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. 2012 Apr;8(4):1450-8.
doi: 10.1016/j.actbio.2011.12.028. Epub 2011 Dec 29.

Nanogel scavengers for drugs: local anesthetic uptake by thermoresponsive nanogels

Todd Hoare  1 , Daryl Sivakumaran, Cristina F Stefanescu, Michael W Lawlor, Daniel S Kohane
Affiliations

Nanogel scavengers for drugs: local anesthetic uptake by thermoresponsive nanogels

Todd Hoare et al. Acta Biomater. 2012 Apr.

Abstract

The use of functional nanogels based on poly(N-isopropylacrylamide) for effectively scavenging compounds (here, the model drug bupivacaine) is demonstrated using an in vitro cell-based assay. Nanogels containing higher loadings of acidic functional groups or more core-localized functional group distributions bound more bupivacaine, while nanogel size had no significant effect on drug binding. Increasing the dose of nanogel applied also facilitated more bupivacaine binding for all nanogel compositions tested. Binding was driven predominantly by acid-base interactions between the nanogels (anionic) and bupivacaine (cationic) at physiological pH, although both non-specific absorption and hydrophobic partitioning also contributed to drug scavenging. Nanogels exhibited minimal cytotoxicity to multiple cell types and were well tolerated in vivo via peritoneal injections, although larger nanogels caused limited splenic toxicity at higher concentrations. The cell-based assay described herein is found to facilitate more robust drug uptake measurements for nanogels than conventional centrifugation-based assays, in which nanogels can be compressed (and thus drug released) during the measurement.

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Figures

Figure 1
Figure 1
Viability (MTT assay) of C2C12 myotubes after 1 day exposure to various concentrations of AA-6S nanogels and bupivacaine. Cell viability is relative to untreated cells. Data represent means ± standard deviations (n = 4 at each data point).
Figure 2
Figure 2
Viability (MTT assay) of C2C12 myotubes after 1 day exposure to various concentrations of AA-20S nanogels and bupivacaine. Cell viability is relative to untreated cells. Data represent means ± standard deviations (n = 4 at each data point)
Figure 3
Figure 3
Viability (MTT assay) of C2C12 myotubes after 1 day exposure to various concentrations of bupivacaine, in the presence of 0.91 mg/mL of 20 mol% acrylic acid-functionalized nanogels of various sizes. Cell viability is relative to untreated cells. Data represent means ± standard deviations (n = 4 at each data point)
Figure 4
Figure 4
Viability (MTT assay) of C2C12 myotubes after 1 day exposure to various concentrations of bupivacaine, in the presence of 0.45 mg/mL of 6 mol% nanogels of various sizes with different functional group distributions. Cell viability is relative to untreated cells. Data represent means ± standard deviations (n = 4 at each data point)
Figure 5
Figure 5
Viability (MTT assay) of C2C12 myotubes after 1 day exposure to 0.91 mg/mL of nanogels functionalized with different mole percentages of DMAEA (base) and AA (acid). Cell viability is relative to untreated cells. Data represent means ± standard deviations (n = 4 at each data point)
Figure 6
Figure 6
Viability (MTT assay) of various cell types after 1 day exposure to nanogels (a) cell viability in response to 2 mg/mL of all nanogels tested in this study; (b) cell viability in the presence of various concentrations of AA-20S nanogels. Cell viability is relative to untreated cells. Data represent means ± standard deviations (n = 4 at each data point)
Figure 7
Figure 7
Representative histological findings following injection of AA-6 nanogels. Hematoxylin and eosin-stained sections of body wall musculature revealed an absence of inflammation on the peritoneal surface (black arrows) independent of the dose and size of AA-6 nanogels injected. Examination of the spleen revealed marked cellular depletion within the red pulp (R) with comparative sparing of the white pulp (W) in animals injected with 20 mg/mL of AA-6L. Foamy macrophages (white arrows) were also observed at higher doses of all AA-6 nanogels. (Scale bar = 100 μm).
Figure 8
Figure 8
Bupivacaine binding of acrylic acid-functionalized nanogels: (a) mass of bupivacaine bound as a function of nanogel mass; (b) moles of bupivacaine bound per mole of nanogel-bound carboxylic acid group as a function of nanogel mass added. Data are calculated from Figures 1–3 and S2–S5 by measuring the bupivacaine concentration at which half the C2C12 myoblasts are viable in the presence of nanogel minus the bupivacaine concentration for half cell viability in the absence of nanogel.
Figure 9
Figure 9
Drug uptake expressed in terms of g drug/g dry nanogel (black bar) and mole drug/mole of nanogel-bound –COOH groups (grey bar) for acrylic acid-functionalized nanogels. Stars indicate samples in which pair-wise t –test comparisons of nanogels with the same mole% of acrylic acid but different sizes or nanogels with the same size but different mole% of acrylic acid yielded drug uptake results that were not significantly different (p > 0.05). Data represent means ± standard deviations (n = 4 at each data point).
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