title: A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors.
abstract: Strategies to target nanoparticles to tumors that rely on surface modification with ligands that bind molecules overexpressed on cancer cells or the tumor neovasculature suffer from a major limitation: with delivery of toxic agents the amount of molecules available for targeting decreases with time; consequently, the efficiency of nanoparticle delivery is reduced. To overcome this limitation, here we propose an autocatalytic tumor-targeting mechanism based on targeting extracellular DNA (exDNA). exDNA is enriched in the tumor microenviroment and increases with treatment with cytotoxic agents, such as doxorubicin (DOX), due to release of DNA by dying tumor cells. We tested this approach using poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface-conjugated with fragments of 3E10 (3E10EN), a lupus anti-DNA autoantibody. We demonstrated that 3E10EN-conjugated nanoparticles bound to DNA and preferentially localized to tumors in vivo. The efficiency of tumor localization of 3E10EN-conjugated, DOX-loaded nanoparticles increased with time and subsequent treatments, demonstrating an autocatalytic effect. 3E10EN-conjugated DOX-loaded nanoparticles exhibited a significant anti-tumor effect that was superior to all controls. This work demonstrates the promise of autocatalytic drug delivery mechanisms and establishes proof of concept for a new anti-DNA autoantibody-based approach for enhancing delivery of nanoparticles to tumors.
authors: Department of Neurosurgery, Yale University, New Haven, CT 06510, USA.|State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, P. R. China.
authors: Zeming
authors: Z
authors: Chen
authors: Department of Medical Oncology, Yale University, New Haven, CT 06510, USA.
authors: Jaymin M
authors: JM
authors: Patel
authors: Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA.
authors: Philip W
authors: PW
authors: Noble
authors: Department of Neurosurgery, Yale University, New Haven, CT 06510, USA.
authors: Cesar
authors: C
authors: Garcia
authors: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, P. R. China.
authors: Zhangyong
authors: Z
authors: Hong
authors: Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA.|Yale Cancer Center, Yale University, New Haven, CT 06510, USA.
authors: James E
authors: JE
authors: Hansen
authors: Department of Neurosurgery, Yale University, New Haven, CT 06510, USA.|Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors: Jiangbing
authors: J
authors: Zhou
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000737:chemistry / Q000627:therapeutic use*; D017151:Antibodies, Catalytic; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004247:DNA / Q000032:analysis; D004317:Doxorubicin / Q000737:chemistry / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D016682:Lupus Coagulation Inhibitor / Q000737:chemistry / Q000627:therapeutic use*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D059016:Tumor Microenvironment
chemical_list: D000974:Antibodies, Antinuclear; D017151:Antibodies, Catalytic; D016682:Lupus Coagulation Inhibitor; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin; D004247:DNA
keywords: anti-DNA autoantibody; autocatalysis; breast cancer; nanoparticles; targeted delivery