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Recognition-mediated activation of therapeutic gold nanoparticles inside living cells.

Kim C, Agasti SS, Zhu Z, Isaacs L, Rotello VM - Nat Chem (2010)

Bottom Line: Use of this methodology in living systems, however, represents a significant challenge owing to the chemical complexity of cellular environments and lack of selectivity of conventional supramolecular interactions.Herein, we present a host-guest system featuring diaminohexane-terminated gold nanoparticles (AuNP-NH(2)) and complementary cucurbit[7]uril (CB[7]).This supramolecular strategy for intracellular activation provides a new tool for potential therapeutic applications.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Massachusetts, 710 North Pleasant Street, Amherst, Massachusetts 01003, USA.

ABSTRACT
Supramolecular chemistry provides a versatile tool for the organization of molecular systems into functional structures and the actuation of these assemblies for applications through the reversible association between complementary components. Use of this methodology in living systems, however, represents a significant challenge owing to the chemical complexity of cellular environments and lack of selectivity of conventional supramolecular interactions. Herein, we present a host-guest system featuring diaminohexane-terminated gold nanoparticles (AuNP-NH(2)) and complementary cucurbit[7]uril (CB[7]). In this system, threading of CB[7] on the particle surface reduces the cytotoxicity of AuNP-NH(2) through sequestration of the particle in endosomes. Intracellular triggering of the therapeutic effect of AuNP-NH(2) was then achieved through the administration of 1-adamantylamine (ADA), removing CB[7] from the nanoparticle surface, causing the endosomal release and concomitant in situ cytotoxicity of AuNP-NH(2). This supramolecular strategy for intracellular activation provides a new tool for potential therapeutic applications.

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Cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] and modulating cytotoxicity of the gold nanoparticles(a) Cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] measured by Alamar blue assay after 24 h incubation in MCF-7. IC50 of AuNP-NH2 was 1.3 μM and no cytotoxicity of AuNP-NH2-CB[7] was observed up to 50 μM. (b) Triggering cytotoxicity using ADA. After 3h incubation of AuNP-NH2-CB[7] (2 μM) in MCF-7 cell, different concentrations (0, 0.2 and 0.4 mM) of ADA in medium added and further incubated at 37 °C for 24 h. The cell viability was then determined by using an Alamar blue assay. As controls, cell viability of AuNP-NH2 and AuNP-NH2-CB[7] was measured after 24 h incubation (34 % and 100%, respectively). Cell viability experiments were performed as triplicate and the error bars represent the standard deviations of these measurements.
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Figure 5: Cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] and modulating cytotoxicity of the gold nanoparticles(a) Cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] measured by Alamar blue assay after 24 h incubation in MCF-7. IC50 of AuNP-NH2 was 1.3 μM and no cytotoxicity of AuNP-NH2-CB[7] was observed up to 50 μM. (b) Triggering cytotoxicity using ADA. After 3h incubation of AuNP-NH2-CB[7] (2 μM) in MCF-7 cell, different concentrations (0, 0.2 and 0.4 mM) of ADA in medium added and further incubated at 37 °C for 24 h. The cell viability was then determined by using an Alamar blue assay. As controls, cell viability of AuNP-NH2 and AuNP-NH2-CB[7] was measured after 24 h incubation (34 % and 100%, respectively). Cell viability experiments were performed as triplicate and the error bars represent the standard deviations of these measurements.

Mentions: Polyamine functionalized macromolecules 38, 39, 40 and nanoparticles 41, 42, 43, 44 interact strongly with cell membranes and subcellular compartments, resulting in membrane disruption and cytotoxicity. Complexation of AuNP-NH2 with CB[7] should attenuate the positive charge of the particle surfaces, reducing the ability of the particles to disrupt membranes (including the endosomal) and hence lower toxicity. The cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] was investigated in the human breast cancer MCF-7 cell line using an Alamar blue assay. The AuNP-NH2-CB[7] complex was substantially less toxic as compared to AuNP-NH2. After 24 h incubation, AuNP-NH2 exhibited cytotoxicity with 1.3 μM of IC50 value (Fig. 5a). On the other hand, AuNP-NH2-CB[7] complex did not inhibit cell proliferation at concentrations ≤ 50 μM under the same experimental conditions, presumably arising from sequestration of the particle in the endosome. Significantly, when the free thiol ligand was added to the cells at concentrations consistent with those used in the study (80 μM, corresponding to the same per-ligand concentration as 2 μM nanoparticle) toxicity was observed with both threaded and unthreaded ligand, demonstrating the modulation of ligand toxicity on the particle.


Recognition-mediated activation of therapeutic gold nanoparticles inside living cells.

Kim C, Agasti SS, Zhu Z, Isaacs L, Rotello VM - Nat Chem (2010)

Cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] and modulating cytotoxicity of the gold nanoparticles(a) Cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] measured by Alamar blue assay after 24 h incubation in MCF-7. IC50 of AuNP-NH2 was 1.3 μM and no cytotoxicity of AuNP-NH2-CB[7] was observed up to 50 μM. (b) Triggering cytotoxicity using ADA. After 3h incubation of AuNP-NH2-CB[7] (2 μM) in MCF-7 cell, different concentrations (0, 0.2 and 0.4 mM) of ADA in medium added and further incubated at 37 °C for 24 h. The cell viability was then determined by using an Alamar blue assay. As controls, cell viability of AuNP-NH2 and AuNP-NH2-CB[7] was measured after 24 h incubation (34 % and 100%, respectively). Cell viability experiments were performed as triplicate and the error bars represent the standard deviations of these measurements.
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Related In: Results  -  Collection

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Figure 5: Cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] and modulating cytotoxicity of the gold nanoparticles(a) Cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] measured by Alamar blue assay after 24 h incubation in MCF-7. IC50 of AuNP-NH2 was 1.3 μM and no cytotoxicity of AuNP-NH2-CB[7] was observed up to 50 μM. (b) Triggering cytotoxicity using ADA. After 3h incubation of AuNP-NH2-CB[7] (2 μM) in MCF-7 cell, different concentrations (0, 0.2 and 0.4 mM) of ADA in medium added and further incubated at 37 °C for 24 h. The cell viability was then determined by using an Alamar blue assay. As controls, cell viability of AuNP-NH2 and AuNP-NH2-CB[7] was measured after 24 h incubation (34 % and 100%, respectively). Cell viability experiments were performed as triplicate and the error bars represent the standard deviations of these measurements.
Mentions: Polyamine functionalized macromolecules 38, 39, 40 and nanoparticles 41, 42, 43, 44 interact strongly with cell membranes and subcellular compartments, resulting in membrane disruption and cytotoxicity. Complexation of AuNP-NH2 with CB[7] should attenuate the positive charge of the particle surfaces, reducing the ability of the particles to disrupt membranes (including the endosomal) and hence lower toxicity. The cytotoxicity of AuNP-NH2 and AuNP-NH2-CB[7] was investigated in the human breast cancer MCF-7 cell line using an Alamar blue assay. The AuNP-NH2-CB[7] complex was substantially less toxic as compared to AuNP-NH2. After 24 h incubation, AuNP-NH2 exhibited cytotoxicity with 1.3 μM of IC50 value (Fig. 5a). On the other hand, AuNP-NH2-CB[7] complex did not inhibit cell proliferation at concentrations ≤ 50 μM under the same experimental conditions, presumably arising from sequestration of the particle in the endosome. Significantly, when the free thiol ligand was added to the cells at concentrations consistent with those used in the study (80 μM, corresponding to the same per-ligand concentration as 2 μM nanoparticle) toxicity was observed with both threaded and unthreaded ligand, demonstrating the modulation of ligand toxicity on the particle.

Bottom Line: Use of this methodology in living systems, however, represents a significant challenge owing to the chemical complexity of cellular environments and lack of selectivity of conventional supramolecular interactions.Herein, we present a host-guest system featuring diaminohexane-terminated gold nanoparticles (AuNP-NH(2)) and complementary cucurbit[7]uril (CB[7]).This supramolecular strategy for intracellular activation provides a new tool for potential therapeutic applications.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Massachusetts, 710 North Pleasant Street, Amherst, Massachusetts 01003, USA.

ABSTRACT
Supramolecular chemistry provides a versatile tool for the organization of molecular systems into functional structures and the actuation of these assemblies for applications through the reversible association between complementary components. Use of this methodology in living systems, however, represents a significant challenge owing to the chemical complexity of cellular environments and lack of selectivity of conventional supramolecular interactions. Herein, we present a host-guest system featuring diaminohexane-terminated gold nanoparticles (AuNP-NH(2)) and complementary cucurbit[7]uril (CB[7]). In this system, threading of CB[7] on the particle surface reduces the cytotoxicity of AuNP-NH(2) through sequestration of the particle in endosomes. Intracellular triggering of the therapeutic effect of AuNP-NH(2) was then achieved through the administration of 1-adamantylamine (ADA), removing CB[7] from the nanoparticle surface, causing the endosomal release and concomitant in situ cytotoxicity of AuNP-NH(2). This supramolecular strategy for intracellular activation provides a new tool for potential therapeutic applications.

Show MeSH