Abstract
Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel.
Highlights
Docetaxel (DOC), a typical taxane, has been approved as a first-line anti-tumor drug in clinical treatments [1,2]
We observed that the particle sizes of DOC(Nc)@mPEG-PLA increased as hydration temperature increased, while the highest drug loading (DL) and EE were reached at 25 ◦C
After incubating with a Phosphate-buffered saline (PBS) buffer or PBS buffer containing 10% Fetal bovine serum (FBS) (10% FBS-PBS buffer) for 8 h, the particle sizes of DOC(Nc), DOC@mPEG-PLA, and DOC(Nc)@mPEG-PLA were changed from 173.5 ± 8.3, 33.8 ± 1.9, and 77.9 ± 3.3 to 176.4 ± 5.3, 30.7 ± 2.8, and 75.2 ± 4.9, respectively, in PBS buffer, while in 10% (v/v) FBS-PBS buffer, the particle sizes were changed from 191.4 ± 15.3, 42.8 ± 1.7, and 83.5 ± 5.0 to 382.5 ± 21.4, 57.2 ± 3.8, and 101.3 ± 6.7 for DOC(Nc), DOC@mPEG-PLA, and DOC(Nc)@mPEG-PLA, respectively. These results show that these nano formulations were stable in a PBS buffer; after incubating with serum, the particle sizes of nanocrystals largely increased, which may be due to the drug-protein interaction [39], and, due to the excellent hydrophilic property of mPEG, the micelles and nanocrystal-loaded micelles exhibited good stability [40]
Summary
Docetaxel (DOC), a typical taxane, has been approved as a first-line anti-tumor drug in clinical treatments [1,2]. Researchers have launched numerous strategies, such as nanoparticles [5,6], nano-emulsion [7], proniosomes [8], liposomes [9], and prodrugs [10], to enhance the oral bioavailability of docetaxel; low bioavailability still hinders the development of oral formulations for docetaxel. In this case, developing intravenous injections with higher safety and efficacy is an additional and promising strategy. Considering docetaxel is a rapidly metabolized drug, enhancing its in vivo circulation may benefit its therapeutic efficacy
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