Dual actions of albumin packaging and tumor targeting enhance the antitumor efficacy and reduce the cardiotoxicity of doxorubicin in vivo.
Doxorubicin (DOX) is an effective chemotherapy drug used to treat different types of cancers. However, DOX has severe side effects, especially life-threatening cardiotoxicity. We herein report a new approach to reduce the toxicity of DOX by embedding DOX inside human serum albumin (HSA). HSA is further fused by a molecular biology technique with a tumor-targeting agent, amino-terminal fragment of urokinase (ATF). ATF binds with a high affinity to urokinase receptor, which is a cell-surface receptor overexpressed in many types of tumors. The as-prepared macromolecule complex (ATF-HSA:DOX) was not as cytotoxic as free DOX to cells in vitro, and was mainly localized in cell cytosol in contrast to DOX that was localized in cell nuclei. However, in tumor-bearing mice, ATF-HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX. More importantly, histopathological examinations of the hearts from the mice treated with ATF-HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX. These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy. Such a tumor-targeted albumin packaging strategy can also be applied to other antitumor drugs.
College of Chemistry, Fuzhou University, Fuzhou, People's Republic of China.
Ke
K
Zheng
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People's Republic of China.
Rui
R
Li
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People's Republic of China.
Xiaolei
X
Zhou
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People's Republic of China.
Ping
P
Hu
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People's Republic of China.
Yaxin
Y
Zhang
Fujian Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People's Republic of China.
Yunmei
Y
Huang
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People's Republic of China.
Zhuo
Z
Chen
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People's Republic of China.
Mingdong
M
Huang
D000418:Albumins / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D066126:Cardiotoxicity / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects*; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D010843:Pichia; D012709:Serum Albumin / Q000737:chemistry; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry
D000418:Albumins; D000970:Antineoplastic Agents; D004337:Drug Carriers; D012709:Serum Albumin; D004317:Doxorubicin; D014568:Urokinase-Type Plasminogen Activator
amino-terminal fragment of urokinase; cytotoxicity; doxorubicin; drug carrier; human serum albumin; urokinase receptor