In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors

Yuan Ding,1,* Wei Cui,2,* Dan Sun,1 Gui-Ling Wang,1 Yu Hei,1 Shuai Meng,1 Jian-Hua Chen,3 Ying Xie,1 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, 2School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 3School of Medicine, Jianghan University, Wuhan, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX)-loaded novel cell-penetrating peptide (CPP)-modified pH-sensitive liposomes (CPPL) (referred to as CPPL(DOX)) with an optimal CPP density of 4%. In CPPL, a polyethylene glycol (PEG) derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate) was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p