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. 2011:6:2641-52.
doi: 10.2147/IJN.S24167. Epub 2011 Oct 31.

Synergistic enhancement of cancer therapy using a combination of docetaxel and photothermal ablation induced by single-walled carbon nanotubes

Lei Wang  1 , Mingyue Zhang, Nan Zhang, Jinjin Shi, Hongling Zhang, Min Li, Chao Lu, Zhenzhong Zhang
Affiliations

Synergistic enhancement of cancer therapy using a combination of docetaxel and photothermal ablation induced by single-walled carbon nanotubes

Lei Wang et al. Int J Nanomedicine. 2011.

Abstract

Background: Single-walled carbon nanotubes (SWNT) are poorly soluble in water, so their applications are limited. Therefore, aqueous solutions of SWNT, designed by noncovalent functionalization and without toxicity, are required for biomedical applications.

Methods: In this study, we conjugated docetaxel with SWNT via π-π accumulation and used a surfactant to functionalize SWNT noncovalently. The SWNT were then conjugated with docetaxel (DTX-SWNT) and linked with NGR (Asn-Gly-Arg) peptide, which targets tumor angiogenesis, to obtain a water-soluble and tumor-targeting SWNT-NGR-DTX drug delivery system.

Results: SWNT-NGR-DTX showed higher efficacy than docetaxel in suppressing tumor growth in a cultured PC3 cell line in vitro and in a murine S180 cancer model. Tumor volumes in the S180 mouse model decreased considerably under near-infrared radiation compared with the control group.

Conclusion: The SWNT-NGR-DTX drug delivery system may be promising for high treatment efficacy with minimal side effects in future cancer therapy.

Keywords: NGR peptide; docetaxel; near-infrared radiation; single-walled carbon nanotubes; tumor-targeting.

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Figures

Figure 1
Figure 1
Docetaxel delivery system using noncovalent functionalization of carbon nanotubes. Abbreviations: DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel.
Figure 2
Figure 2
Effects of different surfactants on loading rate. Concentrations of PVPk30, Poloxamer 188, phospholipids, and HS 15 were 2, 5, and 10 mg/mL, respectively. Notes: Data are presented as the mean ± standard deviation (n = 3). *P < 0.01 versus Poloxamer 188, phospholipids, and HS 15 at 10 mg/mL, respectively.
Figure 3
Figure 3
Characterization of SWNT-NGR-DTX. (A) Thin layer silica gel chromatography image of 1-(NGR), 2-(NGR mechanical mixing with the SWNT-DTX), and 3-(SWNT-NGR-DTX); (B) transmission electron microscopic image of SWNT-NGR-DTX; (C) solubility of SWNT-NGR-DTX; (D) particle size of SWNT-NGR-DTX; and (E) zeta potential of SWNT-NGR-DTX. Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel.
Figure 4
Figure 4
Fluorescence microscopic images of PC3 cells. (A) control group; (B) FITC alone; (C) SWNT-DTX-FITC; and (D) SWNT-NGR-DTX-FITC at 0.5, 1, and 2 hours. Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel; FITC, fluorescein isothiocyanate.
Figure 5
Figure 5
Cytotoxicity of SWNT-NGR in PC3 cells. Note: Data are presented as the mean ± standard deviation (n = 3). Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide.
Figure 6
Figure 6
Inhibition rate of docetaxel, SWNT-DTX, and SWNT-NGR-DTX in PC3 cells. SWNT-NGR-DTX was significantly different (P < 0.05) from the other groups at 24 hours (A) but at 48 hours (B) and 72 hours (C) there was no significant difference between SWNT-DTX and SWNT-NGR-DTX, while the SWNT-NGR-DTX group was significantly different from the docetaxel group (P < 0.05). Note: Data are presented as the mean ± standard deviation (n = 3). Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel.
Figure 7
Figure 7
Mean docetaxel concentration in plasma after intravenous administration of docetaxel, SWNT-DTX, and SWNT-NGR-DTX (mean ± standard deviation, n = 5). The decreasing rates of SWNT-DTX and SWNT-NGR-DTX were not significantly different, but the rate of both were markedly different from that in the docetaxel group (P < 0.05). Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel.
Figure 8
Figure 8
Targeting efficiency (A) and AUC0→3 h of DTX concentration (B) in tissues of mice after intravenous administration of DTX, SWNT-DTX, and SWNT-NGR-DTX. Note: Data are presented as the mean ± standard deviation, (n = 6). Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel; AUC, area under the concentration versus time curve.
Figure 9
Figure 9
Temperature evolution of high, middle, and low concentrations of SWNT-NGR-DTX (SWNT approximately 8.3, 4.2, and 0.9 μg/mL; DTX approximately 10, 5, and 1 μg/mL), respectively, during continuous radiation by 808 nm laser at 1.4 W/cm2. Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel.
Figure 10
Figure 10
Inhibition by SWNT-NGR-DTX of PC3 cells under 808 nm laser irradiation using different concentrations and different laser times. Data presented as the mean ± standard deviation (n = 3). Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel.
Figure 11
Figure 11
Average tumor volume in a S180 mouse model of treatment without (A) and with (B) laser in vivo. The SWNT-NGR-DTX-laser group shows significant (P < 0.05) suppression of tumor growth compared with the other experimental groups (n = 6). Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel; NS, normal saline.
Figure 12
Figure 12
Histologic assessments of major organs and tumor tissues with hematoxylin and eosin staining in mice (200×). (A) NS, (B) SWNT, (C) SWNT-DTX, (D) DTX, (E) SWNT-NGR-DTX, and (F) SWNT-NGR-DTX-laser. Abbreviations: SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel; NS, normal saline.
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