Paclitaxel-Loaded TPGS/Gelatin-Grafted Cyclodextrin/Hyaluronic Acid-Grafted Cyclodextrin Nanoparticles for Oral Bioavailability and Targeting Enhancement.

The clinical applications of paclitaxel (PTX), a natural compound with broad-spectrum antitumor effects, have been markedly limited owing to its poor oral bioavailability and lack of targeting ability. Recently, several drug carriers, such as TPGS, gelatin (Gel), cyclodextrin (CD), and hyaluronic acid (HA), have been identified as promising enhancers of drug efficacy. Therefore, Gel-grafted CD (GEL-CD) and HA-grafted CD (HA-CD) were synthesized via grafting, and PTX-loaded TPGS/GEL-CD/HA-CD nanoparticles (TGHC-PTX-NPs) were successfully prepared using the ultrasonic crushing method. The mean particles size, polydispersity index, and Zeta potential of TGHC-PTX-NPs were 253.57 ± 2.64 nm, 0.13 ± 0.03, and 0.087 ± 0.005 mV, respectively. TGHC-PTX-NPs with an encapsulation efficiency of 61.77 ± 0.47% and a loading capacity of 6.86 ± 0.32% appeared round and uniformly dispersed based on transmission electron microscopy. In vitro release data revealed that TGHC-PTX-NPs had good sustained-release properties. Further, TGHC-PTX-NPs had increased the targeted uptake by HeLa cells as HA can specifically bind to the CD44 receptor at the cell surface, and its intestinal absorption is related to caveolin-mediated endocytosis. The pharmacokinetic results indicated that TGHC-PTX-NPs significantly enhanced the absorption of PTX in vivo compared to the PTX suspension, with a relative bioavailability of 227.21%. Such findings indicate the potential of TGHC-PTX-NPs for numerous clinical applications.