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

Funding: This research received no external funding. Acknowledgments: The author would like to acknowledge the supports of the Imperial College London Central Library and the Maxwell Compute Cluster funded by the University of Aberdeen.Peer reviewedPublisher PD

Analytical Solutions for Simulation of Mathematical Modelling of Liposomal Drug Release to Tumor by Adomian Decomposition Method.

In this paper,  the  system of partial differential equations of the  thermo sensitive liposome-mediated drug delivery  model is solved analytically by applied the Adomian decomposition method with the appropriate initial and boundary  condition as well. Also, to determine the effectiveness of suggested models, simulated results were in comparison to the corresponding experimental information , and an important agreement was reached . So that a quantitative analysis is finally done by numerical simulation by adopting the values of all typical parameters to clarify the drug concentrations behavior with increasing time in different cases. Keywords: Local drug ; Drug delivery ; cancer stem cells ; Adomian decomposition method ; Different locations

Mathematical modelling of drug delivery to solid tumour

Effective delivery of therapeutic agents to tumour cells is essential to the success of most cancer treatment therapies except for surgery. The transport of drug in solid tumour involves multiple biophysical and biochemical processes which are strongly dependent on the physicochemical properties of the drug and biological properties of the tumour. Owing to the complexities involved, mathematical models are playing an increasingly important role in identifying the factors leading to inadequate drug delivery to tumours. In this study, a computational model is developed which incorporates real tumour geometry reconstructed from magnetic resonance images, drug transport through the tumour vasculature and interstitial space, as well as drug uptake by tumour cells. The effectiveness of anticancer therapy is evaluated based on the percentage of survival tumour cells by directly solving the corresponding pharmacodynamics equation using predicted intracellular drug concentration. Computational simulations have been performed for the delivery of doxorubicin through various delivery modes, including bolus injection and continuous infusion of doxorubicin in free form, and thermo-sensitive liposome mediated doxorubicin delivery activated by high intensity focused ultrasound. Predicted results show that continuous infusion is far more effective than bolus injection in maintaining high levels of intracellular drug concentration, thereby increasing drug uptake by tumour cells. Moreover, multiple-administration is found to be more effective in improving the cytotoxic effect of drug compared to a single administration. The effect of heterogeneous distribution of microvasculature on drug transport in a realistic model of liver tumour is investigated, and the results indicate that although tumour interstitial fluid pressure is almost uniform, drug concentration is sensitive to the heterogeneous distribution of microvasculature within a tumour. Results from three prostate tumours of different sizes suggest a nonlinear relationship between transvascular transport of anticancer drugs and tumour size. Numerical simulations of thermo-sensitive liposome-mediated drug delivery coupled with high intensity focused ultrasound heating demonstrate the potential advantage of this novel drug delivery system for localised treatment while minimising drug concentration in normal tissue.Open Acces

QUANTIFICATION OF FACTORS GOVERNING DRUG RELEASE KINETICS FROM NANOPARTICLES: A COMBINED EXPERIMENTAL AND MECHANISTIC MODELING APPROACH

Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies. A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release data. This method also quantified the effects of topotecan dimerization and surface potential on total amount of drug released from these liposomal formulations. The pH-sensitive release of topotecan from unilamellar vesicles was subsequently evaluated with this method. A mechanistic model identified three permeable species in which the zwitterionic lactone form of topotecan was the most permeable. Ring-closing kinetics of topotecan from its carboxylate to lactone form were found to be rate-limiting for topotecan drug release in the neutral pH region. Models were also developed to non-invasively analyze release kinetics of actively-loaded liposomal formulations of topotecan in vivo. The fluorescence excitation spectra of released topotecan were used to observe release kinetics in aqueous solution and human plasma. Simulations of the intravesicular pH in the various release media indicated accelerated release in plasma was a consequence of increased intravesicular pH due to ammonia levels in the plasma instead of alterations in bilayer integrity. Further studies were performed to understand the roles of dimerization, ion-pairing, and precipitation on loading and release kinetics obtained from actively-loaded topotecan. Extension of this type of modeling for other types of nanoparticles was illustrated with doxorubicin-conjugated polymeric micelles. Mathematical modeling of experimental studies monitoring doxorubicin release identified conjugation stability during storage, hydrazone hydrolysis kinetics, and unconjugated doxorubicin partitioning affected micellar doxorubicin release. This work identifies several of the key parameters governing drug release from these liposomal and micellar nanoparticles and lays the framework for future development of in vivo release models for these formulations

A moderate thermal dose is sufficient for effective free and TSL based thermochemotherapy

Hyperthermia, i.e. heating the tumor to a temperature of 40–43 °C is considered by many a valuable treatment to sensitize tumor cells to radiotherapy and chemotherapy. In recent randomized trials the great potential of adding hyperthermia to chemotherapy was demonstrated for treatment of high risk soft tissue sarcoma: +11.4% 5 yrs. overall survival (OS) and for ovarian cancer with peritoneal involvement nearly +12 months OS gain. As a result interest in combining chemotherapy with hyperthermia, i.e. thermochemotherapy, is growing. Extensive biological research has revealed that hyperthermia causes multiple effects, from direct cell kill to improved oxygenation, whereby each effect has a specific temperature range. Thermal sensitization of the tumor cell for chemotherapy occurs for many drugs at temperatures ranging from 40 to 42 °C with little additional increase of sensitization at higher temperatures. Increasing perfusion/oxygenation and increased extravasation are two other important hyperthermia induced mechanisms. The combination of free drug and hyperthermia has not been found to increase tumor drug concentration. Hence, enhanced effectiveness of free drug will de

Pharmaceutical Development of Liposomes Using the QbD Approach

Quality by Design (QbD) is a systematic, risk-based approach to pharmaceutical product and manufacturing development, which uses quality-improving scientific methods upstream in the research, development, and design phases, in order to assure that quality and safety are designed into product at as early stage as possible. This work focuses on the state-of-the-art applications of the QbD principles in the development of liposomes. The QbD approach has recently been proposed as a useful tool to obtain higher-quality liposomal products, as their development is a challenging task, involving intricate formulation and manufacturing processes. Thus, the current strategies to define the relationship between the critical material attributes or process parameters and product critical quality attributes and to establish the design space are overviewed. Additionally, the current characterization methodologies are described, as part of the control strategy required within the QbD paradigm

ADVANCES IN LIPOSOMAL DRUG DELIVERY SYSTEM: FASCINATING TYPES AND POTENTIAL APPLICATIONS

Liposomes are an efficient novel drug delivery system. They are used because of their structure which is stable and due to their ability to accommodate both lipophilic and hydrophilic drug. Various fascinating types of liposomes have been developed in recent past to further enhance their utility. Long-circulating liposomes or stealth liposomes are able to hide from the defence system of the body and circulate for a longer time in the blood. Targeted liposomes namely immuno- liposomes consists of antibodies conjugated on their surface to improve the specificity of the cell. Liposomes have been modified as per the conditions of pH and temperature, specifically designed to improve drug delivery to targeted tumor cells. Liposomes are being used in the treatment of various diseases and there are various liposomal drug formulations available today. Liposomes can be used as carriers for genetic materials such as antisense, DNA, RNA which are useful in the treatment of diseases. Liposomes are also efficient carriers of cytokines which further activate macrophages. This review provides the detailed insight of types and applications of liposomes and the potential challenges in the development of liposomal drug delivery systems

Liposomes

Liposomes have received increased attention in recent years. Nevertheless, liposomes, due to their various forms and applications, require further investigation. These structures can deliver both hydrophilic and hydrophobic drugs. The preparation of liposomes results in different properties for these systems. In addition, there are many factors and difficulties that affect the development of liposome drug delivery structures.The purpose of this book is to concentrate on recent developments in liposomes. The articles collected in this book are contributions by invited researchers with long-standing experience in different research areas. We hope that the material presented here is understandable to a broad audience, not only scientists but also people with a general background in many different biological sciences. This volume offers up-to-date, expert reviews of the fast-moving field of liposomes and is divided in two major sections: 1. Introduction; 2. Liposomes general propertie