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WIREs Nanomed Nanobiotechnol
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Delivery of therapeutics with nanoparticles: what's new in cancer immunotherapy?

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The application of nanotechnology to the treatment of cancer or other diseases has been boosted during the last decades due to the possibility to precise deliver drugs where needed, enabling a decrease in the drug's side effects. Nanocarriers are particularly valuable for potentiating the simultaneous co‐delivery of multiple drugs in the same particle for the treatment of heavily burdening diseases like cancer. Immunotherapy represents a new concept in the treatment of cancer and has shown outstanding results in patients treated with check‐point inhibitors. Thereby, researchers are applying nanotechnology to cancer immunotherapy toward the development of nanocarriers for delivery of cancer vaccines and chemo‐immunotherapies. Cancer nanovaccines can be envisioned as nanocarriers co‐delivering antigens and adjuvants, molecules often presenting different physicochemical properties, in cancer therapy. A wide range of nanocarriers (e.g., polymeric, lipid‐based and inorganic) allow the co‐formulation of these molecules, or the delivery of chemo‐ and immune‐therapeutics in the same system. Finally, there is a trend toward the use of biologically inspired and derived nanocarriers. In this review, we present the recent developments in the field of immunotherapy, describing the different systems proposed by categories: polymeric nanoparticles, lipid‐based nanosystems, metallic and inorganic nanosystems and, finally, biologically inspired and derived nanovaccines. WIREs Nanomed Nanobiotechnol 2017, 9:e1421. doi: 10.1002/wnan.1421 This article is categorized under: Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Envisioned future treatment of cancer. Nanoparticles are targeted to the cancer cells and are uptaken. The chemoterapeutics released from the particles kill the cancer cells, controlling the progression of the tumor. The immune system can then resume its fight against the cancer cells. A second set of nanoparticles, the actual vaccine, is delivered to dendritic cells (DCs), inducing the priming of cytotoxic T‐lymphocytes against the antigens expressed by the tumor. Abbreviations: CTLs: cytotoxic T lymphocytes; DCs: dendritic cells; i.v.: intravenous; siRNA: small interfering RNA; TCV: therapeutic cancer vaccine; TLR: Toll‐like receptor. (Reprinted with permission from Ref . Copyright 2016 Elsevier)
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The different systems presented in this review. Schematics and TEM pictures of the different categories of systems investigated for dual therapeutic delivery in cancer immunotherapy. (a), (c), (e), (g) scale bars 100 nm. (Reprinted with permission from: (a) Ref . Copyright 2016 Elsevier; (b) Ref . Copyright 2015 Elsevier; (c) Ref . Copyright 2016 Wiley; (d) Ref . Copyright 2005 Nature Publishing; (e) Ref . Copyright 2015 Elsevier; (f) Ref . Copyright 2014 Elsevier; (g) Ref . Copyright 2016 ACS Publications)
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Schematic of the leading characters in cancer immunotherapy and their relationship. The three different phases of immunization, T‐cell activation, and immunosuppression in the tumor microenvironment are depicted. (Reprinted with permission from Ref . Copyright 2011 Nature Publishing Group)
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Schematic representation of the production process of viral‐mimicking particles. The E2 protein nanoparticle is covalently modified with CpG internally and with the antigenic peptide externally. The multifunctional system is then incubated with immature dendritic cells. The adjuvant is released, inducing the maturation of the dendritic cells and the subsequent priming of T‐lymphocytes. (Reprinted with permission from Ref . Copyright 2013 ACS Publications)
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Schematic of the proposed system for chemoimmunotherapy. The PSi nanoparticle loads an anticancer drug and is conjugated to an antibody. When it will reach the tumor microenvironment, it will release the drug and interact with effector immune cells to create an antibody‐dependent cell‐mediated cytotoxicity. (Reprinted with permission from Ref . Copyright 2015 Springer)
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Schematic of the proposed system. A dispersion of the mesoporous silica rods in buffer is injected into subcutaneous tissue of mice to form a pocket. After diffusion of the buffer from the pocket, there is the in situ spontaneous assembly of the rods with the formation of three‐dimensional interparticle spaces where host immune cells can be recruited and educated by the payloads. Educated cells may then emigrate from the structure to interact with other immune cells. (Reprinted with permission from Ref . Copyright 2015 Nature Publishing)
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Layer‐by‐layer deposition of adjuvant and antigen on the surface of gold nanoparticles. The system is self‐assembled due to the opposite charge between the elements (gold nanoparticles, adjuvant, and antigen). (Reprinted with permission from Ref . Copyright 2015 ACS Publications)
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Preparation of the nanolipogels. Schematic of the production process. (a) Methacrylate‐f‐CD encapsulate the TGF‐β inhibitor. (b) Then, the nanolipogels are produced from liposomes loaded with the biodegradable crosslinking polymer and the cytokine. The gel is formed after photoinduced polymerization. Abbreviations: CD, cyclodextrin; NHS, N‐Hydroxysuccinimide. (Reprinted with permission from Ref . Copyright 2012 Nature Publishing)
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Delivery of mRNA in dendritic cells with ultrasounds. (a) Mode of action of the system: when the ultrasound is applied, after the sonoporation of the cells, the liposomes deliver their cargo intracellularly. (b) Summary of the methods used to prepare the particles: the liposomes are mixed with the mRNAs; then the avidin molecules on the surface of the microbubbles react with the biotins on the surface of the liposome, binding them to the bubble. (Reprinted with permission from Ref . Copyright 2014 Elsevier)
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Schematic of the immune response induced after administration of PLGA nanoparticles co‐loaded with paclitaxel and an adjuvant, a Toll‐like Receptor (TLR) agonist 4. The administration of paclitaxel to the tumor cells will induce their death, with the releasing of tumor antigens. The antigens will be uptaken by APCs, mainly dendritic cells (DCs) and macrophages (MΦ). The simultaneous administration of the adjuvant will activate the antigen‐presenting cells, stimulating the expression of activation markers (CD40, CD80, and CD86). The activated APCs will secrete cytokines like IL‐12, inducing the activation of T‐cells, both T‐helper and cytotoxic T‐lymphocytes directed against the cancer cells. This resulted in an improved control over the tumor volume in vivo. (Reprinted with permission from Ref . Copyright 2013 ScienceDirect)
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Biology-Inspired Nanomaterials > Lipid-Based Structures
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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