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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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Intracellular localization of the gold nanoparticlesTEM images of cross sectional MCF-7 cells incubated for 24 h with 2 μM (a) AuNP-NH2 and (b) AuNP-NH2-CB[7]. Significant amount of AuNP-NH2 is present in the cytosol, however most of the AuNP-NH2-CB[7] seems to be trapped in organelles such as endosome. (c) TEM images of cross sectional MCF-7 cells incubated for 3 h with 2 μM of AuNP-NH2-CB[7] and then further incubation with ADA for 24 h. In the intracellular environment ADA transforms AuNP-NH2-CB[7] to AuNP-NH2, which then escaped from the endosome and observed to be dispersed in the cytosol. i, ii and iii are the magnified sections from the first panel of part (c).
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Figure 4: Intracellular localization of the gold nanoparticlesTEM images of cross sectional MCF-7 cells incubated for 24 h with 2 μM (a) AuNP-NH2 and (b) AuNP-NH2-CB[7]. Significant amount of AuNP-NH2 is present in the cytosol, however most of the AuNP-NH2-CB[7] seems to be trapped in organelles such as endosome. (c) TEM images of cross sectional MCF-7 cells incubated for 3 h with 2 μM of AuNP-NH2-CB[7] and then further incubation with ADA for 24 h. In the intracellular environment ADA transforms AuNP-NH2-CB[7] to AuNP-NH2, which then escaped from the endosome and observed to be dispersed in the cytosol. i, ii and iii are the magnified sections from the first panel of part (c).

Mentions: The cellular uptake of the nanoparticles was quantified using inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS analysis revealed that the total amount of the nanoparticles taken up by the cells was nearly identical for AuNP-NH2 and AuNP-NH2-CB[7] (Fig. 3). TEM analysis of the cells was employed to evaluate the impact of CB[7] complexation on the intracellular fate/localization of the nanoparticles. As shown in Supplementary Information Fig. S5a and S5b, after 3 h incubation, both AuNP-NH2 and AuNP-NH2-CB[7] are trapped within vesicular structures morphologically consistent with endosomes. This observation is consistent with the behavior observed with other cationic nanoparticles, as reported in our previous work.36, 37 After 24 h of incubation, however, AuNP-NH2 particles had escaped from the endosome and were dispersed in the cytosol (Fig. 4a). In contrast, AuNP-NH2-CB[7] particles remained sequestered in the endosome with no free particles observed in the cytosol. (Fig. 4b and Supplementary Information Fig. S6) after the same period. Significantly, incubation of AuNP-NH2-CB[7]-treated cells with ADA for 24 h resulted in the escape of a substantial number of particles into the cytosol (Fig. 4c), consistent with intracellular transformation of AuNP-NH2-CB[7] to AuNP-NH2 via dethreading.


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

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

Intracellular localization of the gold nanoparticlesTEM images of cross sectional MCF-7 cells incubated for 24 h with 2 μM (a) AuNP-NH2 and (b) AuNP-NH2-CB[7]. Significant amount of AuNP-NH2 is present in the cytosol, however most of the AuNP-NH2-CB[7] seems to be trapped in organelles such as endosome. (c) TEM images of cross sectional MCF-7 cells incubated for 3 h with 2 μM of AuNP-NH2-CB[7] and then further incubation with ADA for 24 h. In the intracellular environment ADA transforms AuNP-NH2-CB[7] to AuNP-NH2, which then escaped from the endosome and observed to be dispersed in the cytosol. i, ii and iii are the magnified sections from the first panel of part (c).
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Related In: Results  -  Collection

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Figure 4: Intracellular localization of the gold nanoparticlesTEM images of cross sectional MCF-7 cells incubated for 24 h with 2 μM (a) AuNP-NH2 and (b) AuNP-NH2-CB[7]. Significant amount of AuNP-NH2 is present in the cytosol, however most of the AuNP-NH2-CB[7] seems to be trapped in organelles such as endosome. (c) TEM images of cross sectional MCF-7 cells incubated for 3 h with 2 μM of AuNP-NH2-CB[7] and then further incubation with ADA for 24 h. In the intracellular environment ADA transforms AuNP-NH2-CB[7] to AuNP-NH2, which then escaped from the endosome and observed to be dispersed in the cytosol. i, ii and iii are the magnified sections from the first panel of part (c).
Mentions: The cellular uptake of the nanoparticles was quantified using inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS analysis revealed that the total amount of the nanoparticles taken up by the cells was nearly identical for AuNP-NH2 and AuNP-NH2-CB[7] (Fig. 3). TEM analysis of the cells was employed to evaluate the impact of CB[7] complexation on the intracellular fate/localization of the nanoparticles. As shown in Supplementary Information Fig. S5a and S5b, after 3 h incubation, both AuNP-NH2 and AuNP-NH2-CB[7] are trapped within vesicular structures morphologically consistent with endosomes. This observation is consistent with the behavior observed with other cationic nanoparticles, as reported in our previous work.36, 37 After 24 h of incubation, however, AuNP-NH2 particles had escaped from the endosome and were dispersed in the cytosol (Fig. 4a). In contrast, AuNP-NH2-CB[7] particles remained sequestered in the endosome with no free particles observed in the cytosol. (Fig. 4b and Supplementary Information Fig. S6) after the same period. Significantly, incubation of AuNP-NH2-CB[7]-treated cells with ADA for 24 h resulted in the escape of a substantial number of particles into the cytosol (Fig. 4c), consistent with intracellular transformation of AuNP-NH2-CB[7] to AuNP-NH2 via dethreading.

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