investigate the combination delivery of anti-angiogenic and cytotoxic drugs from the perspective of intratumoural transport. Simulations are based on a 3-D realistic brain tumour model that is reconstructed from patient magnetic resonance images. The tumour microvasculature is targeted by bevacizumab, and six cytotoxic drugs are included, as doxorubicin, carmustine, cisplatin, fluorouracil, methotrexate and paclitaxel. The treatment efficacy is evaluated in terms of the distribution volume where the drug concentration is above the corresponding LD90. Results demonstrate that the infusion of bevacizumab can slightly improve interstitial fluid flow, but is significantly efficient in reducing the fluid loss from the blood circulatory system to inhibit the concentration dilution. As the transport of bevacizumab is dominated by convection, its spatial distribution and anti-angiogenic effectiveness present high sensitivity to the directional interstitial fluid flow. Infusing bevacizumab could enhance the delivery outcomes of all the six drugs, however, the degree of enhancement differs. The delivery of doxorubicin can be improved most, whereas, the impacts on methotrexate and paclitaxel are limited. Fluorouracil could cover the comparable distribution volume as paclitaxel in the combination therapy for effective cell killing. Results obtain in this study could be a guide for the design of this co-delivery treatment.

Effect of tissue permeability and drug diffusion anisotropy on convection-enhanced delivery.

Although convection-enhanced delivery (CED) can successfully facilitate a bypass of the blood brain barrier, its treatment efficacy remains highly limited in clinic. This can be partially attributed to the brain anisotropic characteristics that lead to the difficulties in controlling the drug spatial distribution. Here, the responses of six different drugs to the tissue anisotropy are examined through a parametric study performed using a multiphysics model, which considers interstitial fluid flow, tissue deformation and interlinked drug transport processes in CED. The delivery outcomes are evaluated in terms of the penetration depth and delivery volume for effective therapy. Simulation results demonstrate that the effective penetration depth in a given direction can be improved with the increase of the corresponding component of anisotropic characteristics. The anisotropic tissue permeability could only reshape the drug distribution in space but has limited contribution to the total effective delivery volume. On the other hand, drugs respond in different ways to the anisotropic diffusivity. The large delivery volumes of fluorouracil, carmustine, cisplatin and doxorubicin could be achieved in relatively isotropic tissue, while paclitaxel and methotrexate are able to cover enlarged regions into anisotropic tissues. Results obtained from this study serve as a guide for the design of CED treatments.

Delivery of liposome encapsulated temozolomide to brain tumour: Understanding the drug transport for optimisation.

Temozolomide presents significant anticancer activities in preclinical trials. However, its clinical applications suffer from serious side effects owing to the high concentration in blood and normal tissues. In this study, mathematical modelling is applied to simulate the liposome-mediated delivery of temozolomide under different conditions in a 3-D realistic brain tumour model reconstructed from MR images. Delivery outcomes are evaluated by the bioavailability of free temozolomide across time. As compared to the oral and intravenous administration of free temozolomide, liposome-mediated delivery can successfully improve the drug accumulation in tumour while reducing the drug exposure in blood and normal tissue. Results show that the delivery is less sensitive to the duration of intravenous infusion but highly dependent on the liposome properties. The treatment can be improved by either enhancing the liposome transvascular permeability or using the liposomes with high extracellular release rates. Intravascular release can only increase the risk of adverse effects rather than improving the drug bioavailability in tumour. Results obtained in this study could be applied for optimising the treatment using liposome encapsulated temozolomide.

Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue.

Surface-modified poly(d,l-lactic-co-glycolic acid) PLGA nanoparticles (NPs) were fabricated via nanoprecipitation for obtaining therapeutic concentration of paclitaxel (PTX) in brain tumor. The cellular uptake and cytotoxicity of NPs were evaluated on C6 glioma cells in vitro, and BALB/c mice were used to study the brain penetration and biodistribution upon intravenous administration. Results showed that by finely tuning nanoprecipitation parameters, PLGA NPs coated with surfactants with a size around 150 nm could provide a sustained release of PTX for >2 weeks. Surface coatings could increase cellular uptake efficiency when compared with noncoated NPs, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) showed the most significant enhancement. The in vivo evaluation of TPGS-PLGA NPs showed amplified accumulation (>800% after 96 h) of PTX in the brain tissue when compared with bare NPs and Taxol®. Therefore, PLGA-NPs with PLGA-TPGS coating demonstrate a promising approach to efficiently transport PTX across blood-brain barrier in a safer manner, with the advantages of easy formulation, lower production cost, and higher encapsulation efficiency.