Folic Acid–Chitosan Oligosaccharide Conjugates Decorated Nanodiamond as Potential Carriers for the Oral Delivery of Doxorubicin.

Oral administration of doxorubicin (DOX) is preferred but challenged owing to poor permeability in the gastrointestinal tract (GIT), efflux of P-glycoprotein, short residence time in the intestine, and rapid hydrolysis. Herein, folic acid–chitosan oligosaccharide conjugate (FA-COS)-modified hydroxylated nanodiamond (ND-OH) was designed to enhance the oral bioavailability of DOX. The carboxyl surface of ND was modified into hydroxyl terminal group to increase the colloidal stability of the system under different pH conditions in GIT. FA-COS modification could prolong retention time, endow the drug with sustained release properties, and actively target intestinal FA receptors. In contrast to DOX/ND-OH, the particle size of DOX/ND-OH/FA-COS increased from 189.5 ± 2.8 to 224.5 ± 1.4 nm, and the zeta potential reversed from − 9.1 ± 0.2 to 14.8 ± 0.4 mV. At 48 h, DOX/ND-OH and DOX/ND-OH/FA-COS released 69.07 ± 5.70% and 35.87 ± 5.64%, respectively. FA-COS modification effectively enhanced the cytotoxicity and intracellular uptake of ND-OH/DOX by Caco-2 cells and prolonged intestinal retention in rats. The internalization of DOX/ND-OH and DOX/ND-OH/FA-COS was mainly mediated by energy-dependent clathrin- and caveolae-mediated endocytosis pathways. Pharmacokinetic study demonstrated that the AUC_0−t of DOX/ND-OH and DOX/ND-OH/FA-COS was enhanced by 3.94- and 6.08-fold compared to DOX solution, respectively. These results illustrated that DOX/ND-OH/FA-COS could be an effective strategy to enhance the oral bioavailability of DOX. [ABSTRACT FROM AUTHOR]