Transferrin receptor-targeted vitamin E TPGS micelles for brain cancer therapy: preparation, characterization and brain distribution in rats

Figures & data

Figure 1. Schematic diagram for (A) synthesis of (i) TPGS-COOH, (ii) TPGS-Tf and (B) preparation of (i) non-targeted (DTX-TPGS-150) and (ii) transferrin receptor-targeted micelles (DTX-TPGS-Tf). DTX-TPGS-150, DTX-loaded TPGS micelles; DTX-TPGS-Tf, transferrin-conjugated DTX-loaded TPGS micelles.

Table 1. Formulas of preparations.

Batches	Drug conc. (mg)	TPGS conc. (mg)	TPGS-Tf conc. (mg)	CHCl3 (ml)	PBS (ml)
DTX-TPGS-150 (non-targeted)	3	150	–	3	15
DTX-TPGS-Tf1	3	100	50	3	15
DTX-TPGS-Tf2	3	75	75	3	15
DTX-TPGS-Tf3	3	50	100	3	15

Conc., concentration; DTX, docetaxel; Tf, transferrin; DTX-TPGS-150, DTX-loaded TPGS micelles; DTX-TPGS-Tf, transferrin-conjugated DTX-loaded TPGS micelles.

Figure 2. FTIR spectra of (A) TPGS (B) TPGS-COOH and (C) TPGS-Tf.

Figure 3. ¹H NMR spectra of (A) TPGS-COOH and (B) TPGS-Tf.

Figure 4. Particle size results of non-targeted and targeted DTX-loaded TPGS micelles. DTX-TPGS-150, DTX-loaded TPGS micelles; DTX-TPGS-Tf, transferrin-conjugated DTX-loaded TPGS micelles.

Figure 5. Histogram showing particle size and size distribution of DTX-loaded TPGS micelles (A) DTX-TPGS-150 (non-targeted), (B) DTX-TPGS-Tf1, (C) DTX-TPGS-Tf2 and (D) DTX-TPGS-Tf3. DTX-TPGS-150, DTX-loaded TPGS micelles; DTX-TPGS-Tf, transferrin-conjugated DTX-loaded TPGS micelles; DTX-TPGS-150, DTX-loaded TPGS micelles; DTX-TPGS-Tf, transferrin-conjugated DTX-loaded TPGS micelles.

Table 2. Particle size, polydispersity index, encapsulation efficiency and drug loading.

Batches	Particle size (nm) (mean ± SD*)	Polydispersity index (mean ± SD*)	Encapsulation efficiency (%) (mean ± SD*)	Drug loading (µg/mg) (mean ± SD*)
DTX-TPGS-150 (non-targeted)	15.29 ± 4.02	0.579 ± 0.010	85.77 ± 0.45	22.81 ± 0.23
DTX-TPGS-Tf1	16.79 ± 3.28	0.275 ± 0.012	84.00 ± 0.90	21.00 ± 0.02
DTX-TPGS-Tf2	18.28 ± 3.24	0.373 ± 0.008	80.83 ± 0.65	19.88 ± 0.09
DTX-TPGS-Tf3	20.36 ± 3.19	0.506 ± 0.006	74.58 ± 0.47	18.62 ± 0.45

*n = 3.

Values represent the mean ± SD.

DTX, docetaxel; Tf, transferrin; DTX-TPGS-150, DTX-loaded TPGS micelles; DTX-TPGS-Tf, transferrin-conjugated DTX-loaded TPGS micelles.

Figure 6. Transmission electron microscope (TEM) image of (A) multiple non-targeted micelles (DTX-TPGS-150) in 100 nm scale, (B) multiple non-targeted micelles (DTX-TPGS-150) in 50 nm scale, (C) multiple-targeted TPGS micelles (DTX-TPGS-Tf3) in 100 nm scale and (D) multiple-targeted micelles (DTX-TPGS-Tf3) in 50 nm scale.

Figure 7. Atomic force microscope (AFM) image of multiple DTX-loaded TPGS micelles (3D image).

Figure 8. In vitro drug release study of non-targeted and targeted DTX-loaded TPGS micelles in phosphate-buffered saline (pH 7.4) (n = 3). DTX-TPGS-150, DTX-loaded TPGS micelles; DTX-TPGS-Tf, transferrin-conjugated DTX-loaded TPGS micelles; 150, TPGS concentration.

Figure 9. (A) Brain distribution and (B) brain distribution kinetics of DTX formulated in Docel™, non-targeted (DTX-TPGS-150) and targeted micelles (DTX-TPGS-Tf3) after 0.5, 2 and 4 h of i.v. administration at the dose of 1 mg/kg (n = 4). DTX-TPGS-150, DTX-loaded TPGS micelles; DTX-TPGS-Tf, transferrin-conjugated DTX-loaded TPGS micelles.

Table 3. Brain distribution kinetics of Docel™, non-targeted micelles (DTX-TPGS-150) and targeted micelles (DTX-TPGS-Tf3) after i.v. injection at an equivalent dose of 1 mg/kg.

Parameters	Docel™	DTX-TPGS-150	DTX-TPGS-Tf3
Tmax (h)	2	2	2
Cmax (ng/g)	96 ± 13.00	504 ± 14.37	2313 ± 26.10
AUC(0–4 h) (ng h/g)	296 ± 40.00	1530 ± 43.60	6453 ± 72.59