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Author : Martin C. Woodle Publisher : Springer Science & Business Media Page : 327 pages File Size : 12,64 MB Release : 2013-06-29 Category : Medical ISBN : 3662221152
This book provides an up-to-date evaluation of clinical aspects of newly available "long-circulating liposome" formulations. Based on results from numerous clinical studies, the book describes the fundamentals of this new technology, discusses how it may influence the pharmacology of existing well-known agents reformulated in this manner, and elaborates on future expectations. It provides the practicing clinician - in particular, oncologists and critical care infectious disease physicians - with the tools needed to use these new formulations towards the best outcome for the patient.
This book provides an up-to-date evaluation of clinical aspects of newly available "long-circulating liposome" formulations. Based on results from numerous clinical studies, the book describes the fundamentals of this new technology, discusses how it may influence the pharmacology of existing well-known agents reformulated in this manner, and elaborates on future expectations. It provides the practicing clinician - in particular, oncologists and critical care infectious disease physicians - with the tools needed to use these new formulations towards the best outcome for the patient.
The development of liposomes as a drug delivery system has fluctuated since its introduction in the late 1960's by A.D. Bangham. While academic research of liposomes as a model membrane system has always flourished, as the exponential growth of papers can testify, the application of these findings to medically useful products has gone through several crises. Following the original optimism in the 70's and early 80's, a period of severe skepticism ensued at the end of the 80's and beginning of the 90's, culminating in a moderate but real optimism in the mid 90's, as a result of a successful launch of the first products in the US and Europe. In this collection of papers, the editors have gathered the most promising ideas, approaches, applications and commercial developments, thereby presenting an up-to-date compilation of the present status of the field. This includes such broad areas as anti-cancer chemotherapy immune stimulation and infectious diseases. Currently, the major areas of progress are in delivery of anti-fungal agents by conventional liposomes or lipid-based carriers and systemic anticancer therapy using long-circulating liposomes. The future applications as characterized by the direction of present day research is in specific targeting and delivery of informational molecules such as DNA plasmids (genes), antisense oligonucleotides or ribozymes. Other future developments may be in topical delivery, vaccination and in diagnostics. Features of this book: . Contributions from almost all the leading labs in the field . Up-to-date, critical reviews bridged by editors' introductions . Organized into a logical framework.
Liposomes are spherical vesicles composed of phospholipids that arise spontaneously in aqueous environments. Such vesicles are composed of the same material and structure as cell membranes, thus making them biocompatible. Liposomes are extremely versatile drug carriers because both the hydrophilic core and hydrophobic shell can be infused with a drug payload. The lipid shell protects the drug while in the blood pool prior to arriving at the target site. Unfortunately, the relatively large diameter and protective coating of long circulating liposomes reduces drug diffusion within the tumor. Key to overcoming this obstacle is activation of particles to release their payload using temperature-sensitive liposomes. Previous temperature sensitive formulations release their cargo in the blood pool prior to arriving at the target, and therefore a major focus of this thesis is to maximize the circulation of efficacious particles.In order to fully protect liposomal cargo in circulation while maintaining the availability of the cargo to tumor cells we explored multiple paradigms. Three temperature sensitive formulations were considered along with one targeted formulation that is designed to enhance cellular internalization. First, we explore changing the liposomal lipid composition, using in vitro and in vivo imaging to quantify liposome stability. Second, we developed a temperature-sensitive liposomal vehicle which releases a covalently-bound drug payload based on bond cleavage in response to a temperature increase. With this method, large molecular cargo can be locally released. Third, stable temperature-sensitive liposomal constructs were then developed by altering the osmolarity of the interior aqueous core of the particle. A final approach to increase drug bioavailability was explored by developing a cancer targeted liposome that uses a ligand to enhance internalization. These four different approaches to increasing the efficacy of drug delivery are promising advances in the field of cancer therapy.In the first approach, stable activatable liposomes were developed by changing the lipid shell by varying the PEG coating, lysolipid content, cholesterol content, and lipid charge. Without activation, tumor accumulation of a model drug using a low-cholesterol and a low-osmolarity temperature-sensitive vehicles was 101 and 66-fold greater, respectively, than the free fluorophore at 24 hours after injection. By comparison, accumulation of a long-circulating cholesterol-rich formulation was 177-fold higher. By combining positron emission tomography and optical imaging the liposomal stability was assessed in vivo. The result was a significant improvement in stability; however, substantial release in circulation was still observed in the optimized formulations.In order to further stabilize the cargo during circulation and facilitate on demand release of large molecular cargo, an activatable particle was created using a covalently bound cargo. Using the intrinsic lipid bilayer phenomenon known as "flip-flop", a cleaving molecule and a drug payload were conjugated to the inner and outer leaflet of the lipid bilayer. An increase in temperature then initiates lipid mixing and stimulates cargo release. A liposomal formulation loaded with a drug payload comprising of 30 mol% of the lipid, DSPC:DSPE-PEG2k:DPPE-PDP, within an hour released 18% and 76% at 30°C and 42°C, respectively. This methodology can be applied to release larger molecules at a target site; however, release requires tens of minutes. One of the most promising strategies for improved stability of temperature-sensitive liposomes was developed through manipulation of osmotic gradients. Previously unstable temperature-sensitive liposomes were stabilized by synthesizing them in a hypotonic buffer solution. Similarly, stable liposomes were transformed into temperature-sensitive liposomes by synthesizing them in a hypertonic buffer. Hyper-osmotic liposomes, HSPC:CHOL:DSPE-PEG2k (56:39:5 mol%, 1650 mOsm), released 4% calcein when incubated over 30 min and released 79% when heated for 5 min at 36°C and 46°C, respectively. Finally, a liposome conjugated with targeting ligands for enhanced cellular internalization and therapeutic efficacy was developed. We applied optical imaging with a pH sensitive probe to demonstrate the enhanced internalization of these targeted liposomes. The resulting NRP-targeted liposomes displayed high specificity for the primary prostatic carcinoma cell line (PPC-1) in vitro, binding 83 fold more than a LPP-targeted control liposome. An NRP-targeted liposomal DOX formulation was tested against NDL-tumor bearing mice resulting in: cessation of tumor growth, knockdown of tumor vasculature, and a reduction in DOX toxicity as compared to a non-targeted liposomal DOX formulation.
Liposome Technology, Volume III: Interactions of Liposomes with the Biological Milieu, Third Edition, is a comprehensively updated and expanded new edition of a classic text in the field. Including step-by-step technical details, Volume III describes technologies for yielding liposomes that can function in a targeted fashion, and highlights methods
Exploring fundamental concepts, Drug Delivery Nanoparticles Formulation and Characterization presents key aspects of nanoparticulate system development for various therapeutic applications and provides advanced methods used to file for regulatory approval.This comprehensive guide features:Process Analytical Techniques (PAT) used in manufacturing Na
Nanotechnology-based therapeutics, operating at scales of billionths of a metre, have great potential for future expansion in altering the scale and methods of drug delivery. The availability of these novel formulations to once-inaccessible areas of the body has greatly expanded the therapeutic window of existing drug molecules. Nanoparticulate drug delivery highlights and examines the transition of nanoparticulate drug delivery systems from the laboratory into a commercially viable sector. The first chapters of the book provide an overview of the use and characterization of nanoparticulate systems as drug carriers, including the assessment of their morphology, sterility and potential toxicity. In the latter part of the book, chapters cover nanotoxicology, regulatory aspect and clinical trials, ending with an overview of several case studies and a look towards future developments. Discusses the issues surrounding nanoparticulate products, based on personal experience of their formulation Provides an overview of new application areas, including RNA interference Outlines the pros and cons of nanoparticulate products, and discusses how these may influence their route into the commercial sector
This book throws light on the various methods of preparation and characterization of liposomes. With the advancements in technology since their discovery, newer methods of generating liposomes have been developed. Needless to say, over time liposomes have been modified to a large extent and engineered to suit many of our growing needs. This book throws light on the various methods of preparation and characterization of liposomes. It also discusses the several biochemical and indirect methods that have made it possible to understand the biological and physicochemical mechanisms of liposomes that decide their fate in vivo. In spite of certain limitations, liposomes have proved to be more suitable for a number of unconventional applications. This versatility of liposomes outlined in the book brings out the importance of these nanoparticles in the future applications of nanotechnology besides targeted drug delivery. Overall, this book provides the necessary information about the various aspects of liposomes for beginners.
Author : D. Robert Lu Publisher : Springer Science & Business Media Page : 621 pages File Size : 13,64 MB Release : 2004-02-25 Category : Medical ISBN : 1592597459
An authoritative and up-to-date survey of the fundamental principles, and practice of drug delivery at the cellular level. On the principles side, the authors discuss the broad spectrum of cellular delivery, ranging from coverage of cell-mediated immunity, gene delivery, and protein targeting, to cellular drug transport, cellular drug permeability, and a variety of carrier system related to targeted drug delivery. On the practice side, the authors focus on technological developments in cellular drug delivery, including novel formulations for the delivery of DNA and antisense oligonucleotides ,as well as drug targeting with immunoglobulin formulations and antibody-mediated approaches.
Integrating various technologies with informational systems provides vast improvements to the overall research and development that occur in the biopharmaceutical industry. One of the first books to explore this area, Functional Informatics in Drug Discovery examines all aspects of technology integration and information flow in a biopharmaceutical