Abstract 5735: Efficient and safe delivery of doxorubicin by DNA fragments: A full preclinical study

Abstract

Abstract The clinical uses of anthracyclines (e.g., doxorubicin) are hampered especially by dose-dependent cardiac toxicity, resulting in a narrow therapeutic window. Doxorubicin formulations have marginally improved its therapeutic efficacy while suffering from difficult and costly manufacturing, poor characterization and quality control, limited scalability in production, and disappointingly low drug loading. This study employs DNA fragments extracted from the salmon sperm cells, which is known for high biocompatibility in various biomedical application, to self-assemble via intercalation by doxorubicin. DNA/DOX nanocomplexes are easy in manufacturing, high scalability, straightforward characterization and quantification, and efficiency in drug loading. Doxorubicin and DNA fragments were dissolved in water and mixed at the optimized 1:6 weight ratio, followed by stirring and incubation for 30 min. DNA/DOX nanocomplexes were characterized for doxorubicin loading and release, size, surface charge, and morphology by UV/fluorescence spectroscopy, stable isotope tracer ultrafiltration assay (SITUA), dynamic light scattering particle analysis, and transmission electron microscopy. The anticancer efficacy of the DNA/DOX nanocomplexes were tested in vitro and in vivo using syngeneic and PDX tumor models. Along with PD/PK studies, DNA/DOX nanocomplexes were also evaluated for their systemic and cardiac toxicity. Characterization and quantification studies revealed DNA/DOX nanocomplexes to be relatively monodisperse with a size of 40 nm in diameter, efficient for drug encapsulation (~100%) and drug loading (14.3%, w/w), and stable for storage while readily releasing doxorubicin in a cell. The self-assembled nanocomplexes were formed when doxorubicin inter- and intra-molecularly chelated DNA fragments. DNA/DOX nanocomplexes were more efficient in killing cancer cells in vitro than both doxorubicin and the liposomal doxorubicin Doxil. PD/PK studies demonstrated that DNA/DOX nanocomplexes circulated longer with less accumulation in the heart than doxorubicin, which altogether lower toxicity. A repeated administration of the DNA/DOX nanocomplexes to Sprague-Dawley rats exhibited a substantially lower cardiotoxicity score than that of doxorubicin. The improved anti-tumor efficacy of the DNA/DOX nanocomplexes were finally confirmed using a syngeneic lymphoma mouse model and PDX mouse models of triple-negative breast and ovarian cancers. Complexing doxorubicin with DNA fragments addresses the current technological challenges in achieving an efficient and safe therapy for a broad range of cancers. DNA/DOX nanocomplexes are amenable to rigorous chemistry, manufacturing, and controls (CMC) evaluation with proven anti-cancer efficacy and improved safety profiles. Clinical trials on DNA/DOX nanocomplexes for cancer chemotherapy are warranted to fully validate their clinical utilities. Citation Format: Minhyeong Park, Youngwoo Kim, Hyunchu Cho, Saad Mohammad, Yeon Su Choi, Hyunjoo Lee, Seonah Lee, Edward Cedrone, Barry Neun, Maria Dobrovolskaia, David Fruman, Juwan Kim, Young Jik Kwon. Efficient and safe delivery of doxorubicin by DNA fragments: A full preclinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5735.