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WIREs Nanomed Nanobiotechnol
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Targeted nanoparticles for image‐guided treatment of triple‐negative breast cancer: clinical significance and technological advances

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Effective treatment of triple‐negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and noninvasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise toward the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle‐based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor‐associated endothelial cells, stromal fibroblasts, and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in‐depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as by others, and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic. WIREs Nanomed Nanobiotechnol 2015, 7:797–816. doi: 10.1002/wnan.1343

Cellular receptor highly expressed in triple‐negative breast cancer (TNBC) tissues for the development of targeted theranostic nanoparticles. Cellular receptors upregulated in TNBC tissues have differential levels in tumor cells and stromal cells. Urokinase plasminogen activator receptor (uPAR), folate receptor, and CXCR4 are expressed in tumor cells, angiogenic endothelial cells, and stromal fibroblasts and macrophages. Epidermal growth factor receptor (EGFR), Wnt receptor, and MUC1 are found in tumor cells. IGF‐1R and CD44 are highly expressed in tumor cells and some stromal cells. Tumor endothelial cell‐targeted theranostic nanoparticles are delivered into TNBC tissues by both active targeting and passive targeting (or EPR effect). Theranostic nanoparticles targeting to tumor cells alone are delivered by passive targeting into the tumor interstitial space. Receptor‐targeted theranostic nanoparticles with cellular targets expressed in tumor cells and stromal fibroblasts and macrophages, but lack the expression in tumor endothelial cells, will also be delivered into the tumor interstitial space by passive targeting. The binding of the targeted theranostic nanoparticles to stromal fibroblast, macrophages, and tumor cells enhances retention of the nanoparticles in the tumor. Receptor‐mediated internalization of nanoparticle drug carriers increases intratumoral cell drug delivery and therapeutic effect.
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Urokinase plasminogen activator receptor (uPAR)‐targeted magnetic iron oxide nanoparticles for multimodal imaging of breast cancer. Balb/c mice bearing 4T1 mammary tumors (TNBC subtype) received a tail vein delivery of 300 pmol of NIR‐830‐dye‐mouse ATF‐IONP. (a) Dual near‐infrared (NIR) optical and magnetic resonance imaging (MRI). Twenty‐four hours following nanoparticle injection, MRI signal decreased in T2‐weighted images (A and B). An ultrashort echo time (UTE) imaging detected an increase in MRI signal (positive MRI signal) shown as SubUTE image by subtraction of a longer echo signal from that of the UTE (SubUTE) image (C and D). T2 maps showed T2 signal decreases in the tumor. Orthotopic mammary tumor (dot‐lined area), A, C, and E: before injection; B, D, and F: postinjection. NIR optical imaging showed strong signal in a mammary tumor (G). Prussian blue staining of the tumor tissue section showed the presence of blue nanoparticle‐positive cells in the tumor (H). (Reprinted with permission from Ref . Copyright 2014 John Wiley and Sons). (b) Targeted fluorescence tomography (FMT). NIR 830‐ATF‐IONP: uPAR‐targeted nanoparticle, NIR‐830‐BSA‐IONP: bovine serum albumin (BSA)‐conjugated nanoparticle as a nontargeted control. FMT detected strong optical signal in the mammary tumor of the mice that received uPAR‐targeted ATF‐IONP (A–C), but not nontargeted BSA‐IONP, which only showed strong signal in the liver area (D–F). A and D: X‐ray/planar fluorescence image of the mice; B and E: cross section of the FMT slice; C and F: sagittal FMT slice. The red square (A and D) indicates the FMT imaging area. (Reprinted with permission from Ref . Copyright 2014 Optical Society). (c) Photoacoustic imaging (PAT). Schematics showed uPAR‐targeted (NIR‐830‐ATF‐IONP) or nontargeted (NIR‐830‐BSA‐IONP). In vivo PAT and fluorescence images showed before and after nanoparticle injection. Macrographs were merged with fluorescence images taken 24 h postinjection with NIR‐830 dye‐labeled uPAR‐targeted (A–D) or nontargeted IONP (E–H). A tumor‐bearing mouse without nanoparticle injection was imaged as a control (I–L). (B–L) PAT images were merged with blood vessel images before injection (B, F, and J), and at 5 h (C, G, and K) and 24 h (D, H, and I) postinjection. (Reprinted with permission from Ref . Copyright 2014 John Wiley and Sons)
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Angiogenic tumor vessel‐targeted and 64Cu‐radiolabeled PAMAM‐PLA‐PEG theranostic nanoparticles for targeted therapy and positron emission tomography (PET) imaging of TNBC. (a) Schematic illustration of the multifunctional PAMAM‐PLA‐b‐PEG‐OCH3/TRC105/NOTA unimolecular micelles for tumor‐targeted drug delivery and PET imaging. (b) Serial coronal PET images of 4T1 tumor‐bearing mice at different time points postinjection of 64Cu‐labeled targeted micelles, nontargeted micelles, or targeted micelles with a blocking dose of TRC105. (Reprinted with permission from Ref . Copyright 2013 Elsevier)
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CD44‐targeted polymeric nanoparticle carrying docetaxel for targeted delivery into triple‐negative breast cancer (TNBC) tumors. Fluorescence images of DiR‐loaded PLGA502H (DiR/PLGA) and DiR‐loaded PLGA502H‐b‐HA5.6k nanoparticles (DiR/SANPs) in MDA‐MB‐231 tumor‐bearing female nude mice after tail vein injection. (a) In vivo whole‐body images and distribution of nanoparticle formulations at varying time intervals. (b) Ex vivo images of excised organs and tumors at 24 h postinjection of the formulations. (c) The schematic illustration of the core–shell structure of docetaxel (DTX)‐loaded PLGA‐b‐HA nanoparticles that target CD44. (Reprinted with permission from Ref . Copyright 2014 Elsevier)
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Receptor‐targeted radioactive immunoliposomes for single‐photon emission‐computed tomography (SPECT) imaging of residual breast tumors in lumpectomy cavity and draining lymph nodes. Stereomicroscopic fluorescent images (a–d) and SPECT images (e and f) of MDA‐MB‐231 rat xenograft injected with 99mTc‐labeled panitumumab (EGFR antibody) liposomes containing RhodDOPE tracer. A schematic of the 99mTc‐labeled panitumumab liposomes (g). (Reprinted with permission from Ref . Copyright 2012 American Society for Pharmacology and Experimental Therapeutics)
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Mauro Ferrari

Mauro Ferrari

started out in mechanical engineering and became interested in nanotechnology with his studies on nanomechanics and nanofluidics. His research work and involvement with setting up some of the premier nano centers and alliances in the world, bringing together universities, hospitals, and federal agencies, showcases interdisciplinarity at work.

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