Design, Synthesis and Applications of Two-Photon Photoactivatable Nucleic Acids in DNA Nanotechnology

Description

This is a chemistry proposal focusing on the design, synthesis and applications of twophoton photoactivatable nucleic acids in DNA nanotechnology. Recently, the development of two-photon photoactive molecules is emerging because the use of two-photon excitation light source is beneficial to biological systems. Unfortunately, synthesis of the reported two-photon photoactive groups does not allow for oligonucleotide conjugation. Many of them are only restricted to mono-functionalization. They are highly limited by experimental and synthetic complexities. To address these problems, we propose to 1) redesign the synthetic pathways of these photoactive molecules and synthesize a series of bi-functional two-photon photocleavable phosphoramidite molecules via typical chemical reactions such as Heck, Suzuki and Sonogashira coupling reactions; 2) to effectively introduce these molecules to DNA strands in a sequence anywhere via standard solidphase synthesis by well-established cyanoethylphosphoramidite chemistry to form lightactivatable nucleic acids; 3) to employ these photocleavable nucleic acids as building scaffolds for construction of DNA-based nanocarriers used in light-triggered cargo release. As expected, these newly synthesized organic molecules will exhibit large twophoton photolysis cross-section values and high photocleavage efficiency. The integrated photoactivatable nucleic acids will irreversibly break in a site-specific manner upon near infrared (NIR) exposure, leading to light-triggered control of oligonucleotide hybridization. This photolysis will give rise to the opening of the self-assembled 3D DNA nanostructures and the release of encapsulated cargos simultaneously. As compared to other photoresponsive nanocarriers, the proposed DNA-based system is highly biocompatible and non-toxicity. The regulation of cargo release by light is in a clean, remote-control, non-contact and non-invasive manner. This would create a new paradigm of inputs that allows for temporal and spatial control with high specificity and overcoming the drawback of chemical inputs including waste accumulation and delivery kinetics. We anticipate that the facile design of synthetic pathways and the synthesis of a new series of two-photon photocleavage phosphoramidite molecules are beneficial to the synthetic chemists and DNA chemists for further development of new caged compounds as light triggers in DNA nanotechnology. Additionally, this proposed work also leads to a step towards employing photon-responsive DNA nanocarriers as versatile tools in controllable drug delivery. In the future, we envision that this newly developed two-photon photoactive DNA nanotechnology can be adopted to function in clinical applications and will be beneficial to the community of human healthcare in strengthening therapeutic activity, reducing the side effects, diminishing the needed drug dosage during treatment.