ICAM-1-Targeted, Lcn2 siRNA-Encapsulating Liposomes are Potent Anti-angiogenic Agents for Triple Negative Breast Cancer

Guo, Peng; Yang, Jiang; Jia, Di; Moses, Marsha A.; Auguste, Debra T.

doi:10.7150/thno.12167

Cited by 105 publications

(85 citation statements)

References 57 publications

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“…As shown in the schematic illustration (Fig. Its antibody has been demonstrated to guide a variety of nanomedicines to selectively recognize and bind human breast cancer cells in vitro and orthotopic breast tumors in vivo (13,27,28). ICAM1 is a cell membrane receptor for host cell entry of human rhinovirus (26) and has been recently identified as a molecular target for human triple negative breast cancer (27).…”

Section: Resultsmentioning

confidence: 99%

Quantitative Analysis of Different Cell Entry Routes of Actively Targeted Nanomedicines Using Imaging Flow Cytometry

et al. 2019

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A rapid, high-throughput, and quantitative method for cell entry route characterization is still lacking in nanomedicine research. Here, we report the application of imaging flow cytometry for quantitatively analyzing cell entry routes of actively targeted nanomedicines. We first engineered ICAM1 antibody-directed fusogenic nanoliposomes (ICAM1-FusoNLPs) and ICAM1 antibody-directed endocytic nanolipogels (ICAM1-EndoNLGs) featuring highly similar surface properties but different cell entry routes: receptor-mediated membrane fusion and receptor-mediated endocytosis, respectively. By using imaging flow cytometry, we characterized their intracellular delivery into human breast cancer MDA-MB-231 cells. We found that ICAM1-FusoNLPs mediated a 2.8-fold increased cell uptake of fluorescent payload, FITC-dextran, with a 2.4-fold increased intracellular distribution area in comparison with ICAM1-EndoNLGs. We also investigated the effects of incubation time and endocytic inhibitors on the cell entry routes of ICAM1-FusoNLP and ICAM1-EndoNLG.Our results indicate that receptor-mediated membrane fusion is a faster and more efficient cell entry route than receptor-mediated endocytosis, bringing with it a significant therapeutic benefit in a proof-of-principle nanomedicine-mediated siRNA transfection experiment. Our studies suggest that cell entry route may be an important design parameter to be considered in the development of next-generation nanomedicines.NANOMEDICINES have emerged as a revolutionary therapeutic approach for treating many diseases including cancer (1-3). They take advantage of rapidly developed nanomaterials to engineer "virus-like" nanovectors that circulate in the body and deliver a variety of therapeutic, diagnostic, and theranostic agents to disease sites. To date, more than 20 nanomedicines (e.g., Doxil, Abraxane, and Onivyde) have been approved by the United States Food and Drug Administration (U.S. FDA) and the European Medical Agency (EMA) for clinical indications due to their fewer adverse effects and better safety profiles than conventional drug formulations(4,5). Moreover, actively targeted nanomedicines (e.g., MM310 and BIND-014) have been under intense pre-clinical and clinical investigations as next-generation targeted therapeutics for cancer treatment. These nanomedicines utilize molecularly targeting ligands (e.g., antibodies, peptides, and aptamers) to guide nanovectors to precisely recognize and ablate cancer cells while sparing normal organs and tissues (4).Cell entry route plays a critical role in the intracellular delivery of actively targeted nanomedicines. In general, nanomedicines are hypothesized to enter cells through two major routes: endocytosis and membrane fusion (6,7). Most actively targeted nanoparticles rely on receptor-mediated endocytosis to enter targeted

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Section: Resultsmentioning

confidence: 99%

Quantitative Analysis of Different Cell Entry Routes of Actively Targeted Nanomedicines Using Imaging Flow Cytometry

et al. 2019

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“…The ICAM-1 targeted, Dox-encapsulating immunoliposome was prepared by the transmembrane gradient assay as described previously [26,27]. Briefly, a lipid formulation consisting of DOPC:DSPE-PEG-COOH (95:5, mol:mol) was used to prepare liposomes.…”

Section: Methodsmentioning

confidence: 99%

“…The density of ICAM-1antibodies conjugated on liposomes was quantified via microbead assay as described previously [25–27]. Liposomes cannot be detected by flow cytometry because of their size, therefore, 2 μm borosilicate beads were encapsulated within DOPC: DSPE-PEG-COOH (95:5, mol:mol) liposomes by sonicating small unilamellar liposomes with microbeads in PBS for 6 h. Microbeads were rinsed three times in PBS via suspension-spin cycles to separate free liposomes.…”

Section: Methodsmentioning

confidence: 99%

A quantitative method for screening and identifying molecular targets for nanomedicine

Guo

Yang

Bielenberg

et al. 2017

Journal of Controlled Release

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Identifying a molecular target is essential for tumor-targeted nanomedicine. Current cancer nanomedicines commonly suffer from poor tumor specificity, “off-target” toxicity, and limited clinical efficacy. Here, we report a method to screen and identify new molecular targets for tumor-targeted nanomedicine based on a quantitative analysis. In our proof-of-principle study, we used comparative flow cytometric screening to identify ICAM-1 as a potential target for metastatic melanoma (MM). We further evaluated ICAM-1 as a MM targeting moiety by characterizing its (1) tumor specificity, (2) expression level, (3) cellular internalization, (4) therapeutic function, and (5) potential clinical impact. Quantitation of ICAM-1 protein expression on cells and validation by immunohistochemistry on human tissue specimens justified the synthesis of antibody-functionalized drug delivery vehicles, which were benchmarked against appropriate controls. We engineered ICAM-1 antibody conjugated, doxorubicin encapsulating immunoliposomes (ICAM-Dox-LPs) to selectively recognize and deliver doxorubicin to MM cells and simultaneously neutralize ICAM-1 signaling via an antibody blockade, demonstrating significant and simultaneous inhibitory effects on MM cell proliferation and migration. This paper describes a novel, quantitative metric system that identifies and evaluates new cancer targets for tumor-targeting nanomedicine.

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“…A liposome is a spherical synthetic lipid vesicle composed of a single lipid bilayer with a nanoscale diameter ranging from 60 nm to a few micrometers. Due to their unique hollow structure, liposomes have been widely used as a drug delivery system to protect and deliver therapeutic agents including chemodrugs, small molecule inhibitors, siRNAs, DNAs, proteins/peptides, and recently developed CRISPR‐Cas gene editing systems . The surface of liposomes is frequently modified with polyethylene glycol (PEG) to reduce cell uptake by immune cells and extend the liposome blood circulation time .…”

Section: Nanoporous Membrane Extrusion Strategiesmentioning

confidence: 99%

Nanomaterial Preparation by Extrusion through Nanoporous Membranes

Guo

Huang

Zhao

et al. 2018

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Template synthesis represents an important class of nanofabrication methods. Herein, recent advances in nanomaterial preparation by extrusion through nanoporous membranes that preserve the template membrane without sacrificing it, which is termed as "non-sacrificing template synthesis," are reviewed. First, the types of nanoporous membranes used in nanoporous membrane extrusion applications are introduced. Next, four common nanoporous membrane extrusion strategies: vesicle extrusion, membrane emulsification, precipitation extrusion, and biological membrane extrusion, are examined. These methods have been utilized to prepare a wide range of nanomaterials, including liposomes, emulsions, nanoparticles, nanofibers, and nanotubes. The principle and historical context of each specific technology are discussed, presenting prominent examples and evaluating their positive and negative features. Finally, the current challenges and future opportunities of nanoporous membrane extrusion methods are discussed.

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ICAM-1-Targeted, Lcn2 siRNA-Encapsulating Liposomes are Potent Anti-angiogenic Agents for Triple Negative Breast Cancer

Cited by 105 publications

References 57 publications

Quantitative Analysis of Different Cell Entry Routes of Actively Targeted Nanomedicines Using Imaging Flow Cytometry

Quantitative Analysis of Different Cell Entry Routes of Actively Targeted Nanomedicines Using Imaging Flow Cytometry

A quantitative method for screening and identifying molecular targets for nanomedicine

Nanomaterial Preparation by Extrusion through Nanoporous Membranes

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