title: A tumor environment responsive doxorubicin-loaded nanoparticle for targeted cancer therapy.
abstract: Doxorubicin (DOX) is a potent cancer chemotherapeutic agent, but its clinical use is severely limited by potentially lethal cardiotoxicity. Delivery of DOX by particulate carriers can be an effective way to reduce its distribution in cardiac tissue. In the present study, we developed a self-assembled, tumor-microenvironment-responsive delivery system for DOX. The core of the carrier was built upon the DOX/DNA intercalation, which was further combined with cationic gelatin (C-gel) to form the complex GDD. GDD was then packaged into a complex, namely, HDD, based on the electrostatic interactions between the positively charged C-gel and negatively charged human serum albumin (HSA). The HSA molecules on the surface of the complex HDD effectively helped the particle evade the filtration of the body when injected into the circulation and passively accumulate into the tumor sites. After entering the tumor tissue, where albumin is rapidly consumed, GDD was release from HDD and the C-gel was then digested by the tumor-specific matrix metalloproteinase (MMPs) to free the DOX/DNA intercalation. Deoxyribonucleases (DNases) in the tissue could completely destroy the DNA molecules to release DOX into the microenvironments. After a series of in vitro optimization tests, we evaluated the anticancer capacity and cardiac toxicity of HDD in two animal models with cancer. The results suggested that HDD had a higher anticancer efficacy and a significantly lower cardiotoxicity than free DOX. Additionally, the main components of the carrier are all clinically approved materials. Taken together, our present delivery system is safe and efficient and has high potential for further clinical trials.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University , Nanjing 210093, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhu
authors.forename: Lixin
authors.initials: L
authors.lastname: Jia
authors.forename: Zhongfei
authors.initials: Z
authors.lastname: Gao
authors.forename: Chunming
authors.initials: C
authors.lastname: Wang
authors.forename: Haoyang
authors.initials: H
authors.lastname: Jiang
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D012709:Serum Albumin; D004317:Doxorubicin
keywords: albumin encapsulated nanoparticle; doxorubicin; tumor environment responsive