Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Abstract

Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel.

Keywords: bioavailability; docetaxel; lymphatic uptake; solid lipid nanoparticles; toxicity; vitamin E TPGS.

Figure 1

Size distributions (left) and transmission electron microscopic images (right) of docetaxel-loaded SLNs (F1 and F2). Note: Scale bars represent 1 μm. Abbreviation: SLN, solid lipid nanoparticle.

Figure 2

Time profiles for in vitro release of docetaxel from Taxotere (●), F1 (○), and F2 (▼) at 37°C in phosphate-buffered saline. Notes: Vertical bars represent standard deviation; n=4.

Figure 3

Remaining fractions of docetaxel at 2 hours after injection of Taxotere® (Sanofi SA, Paris, France), F1, and F2 into rat jejunum, ileum, and colon loops. Notes: *Significantly different from Taxotere (P<0.05); ^#significantly different from F1 (P<0.05); vertical bars represent standard deviation; n=3–4.

Figure 4

Amount of docetaxel recovered from the mesenteric lymph nodes at 0.5 and 1.5 hours (h) after intraduodenal administration of Taxotere® (Sanofi SA, Paris, France), F1, and F2 at a dose of 10 mg/kg. Notes: *Significantly different from Taxotere (P<0.05); vertical bars represent standard deviation; n=4.

Figure 5

Time profiles of arterial plasma docetaxel concentrations after oral administration of Taxotere® (Sanofi SA, Paris, France) (•), F1 (○), and F2 (▼) to rats at a dose of 20 mg/kg. Notes: Vertical bars represent standard deviation; n=4.

Figure 6

Representative histological sections of jejunal segments at 8 hours after oral administration of phosphate-buffered saline (A), Taxotere® (Sanofi SA, Paris, France) (B), F1 (C), and F2 (D) to rats. Note: Scale bars represent 100 μm.