G-Quadruplex-Based Nanoscale Coordination Polymers to Modulate Tumor Hypoxia and Achieve Nuclear-Targeted Drug Delivery for Enhanced Photodynamic Therapy.

Abstract

Photodynamic therapy (PDT) is a light-triggered therapy used to kill cancer cells by producing reactive oxygen species (ROS). Herein, a new kind of DNA nanostructure based on the coordination between calcium ions (Ca2+) and AS1411 DNA G quadruplexes to form nanoscale coordination polymers (NCPs) is developed via a simple method. Both chlorine e6 (Ce6), a photosensitizer, and hemin, an iron-containing porphyrin, can be inserted into the G-quadruplex structure in the obtained NCPs. With further polyethylene glycol (PEG) modification, we obtain Ca-AS1411/Ce6/hemin@pHis-PEG (CACH-PEG) NCP nanostructure that enables the intranuclear transport of photosensitizer Ce6 to generate ROS inside cell nuclei that are the most vulnerable to ROS. Meanwhile, the inhibition of antiapoptotic protein B-cell lymphoma 2 (Bcl-2) expression by AS1411 allows for greatly improved PDT-induced cell apoptosis. Furthermore, the catalase-mimicking DNAzyme function of G-quadruplexes and hemin in those NCPs could decompose tumor endogenous H2O2 to in situ generate oxygen so as to further enhance PDT by overcoming the hypoxia-associated resistance. This work develops a simple yet general method with which to fabricate DNA-based NCPs and presents an interesting concept of a nanoscale drug-delivery system that could achieve the intranuclear delivery of photosensitizers, the down-regulation of anti-apoptotic proteins, and the modulation of the unfavorable tumor microenvironment simultaneously for improved cancer therapy.

• Authors: Yu Yang, Wenjun Zhu, Liangzhu Feng, Yu Chao, Xuan Yi, Ziliang Dong, Kai Yang, Weihong Tan, Zhuang Liu, Meiwan Chen
• Journal: Nano letters (Nano Lett) Vol. 18 Issue 11 Pg. 6867-6875 (11 14 2018) ISSN: 1530-6992 [Electronic] United States
• PMID: 30303384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AGRO 100
• Aptamers, Nucleotide
• Chlorophyllides
• Oligodeoxyribonucleotides
• Porphyrins
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• RNA, Neoplasm
• Bcl2 protein, mouse
• phytochlorin
• Hemin

Topics

• Animals
• Aptamers, Nucleotide
• Cell Line, Tumor
• Cell Nucleus (metabolism, pathology)
• Chlorophyllides
• Drug Delivery Systems (methods)
• Female
• G-Quadruplexes
• Hemin (chemistry, pharmacology)
• Mammary Neoplasms, Animal (diagnostic imaging, drug therapy, metabolism)
• Mice
• Oligodeoxyribonucleotides (chemistry, pharmacology)
• Photochemotherapy
• Porphyrins (chemistry, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• RNA, Messenger (biosynthesis)
• RNA, Neoplasm (biosynthesis)