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

Figures & data

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 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 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 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 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 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 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.

Table 1 The pharmacokinetic parameters of DTX after intravenous administration of DTX, SWNT-DTX, and SWNTNGR- DTX in mice

Parameter	Unit	SWNT-DTX	SWNT-NGR-DTX	DTX
V(c)	L/kg	0.643	0.547	0.477
t½α	h	0.264	0.226	0.123
t½β	h	148.948	738.729	12.728
K21	L/h	0.198	0.245	0.357
K10	L/h	0.062	0.012	0.860
K12	L/h	2.367	2.813	4.479
AUC	(μg/mL) ·h	125.952	777.614	12.188
CL(s)	mL/h/μg	0.0396	0.00643	0.410

Note: All data are the average of five measurements.

Abbreviations: AUC, area under the curve; CL, clearance; V, volume of distribution; t_½, elimination half-life; k, elimination rate constant; SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel; NS, normal saline.

Table 2 Pharmacokinetic parameters calculated by statistical moment for mice treated with intravenous DTX, SWNT-DTX, and SWNT-NGR-DTX

Parameters	Unit	SWNT-DTX	SWNT-NGR-DTX	DTX
AUC (S0)	(μg/mL) ·h	9.888	14.628	7.470
AUMC (S1)	(μg/mL) ·h	58.802	144.793	28.274
AUMC (S2)	(μg/mL) ·h	886.286	3426.139	187.986
MRT	h	5.947	9.898	3.785
VRT	h · h	54.268	136.238	10.893

Abbreviations: AUC, area under the curve; AUMC, area under the first moment of the plasma concentration-time curve; MRT: mean retention time; VRT, variance of residence time; SWNT, single-walled carbon nanotubes; NGR, (Asn-Gly-Arg) peptide; DTX, docetaxel.

Figure 8 Targeting efficiency (A) and AUC_{0→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 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 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 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 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.