Oral delivery system prolongs blood circulation of docetaxel nanocapsules via lymphatic absorption

Abstract

An original oral formulation of docetaxel nanocapsules (NCs) embedded in microparticles elicited in rats a higher bioavailability compared with the i.v. administration of the commercial docetaxel solution, Taxotere. In the present study, various animal studies were designed to elucidate the absorption process of docetaxel from such a delivery system. Again, the docetaxel NC formulation elicited a marked enhanced absorption compared with oral Taxotere in minipigs, resulting in relative bioavailability and Cmax values 10- and 8.4-fold higher, respectively, confirming the previous rat study results. It was revealed that orally absorbed NCs altered the elimination and distribution of docetaxel, as shown in the organ biodistribution rat study, due to their reinforced coating, while transiting through the enterocytes by surface adsorption of apoproteins and phospholipids. These findings were demonstrated by the cryogenic-temperature transmission electron microscopy results and confirmed by the use of a chylomicron flow blocker, cycloheximide, that prevented the oral absorption of docetaxel from the NC formulation in an independent pharmacokinetic study. The lipoproteinated NCs reduced the docetaxel release in plasma and its distribution among the organs. The improved anticancer activity compared with i.v. Taxotere, observed in the metastatic lung cancer model in Severe Combined Immune Deficiency-beige (SCID-bg) mice, should be attributed to the extravasation effect, leading to the lipoproteinated NC accumulation in lung tumors, where they exert a significant therapeutic action. To the best of our knowledge, no study has reported that the absorption of NCs was mediated by a lymphatic process and reinforced during their transit.

Keywords: lymphatic system; nanocarrier; nanoparticles; taxanes.

Fig. 1.

(A) Detection and evaluation of A549-luc-C8 metastatic lung cancer growth in SCID-bg mice using a CCCD camera. Mice were treated once weekly for 4 wk (treatment days are indicated by arrows). Results are presented as the average total luminescence in radiance units (photons/s/cm²) ± SEM, n = 9. No significant difference (P > 0.05) of tumor growth at days 28, 42, 49, and 56 was observed between PBS and Taxotere groups, whereas an extremely significant difference (P < 0.0001) was noted between PBS and Taxotere groups compared with the docetaxel formulation. (B) Representative images of the total tumor luminescence in tumor bearing mice at day 42 after tumor cells inoculation and 35 d following treatments. (C) Survival rate analysis comparing treatment arms.

Fig. 2.

(A) Mean plasma docetaxel level–time profiles following i.v. administration of docetaxel NCs at a dose of 5 mg/kg, oral administration of docetaxel solution with blank MPs, or docetaxel formulation at a dose of 10 mg/kg, n = 4. (B) Organ distribution of docetaxel levels after oral administration of docetaxel formulation at a dose of 10 mg/kg at 1 h, n = 4. (C–F) Mean concentration–time profiles of docetaxel in tissues following i.v. administration of Taxotere or docetaxel NCs at a dose of 5 mg/kg, and oral administration of docetaxel solution with blank MPs, or docetaxel formulation at a dose of 10 mg/kg in fasted rats, n = 4.

Fig. 3.

Cryo-TEM images of Lipiodol NCs. (A and B) Control Lipiodol NCs (A) in water; S denotes the perforated carbon support film. (B) In rat plasma. (C) Rat plasma at 6 h following i.v. administration of Lipiodol NCs into the jugular vein. (D–F) Extract of rat abdominal mesenteric lymph nodes at different time intervals following oral administration by gavage of embedded Lipiodol NCs in MP formulation: at 0 h (D); with nonspecific structures, at 0.5 h (E); a low-magnified image illustrating how many Lipiodol droplets are found, at 1 h (F). (G–I) Rat plasma samples at different time intervals following oral administration by gavage of embedded Lipiodol NCs in MP formulation at 0 (G), 0.5 (H), and 1 h (I). (Scale bars: A–D and F–I, 100 nm; E, 200 nm.)

Fig. 4.

(A) Plasma docetaxel concentration–time profiles (±SD) obtained following oral administration of 10 mg/kg docetaxel MPs formulation to nontreated rats, n = 4, to cycloheximide-treated rats 1 h before administration, n = 2, and 1.5 h before administration, n = 4. (B) Plasma docetaxel concentration–time profiles following oral administration of docetaxel-NCs at a dose of 10 mg/kg to fasted rats, n = 5. The docetaxel NCs were prepared exactly as the NC of docetaxel formulation.