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WIREs Nanomed Nanobiotechnol
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Combined cancer therapeutics—Tackling the complexity of the tumor microenvironment

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Abstract Cancer treatment has yet to find a “silver bullet” capable of selectively and effectively kill tumor cells without damaging healthy cells. Nanomedicine is a promising field that can combine several moieties in one system to produce a multifaceted nanoplatform. The tumor microenvironment (TME) is considered responsible for the ineffectiveness of cancer therapeutics and the difficulty in the translation from the bench to bed side of novel nanomedicines. A promising approach is the use of combinatorial therapies targeting the TME with the use of stimuli‐responsive nanomaterials which would increase tumor targeting. Contemporary combined strategies for TME‐targeting nanoformulations are based on the application of external stimuli therapies, such as photothermy, hyperthermia or ultrasounds, in combination with stimuli‐responsive nanoparticles containing a core, usually composed by metal oxides or graphene, and a biocompatible stimuli‐responsive coating layer that could also contain tumor targeting moieties and a chemotherapeutic agent to enhance the therapeutic efficacy. The obstacles that nanotherapeutics must overcome in the TME to accomplish an effective therapeutic cargo delivery and the proposed strategies for improved nanotherapeutics will be reviewed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies
Tumor microenvironment (TME) characteristics and composition. The metabolism reprograming of tumor cells result in acidification of the TME, and in the increased production of glutathione (GSH) to counteract the increased ROS production. The rapid proliferation of tumor cells creates hypoxic regions that stimulates the formation of an immature and chaotic vascular network. The inflammatory signals at the TME trigger the formation of cancer associated fibroblasts and polarization of tumor associated macrophages. The presence of lymphoid lineage cells is preponderant for tumor prognosis
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Stimuli‐responsive nanoparticles are mainly composed by two distinct layers, an internal core and the coating layer (P. Liu, Xie, et al., 2020; van der Meel et al., 2019). The internal core is frequently composed by metal oxides, graphene or other biocompatible polymers. The coating layer could be composed by biocompatible stimuli responsive or targeting molecules, such as polyethylene glycol (PEG), hyaluronic acid (HA) or MnO2, that under acidic conditions or high concentrations of reactive oxygen species (ROS) found in tumor microenvironment (TME), detach from the core. Chemotherapeutic agents, such as doxorubicin, cisplatin or paclitaxel, are frequently attached or adsorbed to the coating layer to enhance the therapeutic effect of the nanoformulation. External stimuli, such as light, ultrasound or magnetic field enhance the release of coating layer and the solubilization of the materials from the core
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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