title: pH-Responsive Reversible PEGylation Improves Performance of Antineoplastic Agent.
abstract: The reversible PEGylation endows antitumor drugs with various fascinating advantages, including prolonged circulation time in blood, enhanced accumulation in tumor tissue, increased cellular uptake, and promoted intracellular drug release, to improve the therapeutic efficacy and security. Here, the obtained succinic anhydride (SA)-functionalized DOX (SAD) (i.e., insensitive succinic anhydride-functionalized doxorubicin (DOX)) and aconitic anhydride (CA)-modified DOX (CAD) (i.e., acid-sensitive cis-aconitic anhydride-modified DOX) are conjugated to the terminal of poly(ethylene glycol) (PEG) yielding the unresponsive SAD-PEG-SAD and pH-responsive CAD-PEG-CAD prodrugs, respectively. The prepared prodrugs can self-assemble into micelles in aqueous solution. Both micelles are sufficiently stable at normal physiological pH (i.e., 7.4), while CAD-PEG-CAD micelle gradually swells and finally disassembles at intratumoral (i.e., 6.8) and especially endosomal pHs (i.e., 5.5). DOX release from CAD-PEG-CAD at pH 7.4 is efficiently inhibited, whereas it is significantly accelerated by the rapid cleavage of amide bond at pH 5.5. In addition, CAD-PEG-CAD exhibits more efficient cellular uptake and potent cytotoxicity in vitro, as well as improved tissue distribution and superior tumor suppression in vivo than free DOX and SAD-PEG-SAD. More importantly, the PEGylated DOX exhibits favorable security in vivo. In brief, the smart CAD-PEG-CAD with enhanced antitumor efficacy and decreased side effects shows as a promising powerful platform for the clinical chemotherapy of malignancy.
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.
authors: Diankui
authors: D
authors: Sun
authors: Jianxun
authors: J
authors: Ding
authors: Chunsheng
authors: C
authors: Xiao
authors: Jinjin
authors: J
authors: Chen
authors: Xiuli
authors: X
authors: Zhuang
authors: Xuesi
authors: X
authors: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: PEGylation; controlled drug delivery; doxorubicin; malignancy therapy; pH-responsiveness