Cysteine-Functionalized Nanostructured Lipid Carriers for Oral Delivery of Docetaxel: A Permeability and Pharmacokinetic Study

Abstract

Here we report the development and evaluation of cysteine-modified nanostructured lipid carriers (NLCs) for oral delivery of docetaxel (DTX). The NLCs ensure high encapsulation efficiency of docetaxel, while the cysteine bound the NLCs with PEG2000-monostearate (PEG2000-MSA) as a linker, and allowed a specific interaction with mucin of the intestinal mucus layer and facilitated the intestinal transport of docetaxel. The cysteine-modified NLCs (cNLCs) had a small particle size (<100 nm) and a negative zeta potential (-13.72 ± 0.07 mV), which was lower than that of the unmodified NLCs (uNLCs) (-6.39 ± 0.07 mV). This correlates well with the location of the cysteine group on the surface of the NLCs obtained by X-ray photoelectron spectroscopy (XPS). The cNLCs significantly improved the mucoadhesion properties compared with uNLCs. The intestinal absorption of cNLCs in total intestinal segments was greatly improved in comparison with uNLCs and docetaxel solution (DTX-Sol), and the in vivo imaging system captured pictures also showed not only increased intestinal absorption but also improved accumulation in blood. The cNLCs could be absorbed into the enterocytes via both endocytosis and passive transport. The results of the in vivo pharmacokinetic study indicated that the AUC0-t of cNLCs (1533.00 ng/mL·h) was markedly increased 12.3-fold, and 1.64-fold compared with docetaxel solution and uNLCs, respectively. Overall, the cysteine modification makes nanostructured lipid carriers more suitable as nanocarriers for oral delivery of docetaxel.

Preparation and Characterisation of Nobiletin-Loaded Nanostructured Lipid Carriers

“…Acetonitrile and ultrapure water were previously eluted through a 0.22 m membrane filter. The EE was calculated through the following equation [27]:…”

Nanostructured Lipid Carriers: Versatile Oral Delivery Vehicle

“…Also, entrapment of drug in lipid particles provides shielding against the environment and is beneficial for moisture-sensitive and photodegradable drugs. It has also been documented that nanoparticles ranging from 120 to 200 nm prevent uptake via RES, thus enhancing oral bioavailability of drugs [13,76–77]. …”

“…Thiomers also possess the capability to bind to the transmembrane domain of P-gp and thus enabling higher delivery of P-gp substrate drugs [90]. In vitro studies revealed that thiomer (cysteine) conjugation onto the surface of docetaxel-loaded NLCs using postinsertion technique led to higher mucoadhesion (81.6%) with mucin in comparison to unconjugated NLCs (51.9%) [76]. Also, significantly higher permeability constant and absorption constant of docetaxel were obtained in the case of thiomer-conjugated NLCs in comparison to drug solution and conventional NLCs during in situ intestinal perfusion investigation.…”

“…Recently, Fang et al . observed prolonged-plasma concentration (24 h) in case of docetaxel-loaded PEGylated NLCs in comparison to drug solution, which was very low within 12 h postoral administration to rats as PEGylation prevented opsonin binding to intact NLCs in systemic circulation thus avoiding their macrophage uptake [76]. Wang et al .…”

Conjugation of Docetaxel with Multiwalled Carbon Nanotubes and Codelivery with Piperine: Implications on Pharmacokinetic Profile and Anticancer Activity

“…It is an important second generation semisynthetic anticancer drug, belonging to biopharmaceutical classification system (BCS) class IV with limited solubility and permeability. 28 The major challenges with DTX are hepatic metabolism, poor aqueous solubility and poor bioavailability (<10 %). 29 Henceforth, despite immense promises in cancer chemotherapy, DTX offers a huge scope for further research.…”