title: Preclinical evaluation of antitumor activity of acid-sensitive PEGylated doxorubicin.
abstract: The acid-sensitive PEGylated doxorubicin (DOX) with exact chemical structure was designed and prepared as a potential tumor intracellular microenvironment-responsive drug delivery system. First, the insensitive succinic anhydride-functionalized DOX (i.e., SAD) and acid-sensitive cis-aconitic anhydride-modified DOX (i.e., CAD) were synthesized through the ring-opening reaction. Subsequently, the insensitive and acid-sensitive PEGylated DOX (i.e., mPEG-SAD and mPEG-CAD) was prepared by the condensation reaction between the terminal hydroxyl group of mPEG and the carboxyl group in SAD and CAD, respectively. The obtained mPEG-SAD and mPEG-CAD could spontaneously self-assemble into micelles in phosphate-buffered saline at pH 7.4 with diameters of about 100 nm. The DOX release of mPEG-CAD micelle could be accelerated by the decrease of pH from 7.4, 6.8, to 5.5 in relation to that of mPEG-SAD micelle. On the other hand, the result of the cellular proliferation inhibition test indicated that mPEG-CAD micelle exhibited favorable antiproliferative activity in vitro. In addition, the selective intratumoral accumulation and antitumor efficacy of mPEG-CAD micelle were significantly better than those of free DOX and mPEG-SAD. More importantly, the prodrug micelles exhibited upregulated security in vivo as compared to free DOX. Overall, the mPEG-CAD micelle with enhanced antitumor efficacy and decreased side effects was a fascinating prospect for the clinical chemotherapy of malignancy.
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, People's Republic of China.
authors.forename: Diankui
authors.initials: D
authors.lastname: Sun
authors.forename: Jianxun
authors.initials: J
authors.lastname: Ding
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Xiao
authors.forename: Jinjin
authors.initials: J
authors.lastname: Chen
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhuang
authors.forename: Xuesi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000143:Acids / Q000737:chemistry; D000156:Aconitic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000143:Acids; D008823:Micelles; D011092:Polyethylene Glycols; C064873:aconitic anhydride; D004317:Doxorubicin; D000156:Aconitic Acid
keywords: acid-sensitive; controlled drug delivery; doxorubicin; malignancy therapy; poly(ethylene glycol)