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Beyond platinum: synthesis, characterization, and in vitro toxicity of Cu(II)-releasing polymer nanoparticles for potential use as a drug delivery vector.

Harris AN, Hinojosa BR, Chavious MD, Petros RA - Nanoscale Res Lett (2011)

Bottom Line: Metal release was a function of both pH and the presence of competing ligands.The toxicity of the particles was measured in HeLa cells where reductions in cell viability greater than 95% were observed at high Cu loading.The combined pH sensitivity and significant toxicity make this copper delivery vector an excellent candidate for the targeted killing of disease cells when combined with an effective cellular targeting strategy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Chemistry, University of North Texas, 1155 Union Circle, CB#305070, Denton, TX, 76203-5017, USA. petros@unt.edu.

ABSTRACT
The field of drug delivery focuses primarily on delivering small organic molecules or DNA/RNA as therapeutics and has largely ignored the potential for delivering catalytically active transition metal ions and complexes. The delivery of a variety of transition metals has potential for inducing apoptosis in targeted cells. The chief aims of this work were the development of a suitable delivery vector for a prototypical transition metal, Cu2+, and demonstration of the ability to impact cancer cell viability via exposure to such a Cu-loaded vector. Carboxylate-functionalized nanoparticles were synthesized by free radical polymerization and were subsequently loaded with Cu2+ via binding to particle-bound carboxylate functional groups. Cu loading and release were characterized via ICP MS, EDX, XPS, and elemental analysis. Results demonstrated that Cu could be loaded in high weight percent (up to 16 wt.%) and that Cu was released from the particles in a pH-dependent manner. Metal release was a function of both pH and the presence of competing ligands. The toxicity of the particles was measured in HeLa cells where reductions in cell viability greater than 95% were observed at high Cu loading. The combined pH sensitivity and significant toxicity make this copper delivery vector an excellent candidate for the targeted killing of disease cells when combined with an effective cellular targeting strategy.

No MeSH data available.


Related in: MedlinePlus

Proposed intracellular release mechanism based on pH.
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Figure 5: Proposed intracellular release mechanism based on pH.

Mentions: The loading and stimuli-responsive release of transition metals and any drug molecule in general from a delivery are major factors that ultimately determine the success or failure of that vector when applied to targeted drug delivery. One of the goals of this work was to demonstrate that CuCNPs were capable of responding to changes in pH to facilitate Cu release. A general schematic for the expected in vitro behavior is shown in Figure 5 (targeting ligands were not used in the experiments described here, but will be incorporated in the future). Initial Cu release experiments were conducted at pH 5 and 7 to mimic conditions that would be present during endocytosis of the nanoparticle along an endosomal pathway. Those experiments (Figure 3A) were promising and showed release to be much faster at pH 5 vs. pH 7, which would trigger Cu release upon particle internalization. It was postulated that protonation of the carboxylate groups on the nanoparticle would reduce the binding affinity of the ligand for Cu thereby facilitating release. Somewhat surprisingly, however, CuCNPs released virtually no Cu in ultrapure water, which has a neutral to slightly acidic pH. While this feature is promising in terms of the stability of solutions of CuCNPs over long periods of time, Cu release cannot simply be a function of pH but must also depend on the presence of ligands that can compete with the particle-bound carboxylate groups in Cu binding. This feature led to a series of additional experiments to elucidate the effect of competing ligands on Cu release with the idea that the underlying principles governing release could be used in the design/optimization of this class of delivery vectors.


Beyond platinum: synthesis, characterization, and in vitro toxicity of Cu(II)-releasing polymer nanoparticles for potential use as a drug delivery vector.

Harris AN, Hinojosa BR, Chavious MD, Petros RA - Nanoscale Res Lett (2011)

Proposed intracellular release mechanism based on pH.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3211864&req=5

Figure 5: Proposed intracellular release mechanism based on pH.
Mentions: The loading and stimuli-responsive release of transition metals and any drug molecule in general from a delivery are major factors that ultimately determine the success or failure of that vector when applied to targeted drug delivery. One of the goals of this work was to demonstrate that CuCNPs were capable of responding to changes in pH to facilitate Cu release. A general schematic for the expected in vitro behavior is shown in Figure 5 (targeting ligands were not used in the experiments described here, but will be incorporated in the future). Initial Cu release experiments were conducted at pH 5 and 7 to mimic conditions that would be present during endocytosis of the nanoparticle along an endosomal pathway. Those experiments (Figure 3A) were promising and showed release to be much faster at pH 5 vs. pH 7, which would trigger Cu release upon particle internalization. It was postulated that protonation of the carboxylate groups on the nanoparticle would reduce the binding affinity of the ligand for Cu thereby facilitating release. Somewhat surprisingly, however, CuCNPs released virtually no Cu in ultrapure water, which has a neutral to slightly acidic pH. While this feature is promising in terms of the stability of solutions of CuCNPs over long periods of time, Cu release cannot simply be a function of pH but must also depend on the presence of ligands that can compete with the particle-bound carboxylate groups in Cu binding. This feature led to a series of additional experiments to elucidate the effect of competing ligands on Cu release with the idea that the underlying principles governing release could be used in the design/optimization of this class of delivery vectors.

Bottom Line: Metal release was a function of both pH and the presence of competing ligands.The toxicity of the particles was measured in HeLa cells where reductions in cell viability greater than 95% were observed at high Cu loading.The combined pH sensitivity and significant toxicity make this copper delivery vector an excellent candidate for the targeted killing of disease cells when combined with an effective cellular targeting strategy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Chemistry, University of North Texas, 1155 Union Circle, CB#305070, Denton, TX, 76203-5017, USA. petros@unt.edu.

ABSTRACT
The field of drug delivery focuses primarily on delivering small organic molecules or DNA/RNA as therapeutics and has largely ignored the potential for delivering catalytically active transition metal ions and complexes. The delivery of a variety of transition metals has potential for inducing apoptosis in targeted cells. The chief aims of this work were the development of a suitable delivery vector for a prototypical transition metal, Cu2+, and demonstration of the ability to impact cancer cell viability via exposure to such a Cu-loaded vector. Carboxylate-functionalized nanoparticles were synthesized by free radical polymerization and were subsequently loaded with Cu2+ via binding to particle-bound carboxylate functional groups. Cu loading and release were characterized via ICP MS, EDX, XPS, and elemental analysis. Results demonstrated that Cu could be loaded in high weight percent (up to 16 wt.%) and that Cu was released from the particles in a pH-dependent manner. Metal release was a function of both pH and the presence of competing ligands. The toxicity of the particles was measured in HeLa cells where reductions in cell viability greater than 95% were observed at high Cu loading. The combined pH sensitivity and significant toxicity make this copper delivery vector an excellent candidate for the targeted killing of disease cells when combined with an effective cellular targeting strategy.

No MeSH data available.


Related in: MedlinePlus