title: A pH-sensitive doxorubicin prodrug based on folate-conjugated BSA for tumor-targeted drug delivery.
abstract: Doxorubicin (DOX) is one of the most effective anti-cancer drugs, but its therapeutic efficacy is greatly hampered by its non-specific delivery to the target tissue and the resultant cumulative cardiotoxicity and nephrotoxicity. In order to overcome this limitation, we prepared a folate-bovine serum albumin (BSA)-cis-aconitic anhydride-doxorubicin prodrug, denoted by FA-BSA-CAD. A tumor-targeting agent, folic acid, was linked to BSA to increase the selective targeting ability of the conjugate. BSA provided a large number of reactive sites for multivalent coupling of bioactive molecules and improved the water-solubility of the prodrug. DOX is attached to the BSA via a pH-sensitive linker, cis-aconitic anhydride, which hydrolyzes in the acidic lysosomal environment to allow pH-responsive release of DOX. The in vitro results demonstrate a pH-responsive drug release under different pH conditions. Furthermore, the targeting ability and therapeutic efficacy of the prodrug were assessed both in vitro and in vivo. The results demonstrate that FA-BSA-CAD prodrug selectively targeted tumor cells and tissue, with associated reduction in non-specific toxicity to the normal cells. More importantly, the therapeutic efficacy of the prodrug for FA-positive tumors increased compared to the non-conjuagted DOX.
authors: State Key Laboratory of Natural Medicines, and Department of Biomedical Engineering, China Pharmaceutical University, Nanjing 210009, China.
authors: Changli
authors: C
authors: Du
authors: Dawei
authors: D
authors: Deng
authors: Lingling
authors: L
authors: Shan
authors: Shunan
authors: S
authors: Wan
authors: Jie
authors: J
authors: Cao
authors: Junmei
authors: J
authors: Tian
authors: Samuel
authors: S
authors: Achilefu
authors: Yueqing
authors: Y
authors: Gu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D005492:Folic Acid / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000473:pathology*; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D012710:Serum Albumin, Bovine; D004317:Doxorubicin; D005492:Folic Acid