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WIREs Nanomed Nanobiotechnol
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Recent advances in development of dendritic polymer‐based nanomedicines for cancer diagnosis

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Abstract Dendritic polymers have highly branched three‐dimensional architectures, the fourth type apart from linear, cross‐linked, and branched one. They possess not only a large number of terminal functional units and interior cavities, but also a low viscosity with weak or no entanglement. These features endow them with great potential in various biomedicine applications, including drug delivery, gene therapy, tissue engineering, immunoassay and bioimaging. Most review articles related to bio‐related applications of dendritic polymers focus on their drug or gene delivery, while very few of them are devoted to their function as cancer diagnosis agents, which are essential for cancer treatment. In this review, we will provide comprehensive insights into various dendritic polymer‐based cancer diagnosis agents. Their classification and preparation are presented for readers to have a precise understanding of dendritic polymers. On account of physical/chemical properties of dendritic polymers and biological properties of cancer, we will suggest a few design strategies for constructing dendritic polymer‐based diagnosis agents, such as active or passive targeting strategies, imaging reporters‐incorporating strategies, and/or internal stimuli‐responsive degradable/enhanced imaging strategies. Their recent applications in in vitro diagnosis of cancer cells or exosomes and in vivo diagnosis of primary and metastasis tumor sites with the aid of single/multiple imaging modalities will be discussed in great detail. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging Diagnostic Tools > in vitro Nanoparticle‐Based Sensing
Illustration of various dendritic polymers
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Dendritic nano‐scale systems for multi‐modality imaging of cancer. (a) A low generation dendrimer‐based system for dual MR/CT imaging of orthotopic brain gliomas. (a1) Schematic illustration of RGD‐Au‐Mn DENPs. (a2) X‐ray attenuation of RGD‐Au‐Mn DENPs compared to Omnipaque at various Au or I concentrations. (a3) T1‐weighted MR images of C6 orthotopic brain gliomas before and after i.v. injection of Au‐Mn DENPs (images above) and RGD‐Au‐Mn DENPs (images below). (Reprinted with permission from X. Xu, Liu, et al., 2019. Copyright 2019 The Royal Society of Chemistry). (b) Endoglin‐targeted dendrimer particles for dual MR/optical imaging of tiny hepatic tumor xenografts. (b1) Schematic representation of endoglin‐targeted Den‐Apt1. (b2) Tumor‐to‐normal‐tissue ratio of various mice groups administrated with Den‐PEG, Den‐Apt1, and Den‐Apt1 with pre‐blocking by endoglin from MR images. (b3) Fluorescent images of major organs excised at 24 hr post‐injection of Den‐Apt1. (Reprinted with permission from Omata et al., 2017. Copyright 2018 American Chemical Society)
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Dendritic nano‐scale systems for optical imaging of cancer. (a) Preparation route for PDI‐PLL dendrimers from generation 0 to generation 8. (b) TEM image of PDI‐PLL‐G8. (c) Fluorescence quantum yield and average lifetime of PDI‐PLL of different generations at 645 nm. (d) Fluorescence images of 4T1 cells preincubated with Cy5 (images above) and PDI‐PLL‐G5(images below) at different time points. (e) Tumor‐to‐normal‐tissue ratio of several mice groups at different time points after i.v. injection of various biotin‐targeted fluorescent PDI‐PLL‐G5. (f) Representative bioluminescence/bright/fluorescence pictures of mice bearing systemic metastasis. From the left to the right, bioluminescence images of mice 12 days after intracardiac injection of 4T1‐Luc cells, bright image and corresponding fluorescence image of lymph node metastasis at 8 hr post‐injection of fluorescent G5‐PEG‐5B dendrimer. (Reprinted with permission from Cong et al., 2020. Copyright 2020 American Chemical Society)
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Dendritic nano‐scale systems for nuclear medical imaging of cancer. (a) Preparation of radiolabeled and PEGylated hyperbranched semiconducting polymeric (HSP‐PEG) NPs. SPECT images of mice bearing 4T1 tumor (b) and patient‐derived prostate tumor tissue (c) after i.v. injection of 99mTc‐labeled HSP‐PEG NPs were obtained at different time points. (Reprinted with permission from Yi et al., 2018. Copyright 2018 American Chemical Society). SPECT, single photon emission computed tomography
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Dendritic nano‐scale systems for CT imaging of cancer. (a) Schematic illustration of Au DSNs‐DTA‐FA. (a1) Preparation route for Au DSNs‐DTA‐FA, and (a2) TEM images of Au DSNs‐DTA‐FA. (b) X‐ray attenuation of [(Au0)120‐G5.NHAc‐DTA‐(PEG‐GA)‐mPEG] dendrimer‐stabilized NPs (DSNs) in comparison with that of [(Au0)120‐G5.NHAc‐mPEG] dendrimer‐entrapped NPs (DENs) at various Au concentrations. (c) X‐ray attenuation of [(Au0)120‐G5.NHAc‐DTA‐(PEG‐GA)‐mPEG] DSNs in comparison with that of clinically used Omnipaque at various I concentrations. (Reprinted with permission from T. Xiao et al., 2020. Copyright 2020 American Chemical Society). CT, computed tomography
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Dendritic nano‐scale systems for MR imaging of cancer. (a) Scheme representation of a hypoxia‐targeting dendritic MR contrast agent with internal hydroxyl groups. (b) The in vitro longitudinal relaxivity of G3(DTPA‐Gd)‐SA, G3(DTPA‐Gd)‐Cys, and Magnevist. (c) T1‐weighted MR images of orthotopic breast tumor‐bearing mice before and after i.v. injection of different MR agents. (Reprinted with permission from Han et al., 2019. Copyright 2019 Elsevier Ltd.)
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Dendritic nano‐scale systems for in vitro diagnosis of cancer. (a) A dendrimer‐based system for effective capture of CTCs after TGF β1‐induced EMT. (a1) The capture efficiency of controls and the dendrimer‐based cocktails platform against TGF β1‐untreated cells and TGF β1‐treated cells. (a2) Capture purity of CTCs from clinical samples of prostate cancer patients. (Reprinted with permission from Myung et al., 2019. Copyright 2019 American Chemical Society). (b) A dual layer poly(amidoamine) dendrimer surface configuration for capture of tumor‐derived exosomes. (b1) Various capture surface configurations; (b2) capture ability of MCF‐7 cells‐derived exosomes from various surface configurations in (b1). (b3) Free energy profiles indicated an enhanced adhesion was brought by a dual layer dendrimer surface at a distance of less than 10 nm. (Reprinted with permission from Poellmann et al., 2020. Copyright 2020 American Chemical Society). CTCs, circulating tumor cells; EMT, epithelial‐mesenchymal transition; TGF, transforming growth factor
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Size dependence of G4 (~4.3 nm) and G6 (~6.7 nm) PAMAM dendrimers for their passive tumor targeting or kinetics in orthotopic brain tumor bearing mice. (a) Fluorescently labeled G4 and G6 dendrimers were administrated into a GL261 mice model of glioblastoma through intravenous injection. (a1) Quantitative analysis of their accumulation in the tumor and the contralateral hemisphere (contra for short) at different post‐injection time points. (a2) Their corresponding fluorescent images obtained at 24 hr after injection. (b) Comparison of Cy3‐labeled G4 and Cy5‐labeled G6 dendrimers' kinetics in the 9L mice model of gliosarcoma. (b1) Quantitive analysis and (b2) corresponding confocal images of their distribution in the tumor, peritumor areas (peri for short), and contra at different time points after the i.v. injection. (Reprinted with permission from Liaw et al., 2020. Copyright 2020 The Authors Wiley Periodicals, Inc.)
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Schematic illustration of main synthesis routes to prepare dendrigraft polymer: (a) Graft‐to route. (b) Graft‐from route. (c) Macromonomer route
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Schematic representation of various preparation strategies of hyperbranched polymer. (Reprinted with permission from Aydogan et al., 2018. Copyright 2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
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Representation of (a) divergent, and (b) convergent preparation strategy, and (c) surface modification of dendrimers
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Diagnostic Tools > In Vitro Nanoparticle-Based Sensing
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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