Control of Carbon Nanotube Solvatochromic Response to Chemotherapeutic Agents

Alkylating agents such as cisplatin play an essential role in chemotherapy regimens, but initial and acquired resistance in many cancer types often dampen therapeutic response. The poor understanding of the mechanisms of resistance highlight the need for quantitative measurements of alkylating agent distribution at both the tissue and subcellular levels. Sensors for use in live animals and cells would allow for more effective study of drug action and resistance. Toward this end, single-walled carbon nanotubes suspended with single-stranded DNA have suitable optical properties for in vivo sensors, such as near-infrared emission and sensitivity to the local environment via solvatochromic responses. Currently, solvatochromic changes of such sensors have been limited by the chemical nature of the analyte, making it impossible to control the direction of energy emission changes. Here, we describe a new approach to control the direction and magnitude of solvatochromic responses of carbon nanotubes. We found that the alkylation of DNA on the nanotube surface can result in small changes in DNA conformation that allow the adsorption of amphiphiles to produce large differences (>14 nm) in response to different drugs. The technique surprisingly revealed differences among drugs upon alkylation. The ability to control carbon nanotube solvatochromism as desired may potentially expand the application of nanotube-based optical sensors for new classes of analytes

Relationship between the extent of vaccine strain replication and ADCC activity.

<p>The extent of SIV_mac239Δ<i>nef</i> or SIV_mac239Δ<i>nef</i>/E543-3<i>env</i> replication was estimated from the area under the curve (AUC) of log₁₀-transformed vaccine strain viral loads over weeks 0 through 21 or 22, and compared to ADCC activity at week 21 or 22. Vaccine strain viral load AUC values were correlated with 50% ADCC titers (A) against Env-matched (R_S = 0.68, P<0.0001) and Env-mismatched (R_S = 0.55, P = 0.006) SIV strains, and also with AUC values for ADCC activity (B) against Env-matched (R_S = 0.64, P<0.0001) and Env-mismatched (R_S = 0.42, P = 0.0421) SIV strains. Linear regression lines are drawn.</p

ADCC against viruses matched or mismatched to the vaccine strain in Env.

<p>Sera drawn 0, 6, or 22 weeks after inoculation with SIV_mac239Δ<i>nef</i> (A) or with the recombinant vaccine strain SIV_mac239Δ<i>nef</i>/E543-3<i>env</i> (B) were tested for ADCC against target cells infected with SIV_mac239 (black), SIV_mac239/E543-3<i>env</i> (green), or SHIV_SF162P3 (gray). Dashed lines indicate 50% activity.</p

ADCC titers elicited by SIV_mac239Δ<i>nef</i> versus single-cycle SIV.

<p>Plasma samples collected on weeks 2 and 12 after a series of inoculations with single-cycle SIV were titered for ADCC against SIV_mac239-infected cells (A). Target cells infected with SHIV_SF162P3 served as a negative control (gray). Dashed lines indicate 50% activity. Geometric mean vaccine strain viral loads reflecting virus particles produced <i>in vivo</i> after inoculation with SIV_mac239Δ<i>nef</i> or single-cycle SIV are shown (B). Animals in Group A were inoculated 3 times with single-cycle SIV that was <i>trans</i>-complemented with the vesicular stomatitis virus glycoprotein (VSV G), whereas the animals in Group B were inoculated 6 times with single-cycle SIV that was not <i>trans</i>-complemented <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002890#ppat.1002890-Jia1" target="_blank">[38]</a>. The 50% ADCC titers (C) and the AUC values for ADCC (D) elicited by SIV_mac239Δ<i>nef</i> were significantly higher than those elicited by single-cycle SIV (2-tailed Mann-Whitney U tests, P = 0.0062 to P<0.0001). Binding titers measured by ELISA against SIV_mac239 gp120 were correlated with 50% ADCC titers (E), and with AUC values for ADCC (F). Binding titers against SIV_mac239 gp140 were also correlated with 50% ADCC titers (G), and with AUC values for ADCC (H).</p

Development of neutralizing antibody and ADCC titers in macaques inoculated with SIV_mac239Δ<i>nef</i>.

<p>Plasma collected from 10 animals at 0, 3, 5, 7, 13 or 15, and 21 weeks after inoculation with SIV_mac239Δ<i>nef</i> was evaluated for its capacity to neutralize SIV_mac239 (A) and to direct ADCC against SIV_mac239-infected cells (B). The loss of relative light units (RLU) indicates the loss of virus-infected cells during an 8-hour incubation in the presence of plasma and an NK cell line. Target cells infected by SHIV_SF162P3 served as a negative control for all ADCC assays (gray). Dashed lines indicate 50% activity. Neutralizing antibody titers were compared with 50% ADCC titers (C), and with AUC values for ADCC (D). An odds ratio (OR) for the probability of detecting neutralization per log₁₀ increase in 50% ADCC titer, or per 1 AUC unit increase in ADCC activity, was estimated by logistic regression.</p

Neutralization and ADCC on the day of intravenous challenge with SIV_mac251_NE.

<p>Macaques were challenged with an intravenous dose of SIV_mac251_NE on week 46 after inoculation with SIV_mac239Δ<i>nef</i> or SIV_mac239Δ<i>nef</i>/E543-3<i>env</i>. Sera collected the day of challenge were evaluated for neutralization of SIV_mac251_NE (A) and ADCC against SIV_mac251_NE-infected cells (B). Solid black symbols indicate animals that became infected by SIV_mac251_NE. Dashed lines indicate 50% activity. Target cells infected with SHIV_SF162P3 served as a negative control for ADCC assays (gray). Differences in 50% ADCC titers were not significant (C). However, AUC values for ADCC were higher among the immunized animals that remained uninfected versus the immunized animals that became infected (2-tailed Mann-Whitney U test, P = 0.0091) (D). None of these macaques had the MHC class I alleles <i>Mamu</i>-<i>A*01</i>, <i>-B*08</i> or -<i>B*17</i> associated with reduced viral replication <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002890#ppat.1002890-Pal1" target="_blank">[67]</a>–<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002890#ppat.1002890-Yant1" target="_blank">[69]</a>.</p