Intestine-penetrating, pH-sensitive and double-layered nanoparticles for oral delivery of doxorubicin with reduced toxicity

Abstract

Herein, intestine-penetrating and pH-sensitive oral nanoparticles (NP2, ∼350 nm) with a double-layered structure have successfully been fabricated for enhanced oral delivery of doxorubicin with reduced systemic toxicity. Their core is composed of poly(ortho ester urethane) (POEU), which is biocompatible and acid-sensitive. Carboxymethyl chitosan (CMC) was used as the external coating layer, which effectively protected the nanoparticles in gastric fluid (pH 1.0). In addition, CMC-coated nanoparticles could promote penetration in the small intestine (pH 5.0-8.0) through tight-junction opening-mediated paracellular pathways, transcytosis, and lymphatic uptake of M cells. NP2 demonstrated good biocompatibility in vitro and in vivo. Doxorubicin-loaded NP2 (NP2/DOX) hardly released the loaded drug in the simulated gastric fluid (SGF), while 74.83% of DOX was released under mildly acidic conditions (pH 5.0). High bioavailability (75.4%) and reasonable drug distribution were achieved by passive targeting after oral administration of NP2/DOX. More importantly, continual NP2/DOX oral therapy could effectively inhibit the amplification of the H22 tumour without any noticeable systemic toxicity in vivo. These results demonstrated that NP2/DOX had great potential to overcome the obstacles of clinical oral delivery of DOX.