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 C max 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. lymphatic system | nanoparticles | nanocarrier | taxanes

Polymeric nanoparticle drug delivery technologies for oral delivery applications

“…Taxanes are one example of a chemotherapeutic agents limited by low bioavailabiity due to P-gp pumps [108]. In a recent study, encapsulating docetaxel in NPs resulted in increased absorption after oral administration relative to oral Taxotere in mini pigs [109]. Furthermore, the study showed that docetaxel NPs were trafficked through the lymphatic system, avoiding first-pass liver metabolism effects such as degradation by cytochrome P450 3A4 (CYP3A4).…”

Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

“…Some authors reported that oral administration of drugs in polymeric NC offers advantages over other nanostructured systems, such as liposomes, lipid-based systems, or most micelles, because the polymeric NC are more stable in the GIT (24,25). The polymeric wall of NC may confer a higher stability to encapsulated drugs and improve the drug body exposure (area under the concentration-time curve [AUC]) and its lymphatic transport by the oral route, as previously demonstrated (26,27). Thus, an alternative pharmaceutical formulation involving polymeric NC loaded with LYC dissolved in the oily core was developed in order to reduce the contact of the active substance with the intestinal fluids to circumvent the above-mentioned set of difficulties (14,18).…”

Nanoparticles for oral delivery: Design, evaluation and state-of-the-art

“…The use of C 18 unsaturated fatty acid glycerides (Labrafil 1944 CS) in the nanocapsule core may have contributed to intestinal lymphatic targeting (See section 2.3), though this effect was not explored. In another study [193] they found that docetaxel was not systemically absorbed upon oral administration of MPs-DTX-NCs (equivalent to 10 mg/kg of docetaxel) when the rats were pre-treated with cycloheximide 1.5 h before the oral administration of MPs-DTX-NCs (Figure 9), thus suggesting oral bioavailability is due to lymphatic transport.…”