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During the past decade, the rapid growth of molecular and cellular knowledge of macrophages, as a specialized host defense and homeostatic system, has begun to offer attractive targets for therapeutic intervention. Macrophages play a central role in a wide range of disease processes, from genetically determined lysosomal storage diseases, to acute sepsis, chronic inflammation and repair, tissue injury and cell death. Under- or overactivity of macrophage clearance, immune effector functions and responses to metabolic abnormalities contribute to common disorders such as autoimmunity, atherosclerosis, Alzheimer’s disease and major infections including AIDS and Tuberculosis. Whilst the goals of therapeutic intervention based on improved understanding of macrophage functions and their contribution to pathogenesis may seem self evident, there are considerable difficulties in producing useful new agents. The present volume covers a range of subjects and provides opportunities for a more focused macrophage-targeted approach. The individual chapters review selected topics briefly, to place cellular processes and molecular targets in perspective. Overall, the volume should provide a broad sample of the state of the art. Useful reviews and references in the literature are cited within individual chapters.
The proposed book is envisioned for the nascent and entry-level researchers who are interested to work in the field of drug delivery and its applications specifically for macrophage targeting. Macrophages have gained substantial attention as therapeutic targets for drug delivery considering their major role in health and regulation of diseases. Macrophage-targeted therapeutics have now added significant value to the lives and quality of life of patients, without undue adverse effects in multiple disease settings. We anticipate examining and integrating the role of macrophages in the instigation and advancement of various diseases. The major focus of the book is on recent advancements in various targeting strategies using delivery systems or nanocarriers followed by application of these nanocarriers for the treatment of macrophage associated disorders. Macrophage Targeted Delivery Systems is primarily targeted to Pharmaceutical Industry & Academia, Medical & Pharmaceutical Professionals, Undergraduate & Post graduate students and Research Scholars, Ph.D, post docs working in the field of medical and pharmaceutical sciences.
Previous studies on the mechanistic induction of anti-tumor responses by IL-12 cytokine therapy have focused on the adaptive immune response, specifically the activation NK cells and T cells as the primary targets of IL-12 treatment. In contrast, little attention has been given to the potential role of macrophages in the initiation of anti-tumor responses by IL-12 therapy despite reports that macrophages play a major role in promoting tumor growth and metastasis and in suppressing anti-tumor immune responses. Based on the functional adaptivity hypothesis, which is the concept that macrophages functionally adapt, rather than differentiate into specific mature subsets, in response to environmental stimuli, we hypothesized that tumor infiltrating (TIMs) as well as tumor-associated macrophages (TAMs) could be converted from tumor supportive activities to pro-immunogenic activities by IL-12 therapy. We examined the functional activities displayed by TIMs and TAMs after treatment with IL-12. Our data demonstrate (1) that tumor cells and tumor exosomes activate TIMs and TAMs by cell-contact dependent mechanisms involving ligation of CD40 and/or NKG2D, (2) that IL-12 treatment both in vivo and in vitro induces a rapid reduction of tumor supportive activities and a concomitant increase in pro-inflammatory activities in TIMs as well as TAMs, (3) that IL-12 induces a rapid release of cytoplasmic IL-I5 from the in situ activated tumor associated macrophages and (4) the release of IL-15 in essential to the recruitment of lymphocytes to the tumor and the metastatic lung, and to the destruction of the tumor and clearance of metastasis. It is concluded that macrophages in the tumor environment are activated and functionally modulated by the tumor. TIMs and TAMs respond to IL-12 treatment by rapidly converting from suppressive, tumor supportive activities to inflammatory, pro-immunogenic activities. Tumor associated macrophages thus are a critical target of IL-12 therapy and may orchestrate the subsequent NK and T cell cytotoxic response against the tumor.
Macrophage has been recognized as an important therapeutic target owing to its multiple supportive roles in cancer development. Meantime, it has also been exploited as a potential tool for cancer treatment by taking advantage of its intrinsic properties. In the first chapter of my dissertation, I have reviewed the multiple roles of macrophage in cancer development as well as different strategies exploiting macrophages for cancer treatment. The second chapter is about using macrophage as a cellular drug delivery vehicle by making use of its tumor-tropic migration property. A drug-encapsulated silica nanocapsule is loaded into macrophages via internalization. A layer of silica shell is coated on top of the nanocapsule to prevent early leakage of drug payload during the migration towards tumor tissue. The nanocapsule-laden macrophages can efficiently home to tumor site, offering high drug delivery efficiency and enhanced therapeutic efficacy. The third chapter is about increasing the intratumoral macrophage content for enhanced tumor uptake of nanomedicine. As reviewed in the first chapter, macrophages in the tumor microenvironment can not only accumulate nanoparticles by phagocytosis, but also remodel the tumor microvironment to render a higher leakiness for the deposition of nanoparticles into tumor tissue. In this study, increasing the intratumoral macrophage number via intratumoral injection of macrophages shows promise in increasing the tumor deposition of iron oxide nanoparticles and doxove (liposomal doxorubicin, a type of therapeutic nanomedicines) in U-87MG human glioblastoma model, therefore benefiting the tumor imaging in T2 magnetic resonance imaging (MRI) and contributing to an improved therapeutic result. In the fourth chapter, nanoparticle-laden macrophage is exploited to enhance intratumoral immunogenic cell death (ICD) process. By taking advantage of the functional plasticity of macrophage, metal oxide nanoparticles with low cytotoxicity serve as a stimulus to promote the production of damage associated molecular pattern (DAMP) molecules of macrophage. This converts macrophage into a cellular reactor for DAMP generation, which activates the ICD process in tumor site for anti-tumor immunogenicity.
Maurie Markman and a panel of distinguished clinicians and leading clinical investigators comprehensively review the current status of regional antineoplastic drug delivery in the management of malignant disease. These authorities present a critical analysis of both the rationale and limitations of regional therapy and discuss potential clinical trials designed to explain the effectiveness of this method of therapy in special settings. Their presentations describe many exciting and innovative strategies for using regional drug delivery in anticancer therapy, including coverage of such areas of special interest as colorectal, skin, lung, pancreatic, ovarian, and gastrointestinal cancers. Comprehensive and authoritative, Regional Chemotherapy: Clinical Research and Practice offers surgical and medical oncologists and clinical cancer investigators a gold-standard review of the current role and future development of this increasingly powerful weapon in the battle against cancer.
Advances in Cancer Research, Volume 139, provides invaluable information on the exciting and fast-moving field of cancer research. Original reviews are presented on a variety of topics relating to the rapidly developing intersection between nanotechnology and cancer research, with unique sections in the new release focusing on Exosomes as a theranostic for lung cancer, Nanotechnology and cancer immunotherapy, Ultrasound imaging agents and delivery systems, Dendronized systems for the delivery of chemotherapeutics, Thermosensitive liposomes for image-guided drug delivery, Supramolecular Chemistry in Tumor Analysis and Drug Delivery, Gold nanoparticles for delivery of cancer therapeutics, and Single cell barcode microchip for cancer research and therapy. Provides the latest information on cancer research Offers outstanding and original reviews on a range of cancer research topics Serves as an indispensable reference for researchers and students alike