Novel DSPE-PEG-Cholic Acid-Modified Liposomes with Hepatic Targeting Properties Improve the Anti-Tumor Efficacy of Oral Doxorubicin Hydrochloride for Liver Tumor-Bearing Mice

To overcome both the marked cardiotoxicity and restricted intestinal permeability of doxorubicin hydrochloride (DOX center dot HCl) for oral chemotherapy against liver cancers, DSPE-PEG-cholic acid-modified liposomes (functional liposomes) with hepatic targeting via oral administration properties were explored for the loading of DOX center dot HCl. DSPE-PEG-cholic acid-modified DOX center dot HCl liposomes (functional DOX center dot HCl liposomes) were developed as an oral therapy that targets hepatic cancers. Subsequently, the effects of liposome formulations were investigated using in vitro HepG2 cell uptake assays, in vivo intestine distribution and targeting efficacy experiments in orthotopic HepG2 nude mice xenograft tumors and subcutaneous H22 mice xenograft tumors. Functional DOX center dot HCl liposomes of approximately 100 nm in diameter significantly increased the intracellular uptake of DOX center dot HCl, revealing strong inhibitory effects on HepG2 cells. Moreover, orally administered functional DOX center dot HCl liposomes demonstrated stronger antitumor efficacy than DOX center dot HCl and DOX center dot HCl liposomes in orthotopic HepG2 xenograft mice, but similar antitumor efficacy to DOX center dot HCl liposomes in subcutaneous H22 xenograft mice. In further analyses, cardiac and kidney toxicities were significantly reduced after orally administering functional DOX center dot HCl liposome formulations. The present data indicate that the oral administration of functional DOX center dot HCl liposomes increases hepatic targeting, provides superior efficacy of suppressing xenograft tumor, and overcomes limited cardiac and kidney toxicity.