Controlling Ligand Density on Nanoparticles as a Means to Enhance Biological Activity

Lee, Hyojin; Odom, Teri W.

doi:10.2217/nnm.14.204

Cited by 13 publications

(10 citation statements)

References 21 publications

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“…29 We posit that the difference in particle size and antibody loading density between N1-34a-NPs and our previous NP formulation is responsible for the disparity in obtaining preferential and specific binding to MDA-MB-231 TNBC cells. This would be in agreement with prior studies that show cellular binding of NPs is significantly impacted by the size and shape of the NP [30][31][32][33] and by the density of the targeting moiety presented on the surface of the NP. 32,33 Future studies are needed to define the optimal size of the particles and density of Notch1 antibodies on these NPs to maximize TNBC cell-specific binding and potentially increase downstream Notch signaling inhibition.…”

Section: Discussionsupporting

confidence: 93%

“…This would be in agreement with prior studies that show cellular binding of NPs is significantly impacted by the size and shape of the NP [30][31][32][33] and by the density of the targeting moiety presented on the surface of the NP. 32,33 Future studies are needed to define the optimal size of the particles and density of Notch1 antibodies on these NPs to maximize TNBC cell-specific binding and potentially increase downstream Notch signaling inhibition. While N1-34a-NPs did not display enhanced binding to TNBC cells in this work relative to IgG-functionalized NPs, we did find that Notch1 antibody functionalization was critical for eliciting significant therapeutic effect.…”

Section: Discussionsupporting

confidence: 93%

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Dual Regulation of miR-34a and Notch Signaling in Triple-Negative Breast Cancer by Antibody/miRNA Nanocarriers

Valcourt

Day

2020

Molecular Therapy - Nucleic Acids

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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the three most common receptors present on other subtypes, leaving it unsusceptible to current targeted or hormonal therapies. In this study, we introduce an alternative treatment strategy for TNBC that exploits its overexpression of Notch1 receptors and its underexpression of the tumor suppressive microRNA (miRNA) miR-34a. Studies have shown that introducing mimics of miR-34a to TNBC cells effectively inhibits cancer growth, but miR-34a cannot be administered in the clinic without a carrier. To enable delivery of miR-34a to TNBC cells, we encapsulated miR-34a mimics in poly(lactic-co-glycolic acid) nanoparticles (NPs) that were functionalized with Notch1 antibodies to produce N1-34a-NPs. In addition to binding Notch1 receptors overexpressed on the surface of TNBC cells, the antibodies in this formulation enable suppression of Notch signaling through signal cascade interference. Herein, we present the results of in vitro experiments that demonstrate N1-34a-NPs can regulate Notch signaling and downstream miR-34a targets in TNBC cells to induce senescence and reduce cell proliferation and migration. These studies demonstrate that NP-mediated co-delivery of miR-34a and Notch1 antibodies is a promising alternative treatment strategy for TNBC, warranting further optimization and in vivo investigation in future studies.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Dual Regulation of miR-34a and Notch Signaling in Triple-Negative Breast Cancer by Antibody/miRNA Nanocarriers

Valcourt

Day

2020

Molecular Therapy - Nucleic Acids

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“…Uses for NPs as carrier systems for chemotherapeutic drugs are gaining attention due to the specificity of NPs for cancer cells, enhanced efficiency, and reduced systemic toxicity (Lee and Odom, 2015). AuNPs have several advantages, including a bio-compatible core, which makes them an ideal starting point for a nano-carrier system (Jain et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

PLGA-Loaded Gold-Nanoparticles Precipitated with Quercetin Downregulate HDAC-Akt Activities Controlling Proliferation and Activate p53-ROS Crosstalk to Induce Apoptosis in Hepatocarcinoma Cells

Bishayee¹,

Khuda‐Bukhsh²,

Huh³

2015

Molecules and Cells

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Controlled release of medications remains the most convenient way to deliver drugs. In this study, we precipitated gold nanoparticles with quercetin. We loaded gold-quercetin into poly(DL-lactide-co-glycolide) nanoparticles (NQ) and tested the biological activity of NQ on HepG2 hepatocarcinoma cells to acquire the sustained release property. We determined by circular dichroism spectroscopy that NQ effectively caused conformational changes in DNA and modulated different proteins related to epigenetic modifications and c ell cycle control. The mitochondrial membrane potential (MMP), reactive oxygen species (ROS), cell cycle, apoptosis, DNA damage, and caspase 3 activity were analyzed by flow cytometry, and the expression profiles of different anti- and pro-apoptotic as well as epigenetic signals were studied by immunoblotting. A cytotoxicity assay indicated that NQ preferentially killed cancer cells, compared to normal cells. NQ interacted with HepG2 cell DNA and reduced histone deacetylases to control cell proliferation and arrest the cell cycle at the sub-G stage. Activities of cell cycle-related proteins, such as p21WAF, cdk1, and pAkt, were modulated. NQ induced apoptosis in HepG2 cells by activating p53-ROS crosstalk and induces epigenetic modifications leading to inhibited proliferation and cell cycle arrest.

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“…The density of targeting ligands can be adjusted to minimize their impact on the nanomedicine's blood circulation and tumor accumulation while increasing cellular uptake . Shielding the targeting/functional groups during blood circulation but exposing them once in tumors is the prevailing approach to this dilemma.…”

Section: Approaches To Achieve the 3s Transitionsmentioning

confidence: 99%

Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization

et al. 2017

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Current cancer nanomedicines can only mitigate adverse effects but fail to enhance therapeutic efficacies of anticancer drugs. Rational design of next-generation cancer nanomedicines should aim to enhance their therapeutic efficacies. Taking this into account, this review first analyzes the typical cancer-drug-delivery process of an intravenously administered nanomedicine and concludes that the delivery involves a five-step CAPIR cascade and that high efficiency at every step is critical to guarantee high overall therapeutic efficiency. Further analysis shows that the nanoproperties needed in each step for a nanomedicine to maximize its efficiency are different and even opposing in different steps, particularly what the authors call the PEG, surface-charge, size and stability dilemmas. To resolve those dilemmas in order to integrate all needed nanoproperties into one nanomedicine, stability, surface and size nanoproperty transitions (3S transitions for short) are proposed and the reported strategies to realize these transitions are comprehensively summarized. Examples of nanomedicines capable of the 3S transitions are discussed, as are future research directions to design high-performance cancer nanomedicines and their clinical translations.

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Controlling Ligand Density on Nanoparticles as a Means to Enhance Biological Activity

Cited by 13 publications

References 21 publications

Dual Regulation of miR-34a and Notch Signaling in Triple-Negative Breast Cancer by Antibody/miRNA Nanocarriers

Dual Regulation of miR-34a and Notch Signaling in Triple-Negative Breast Cancer by Antibody/miRNA Nanocarriers

PLGA-Loaded Gold-Nanoparticles Precipitated with Quercetin Downregulate HDAC-Akt Activities Controlling Proliferation and Activate p53-ROS Crosstalk to Induce Apoptosis in Hepatocarcinoma Cells

Rational Design of Cancer Nanomedicine: Nanoproperty Integration and Synchronization

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