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      Rationalizing the use of functionalized poly-lactic-co-glycolic acid nanoparticles for dendritic cell-based targeted anticancer therapy

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          Abstract

          <div class="section"> <a class="named-anchor" id="d9468271e262"> <!-- named anchor --> </a> <h5 class="section-title" id="d9468271e263">Background:</h5> <p id="d9468271e265">Delivery of PLGA (poly [D, L-lactide-co-glycolide])-based biodegradable nanoparticles (NPs) to antigen presenting cells, particularly dendritic cells, has potential for cancer immunotherapy. </p> </div><div class="section"> <a class="named-anchor" id="d9468271e267"> <!-- named anchor --> </a> <h5 class="section-title" id="d9468271e268">Materials &amp; methods:</h5> <p id="d9468271e270">Using a PLGA NP vaccine construct CpG-NP-Tag (CpG-ODN-coated tumor antigen [Tag] encapsulating NP) prepared using solvent evaporation technique we tested the efficacy of <i>ex vivo</i> and <i>in vivo</i> use of this construct as a feasible platform for immune-based therapy. </p> </div><div class="section"> <a class="named-anchor" id="d9468271e278"> <!-- named anchor --> </a> <h5 class="section-title" id="d9468271e279">Results:</h5> <p id="d9468271e281">CpG-NP-Tag NPs were avidly endocytosed and localized in the endosomal compartment of bone marrow-derived dendritic cells. Bone marrow-derived dendritic cells exposed to CpG-NP-Tag NPs exhibited an increased maturation (higher CD80/86 expression) and activation status (enhanced IL-12 secretion levels). <i>In vivo</i> results demonstrated attenuation of tumor growth and angiogenesis as well as induction of potent cytotoxic T-lymphocyte responses. </p> </div><div class="section"> <a class="named-anchor" id="d9468271e286"> <!-- named anchor --> </a> <h5 class="section-title" id="d9468271e287">Conclusion:</h5> <p id="d9468271e289">Collectively, results validate dendritic cells stimulatory response to CpG-NP-Tag NPs <i>(ex vivo)</i> and CpG-NP-Tag NPs’ tumor inhibitory potential <i>(in vivo)</i> for therapeutic applications, respectively. </p> </div>

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          Most cited references 21

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          Nanoparticle vaccines.

          Nanotechnology increasingly plays a significant role in vaccine development. As vaccine development orientates toward less immunogenic "minimalist" compositions, formulations that boost antigen effectiveness are increasingly needed. The use of nanoparticles in vaccine formulations allows not only improved antigen stability and immunogenicity, but also targeted delivery and slow release. A number of nanoparticle vaccines varying in composition, size, shape, and surface properties have been approved for human use and the number of candidates is increasing. However, challenges remain due to a lack of fundamental understanding regarding the in vivo behavior of nanoparticles, which can operate as either a delivery system to enhance antigen processing and/or as an immunostimulant adjuvant to activate or enhance immunity. This review provides a broad overview of recent advances in prophylactic nanovaccinology. Types of nanoparticles used are outlined and their interaction with immune cells and the biosystem are discussed. Increased knowledge and fundamental understanding of nanoparticle mechanism of action in both immunostimulatory and delivery modes, and better understanding of in vivo biodistribution and fate, are urgently required, and will accelerate the rational design of nanoparticle-containing vaccines. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
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            Cancer immunotherapy by dendritic cells.

            Cancerous lesions promote tumor growth, motility, invasion, and angiogenesis via oncogene-driven immunosuppressive leukocyte infiltrates, mainly myeloid-derived suppressor cells, tumor-associated macrophages, and immature dendritic cells (DCs). In addition, many tumors express or induce immunosuppressive cytokines such as TGF-beta and IL-10. As a result, tumor-antigen crosspresentation by DCs induces T cell anergy or deletion and regulatory T cells instead of antitumor immunity. Tumoricidal effector cells can be generated after vigorous DC activation by Toll-like receptor ligands or CD40 agonists. However, no single immunotherapeutic modality is effective in established cancer. Rather, chemotherapies, causing DC activation, enhanced crosspresentation, lymphodepletion, and reduction of immunosuppressive leukocytes, act synergistically with vaccines or adoptive T cell transfer. Here, I discuss the considerations for generating promising therapeutic antitumor vaccines that use DCs.
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              Surface charge affects cellular uptake and intracellular trafficking of chitosan-based nanoparticles.

              Chitosan-based nanoparticles (NPs) are widely used in drug delivery, device-based therapy, tissue engineering, and medical imaging. In this aspect, a clear understanding of how physicochemical properties of these NPs affect the cytological response is in high demand. The objective of this study is to evaluate the effect of surface charge on cellular uptake profiles (rate and amount) and intracellular trafficking. We fabricate three kinds of NPs (∼ 215 nm) with different surface charge via SPG membrane emulsification technique and deposition method. They possess uniform size as well as identical other physicochemical properties, minimizing any differences between the NPs except for surface charge. Moreover, we extend our research to eight cell lines, which could help to obtain a representative conclusion. Results show that the cellular uptake rate and amount are both positively correlated with the surface charge in all cell line. Subsequent intracellular trafficking indicates that some of positively charged NPs could escape from lysosome after being internalized and exhibit perinuclear localization, whereas the negatively and neutrally charged NPs prefer to colocalize with lysosome. These results are critical in building the knowledge base required to design chitosan-based NPs to be used efficiently and specifically.
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                Author and article information

                Journal
                Nanomedicine
                Nanomedicine
                Future Medicine Ltd
                1743-5889
                1748-6963
                March 2016
                March 2016
                : 11
                : 5
                : 479-494
                Article
                10.2217/nnm.15.213
                5563943
                26892440
                © 2016
                Product

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