Peptide Liposome Model Systems For Triggered Release

Liposomes are widely used in drug delivery to improve drug efficacy and to reduce side effects. For liposome-encapsulated drugs to become bioavailable and provide a therapeutic effect they must be released, which typically is a slow process that primarily relies on passive diffusion, liposome rupture or endocytotic uptake. Achieving drug concentrations within the therapeutic window can thus be challenging, resulting in poor efficacy and higher risks drug resistance. Finding means to modulate lipid membrane integrity and to trigger rapid and efficient release of liposomal cargo is thus critical to improve current and future liposomal drug delivery systems. The possibilities to tailor lipid composition and surface functionalization is vital for drug delivery applications but also make liposomes attractive model systems for studies of membrane active biomolecules. The overall aim of this thesis work has been to develop new strategies for triggering and controlling changes in lipid membrane integrity and to study the interactions of membrane active peptides with model lipid membranes using both de novo designed and biologically derived synthetic amphipathic cationic peptides. Two different sets of designed peptides have been explored that can fold and heterodimerize into a coiled coil and helix-loop-helix fourhelix bundle, respectively. Conjugation of the cationic lysine rich peptides to liposomes triggered a rapid and concentration dependent release. The additions of their corresponding glutamic acid-rich complementary peptides inhibited the release of liposomal cargo. Possibilities to reduce the inhibitory effect by both proteolytic digestion of the inhibitory peptide and by means of heterodimer exchange have been investigated. Moreover, the effects of peptide size and composition and ability to fold have been studied in order to elucidate the factors that influence the membrane permeabilizing effects of the peptides. In addition, the membrane activity of a the two-peptide bacteriocin PLNC8? and PLNC8? has been explored using liposomes as a model system. PLNC8?? are expressed by Lactobacillus plantarum and were shown to display pronounced membrane-partition folding coupling, leading to rapid release of liposome encapsulated carboxyfluorescein. PLNC8?? also kill and suppressed growth of the gram-negative bacteria Porphyromonas gingivalis by efficiently damaging the bacterial membrane. Although membrane active peptides are highly efficient in perturbing lipid membrane integrity, possibilities to trigger release using external stimuli are also of large interest for therapeutic applications. Light-induced heating of liposome encapsulated gold nanoparticles (AuNPs) has been shown by others as a potential strategy to trigger drug release. To facilitate fabrication of thermoplasmonic liposome systems we developed a simple method for synthesis of small AuNPs inside liposomes, using the liposomes as nanoscale reaction vessels. The work presented in this thesis provides new knowledge and techniques for future development of liposome-based drug delivery systems, peptide-based therapeutics and increase our understanding of peptide-lipid interactions.

This volume describes the protocols for fabrication of liposomal drug delivery system, and consists of two parts. The first part emphasizes the basic protocols and concepts for fabrication of drug-loaded liposomes. For new investigators, laying the groundwork is the first step. This part focuses on the fabrication details in liposomes formulations, which are the so-called small tricks while usually not disclosed in mostly published research articles. However, these processing details are crucial for the preparation of liposomes. And the second part focuses on the strategies in modified and/or functionalized liposomes to adapt to pathophysiological environment, as well as their application in treating diseases. As new analytical and synthetic technologies become available, and improved understanding of pathophysiology, various functionalized drug liposomes are developing to fit the requirements of different therapeutic purposes, exhibiting a broad range of applications. Accordingly, the objectives of this part are aimed at deeply unearthing the formulation of drug-loaded liposomes, describing the detailed operation of liposomal formulation, and further demonstrating their potential applications. Therefore, this volume shows the features of experimental report or protocol for proving a guide to scientists, research students, and young investigators in pharmaceutical enterprises.

Nanoencapsulation Technologies for the Food and Nutraceutical Industries is a compendium which collects, in an easy and compact way, state-of-the-art details on techniques for nanoencapsulation of bioactive compounds in food and nutraceutical industries. The book addresses important modern technologies, including biopolymer based nano-particle formation techniques, formulation based processes, such as nano-liposomes and nano-emulsions, process based nano-encapsulation, such as electro-spinning and nano-spray drying, natural nano-carrier based processes, like casein and starch nano-particles, and other recent advances. This definitive reference manual is ideal for researchers and industry personnel who want to learn more about basic concepts and recent developments in nanotechnology research. Serves as a compendium of recent techniques and systems for nanoencapsulation of bioactive compounds Brings together basic concepts and the potential of nanoencapsulation technologies, also including their novel applications in functional foods and nutraceutical systems Includes biopolymer based nano-particle formation techniques, formulation based processes, process based nanoencapsulation, and nano-carrier based process

This cutting-edge book focuses on the emerging area of biomaterials and biodevices that incorporate therapeutic agents, molecular targeting, and diagnostic imaging capabilities The design and development of biomaterials play a significant role in the diagnosis, treatment, and prevention of diseases. When used with highly selective and sensitive biomaterials, cutting-edge biodevices can allow the rapid and accurate diagnosis of disease, creating a platform for research and development, especially in the field of treatment for prognosis and detection of diseases in the early stage. This book emphasizes the emerging area of biomaterials and biodevices that incorporate therapeutic agents, molecular targeting, and diagnostic imaging capabilities. The 15 comprehensive chapters written by leading experts cover such topics as: The use of severe plastic deformation technique to enhance the properties of nanostructured metals Descriptions of the different polymers for use in controlled drug release Chitin and chitosan as renewable healthcare biopolymers for biomedical applications Innovated devices such as “label-free biochips” and polymer MEMS Molecular imprinting and nanotechnology Prussian Blue biosensing applications The evaluation of different types of biosensors in terms of their cost effectiveness, selectivity, and sensitivity Stimuli-responsive polypeptide nanocarriers for malignancy therapeutics

Colorectal Cancer: Disease and Advanced Drug Delivery Strategies examines the combined impact of basic clinical and medical treatments as well as recent advances in the field of colorectal cancer. With a strong focus towards colorectal cancer diagnosis, disease drug delivery, and diagnosis, the book also examines the Tumor microenvironment-responsive and site-specific nanoparticles for cancer theragnostics. In 16 chapters Colorectal Cancer: Disease and Advanced Drug Delivery Strategies not only provides the opportunity to understand and diagnose the disease, but it also describes screening methods, drugs including nano- and immunotherapy, and gives insight into the role of nanoparticles, lipids, and biomarkers in colorectal cancer. Content includes clinical trials in colorectal cancer research and disease models. This book directs researchers and clinicians how to better diagnose and treat colorectal cancer. Provides a wealth of information on the latest research and developments in the science and treatment of colorectal cancer Contains new and innovative ways to treat colorectal cancer Reflects on basic clinical and medical methods and recent advances in colorectal cancer science Gives specific details about how nanoparticles can be used to target cancer cells or cancer treatment Covers tumor microenvironment, their challenges, and opportunities in colorectal cancer research

This volume focuses on antibiotics research, a field of topical significance for human health due to the worrying increase of nosocomial infections caused by multi-resistant bacteria. It covers several basic aspects, such as the evolution of antibiotic resistance and the influence of antibiotics on the gut microbiota, and addresses the search for novel pathogenicity blockers as well as historical aspects of antibiotics. Further topics include applied aspects, such as drug discovery based on biodiversity and genome mining, optimization of lead structures by medicinal chemistry, total synthesis and drug delivery technologies. Moreover, the development of vaccines as a valid alternative therapeutic approach is outlined, while the importance of epidemiological studies on important bacterial pathogens, the problems arising from the excessive use of antibiotics in animal breeding, and the development of innovative technologies for diagnosing the “bad bugs” are discussed in detail. Accordingly, the book will appeal to researchers and clinicians alike.

The book provides a single volume covering detailed descriptions about various delivery systems, their principles and how these are put in use for the treatment of multiple diseases. It is divided into four sections where the first section deals with the introduction and importance of novel drug delivery system. The second section deals with the most advanced drug delivery systems like microbubbles, dendrimers, lipid-based nanoparticles, nanofibers, microemulsions etc., describing the major principles and techniques of the preparations of the drug delivery systems. The third section elaborates on the treatments of diverse diseases like cancer, topical diseases, tuberculosis etc. The fourth and final section provides a brief informative description about the regulatory aspects of novel drug delivery system that is followed in various countries.