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WIREs Nanomed Nanobiotechnol
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Remodeling tumor microenvironment with nanomedicines

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Abstract The tumor microenvironment (TME) has been recognized as a major contributor to cancer malignancy and therapeutic resistance. Thus, strategies directed to re‐engineer the TME are emerging as promising approaches for improving the efficacy of antitumor therapies by enhancing tumor perfusion and drug delivery, as well as alleviating the immunosuppressive TME. In this regard, nanomedicine has shown great potential for developing effective treatments capable of re‐modeling the TME by controlling drug action in a spatiotemporal manner and allowing long‐lasting modulatory effects on the TME. Herein, we review recent progress on TME re‐engineering by using nanomedicine, particularly focusing on formulations controlling TME characteristics through targeted interaction with cellular components of the TME. Importantly, the TME should be re‐engineering to a quiescent phenotype rather than be destroyed. Finally, immediate challenges and future perspectives of TME‐re‐engineering nanomedicines are discussed, anticipating further innovation in this growing field. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Tumors are composed of malignant cancer cells and their microenvironment (i.e., the stroma). The cancer cells induce dysregulated angiogenesis, desmoplasia, and inflammation. To do so, cancer cells coopt nonmalignant stromal components, including fibroblasts, immune cells, and blood and lymphatic vascular cells and the extracellular matrix. As a result, the tumor microenvironmet has pathological molecular, metabolic, and physical features that promote disease progression and resistance to therapy while limiting host immune response
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(a) tumor volume as a function of time of murine breast tumors treated with saline (control), the mechanotherapeutic tranilast (200 mg/kg), anti‐CTLA‐4/anti‐PD‐1 immunotherapy cocktail (5 and 10 mg/kg, respectively), the cytotoxic nanomedicine Doxil with anti‐angiogenic properties (3 mg/kg), and the combinations. A mechanotherapeutic combined with a cytotoxic nanomedicine that normalizes vessels administered before immunotherapy stalls tumor growth. Statistical analyses were performed by comparing the treated groups with the control * and the tranilast‐Doxil‐ anti‐CTLA‐4/anti‐PD‐1 immunotherapy cocktail groups with all other treatment groups **, p ≤ 0.05 (n = 8–10 mice per group). (b) Schematic of the proposed mechanotherapeutic (tranilast) in combination with anti‐angiogenic therapy (Doxil nanomedicine) mechanism of action. Tumor re‐engineering normalizes tumor vessels leading to increased perfusion, increased tumor oxygenation, increased immune stimulation, and increased oxygenation enhance the efficacy of ICBs inhibiting primary tumor growth. (Reprinted with permission from Panagi et al. (2020) under a Creative Commons Attribution License; https://creativecommons.org/licenses/by/4.0/)
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Careful modulation of pericyte coverage of tumor blood vessels is required to increase nanomedicine penetration. (a–c) Representative intravital microscopy images of mouse tumors treated with four daily doses of (a) control, (b) 3 mg/kg, or (c) 30 mg/kg dexamethasone 1 h after injection of 70 kDa (13 nm, red) and 500 kDa (32 nm, green) fluorescent dextrans. (d) Quantification of permeability, which measures the rate that dextrans are penetrating after treatment with daily dexamethasone 3 mg/kg (orange), 30 mg/kg (gray) and control (blue, N = 3–4). Data expressed as mean ± standard error of the mean (*, p < 0.05). (e) Mathematical model predictions of the effective vessel wall pore diameter of control (blue bar), 3 mg/kg (orange bar) and 30 mg/kg dexamethasone (gray bar) treated tumors. The model is solved using the data from the effective permeability experiments to predict the effective vessel wall pore diameter. (Reprinted with permission from Martin, Panagi, et al. (2019). Copyright 2019 American Chemical Society)
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(a, b) Tumor blood vessels are leaky and compressed. (a) An intravital microscopy image of tumor blood vessels in mice (black; negative contrast). 24 h post‐injection, 90‐nm liposomes (bright red) leak out of hyperpermeable vessels but cannot penetrate. Scale bar, 100 μm. (b) A histological image of tumor blood vessels in mice. Only a few vessels (red) in this collagen‐rich (blue) tumor have blood flow (yellow). Scale bar, 100 μm. (c,d) Depictions of perfusion before and after vascular normalization. (c) In the top panel, there are untreated tumor vessels, with one vessel hypo‐perfused (few red blood cells) and the other vessel well‐perfused (many red blood cells). The tissue around the perfused vessel is normoxic (pink), while the tissue farther from the vessels is hypoxic (purple). Normoxic tissue surrounding each vessel is denoted by a black dashed line. (c) Vessel normalization occurring with pericyte recruitment to produce an intact perivascular layer (green) leading to increased blood flow that increases oxygen delivery to the surrounding tissue. (d) Vessel decompression occurs after reducing solid stress. Then, the blood vessel re‐perfuses and oxygen delivery is restored. (e, f) Vnormalization without depletion of vessels leads to homogenous perfusion. (e) In untreated tumors (green, top panel), perfused vessels have low density (red). Vascular normalization without depletion leads to an even distribution of perfused vessels (bottom). Scale bars, 500 μm. (f) In untreated tumors (top panel), collagen (blue) and other ECM compress vessels and large regions lack perfused vessels (green). Re‐engineering CAFs/ECM through normalization of CAFs to a quiescent phenotype (bottom) reduces collagen levels and increases the amount of perfused vessels. Scale bars, 500 μm. (Reprinted with permission from Martin, Seano, and Jain (2019). Copyright 2019 Annual Reviews)
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Ligand‐installed and/or stimuli‐responsive nanomedicines are limited in microdistribution throughout tumors because of the tumor microenvironment. With insufficient penetration, the advanced functions of these nanomedicines become comparable with passively accumulating and releasing nanomedicines. Microenvironment re‐engineering therapies increase and homogenize the microdistribution of nanomedicines. Following re‐engineering, functionalized nanomedicines are more likely to reach their target cell thereby demonstrating a larger improvement over passive nanomedicine. Thus, re‐engineering the microenvironment could help fulfill the potential of targeted and/or stimuli‐responsive nanomedicines. (Reprinted with permission from Martin et al. (2020). Copyright 2020 Springer Nature)
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