The early diagnosis and targeted treatment of all forms of cancer remain a significant concern for the medical community and physician-scientists around the world. Biocompatible nanomedicines have been the focus of extensive research due to their many interesting properties. Research by Southern University of Science and Technology (SUSTech) have developed new strategies for nanomedicines based on functional nucleic acids.

Associate Professor Leilei Tian (Materials Science and Engineering) led her research team to publish two ground-breaking papers in high-impact academic journals, Angewandte Chemie International Edition (Angew Chem Int Ed) (IF = 12.257) and CCS Chemistry, the flagship journal of the Chinese Chemical Society.

The paper published in Angew Chem Int Ed was titled “Organic Spherical Nucleic Acids for the Transport of a NIR‐II‐Emitting Dye Across the Blood-Brain Barrier.” The researchers sought to use DNA nanotechnology to transport a NIR-II-emitting nanofluorophore across the blood-brain barrier (BBB).

Figure 1. DNA amphiphilic block polymers can assemble into spherical micelles. Through dense packing, the biological stability and intracellular delivery capacity of nucleic acids are increased. The hydrophobic lumen can be used to confer new functions, such as the introduction of NIR-II emitting molecules.

Perfecting such a technique would facilitate non-invasive imaging of brain tumors (Figure 1). Specifically, the DNA block copolymer, PS-b-DNA, was synthesized through a solid-phase click reaction. The researchers demonstrated that its self-assembled structure showed exceptional cluster effects, among which BBB-crossing is the most notable.

Figure 2. (a) Illustration of the in vitro BBB model. (b) Transcytosis efficiency of different samples along with time. (c) NIR-II fluorescence imaging of mouse heads and ex vivo brain tissues using different NIR-II-emitting materials under 808 nm irradiation. (e) Quantitative analysis of fluorescence intensity of the ex vivo images of different organs from the mice injected with different samples.

PS-b-DNA was utilized to fabricate a NIR-II nanofluorephore and applied to in vivo bioimaging. Following those results, the NIR-II fluorescence signal of the DNA-based nanofluorophore localized at a brain tumor was significantly higher than the existing technology (Figure 2). It showed much better imaging resolution, which will provide better diagnosis and therapy for brain tumors.

Doctoral candidate Fan Xiao is the first author of the paper. Associate Professor Leilei Tian is the corresponding author, with SUSTech as the corresponding unit. Additional contributions came from the Department of Materials Science and Engineering and the School of Medicine.

Paper link: https://doi.org/10.1002/anie.202002312

The paper published in CCS Chemistry was entitled “Robust and Tumor-Environment-Activated DNA Crosslinker Driving Nanoparticle Accumulation for Enhanced Therapeutics.” In this work, the researchers used stimuli-responsive polymers to improve the stability of functional nucleic acids during blood circulation. They sought to activate the nucleic acid function in situ at the tumor site through stimuli-responsive design (Figure 3).

Figure 3. Functional nucleic acids are protected by a polymer-grafting method; the nucleic acid functions are activated by tumor markers. This method can significantly improve the function of nucleic acids in tumor treatment.

The agglomeration of therapeutic nanoparticles to respond to the microenvironments created by tumors is thought to be a promising approach for treatment. Researchers believe that it enhances the therapeutic performance and efficacy of treatment medication.

Cytosine-rich DNA sequences have potential to drive nanoparticles to collect together. Previous research has shown that they can respond to weak acidity and form inter-chain folding. However, the in vivo application of DNA is generally limited by its poor bio-stability. As a consequence, modification of un-protected DNA crosslinkers can only slightly enhance the accumulation of nanoparticles at the tumor site.

Facing this challenge, the researchers designed and developed a strategy of protection and tumor-environment activation to enable the in vivo application of DNA crosslinker. ROS-responsive PEG was modified on the nanoparticle surface together with the DNA crosslinker. It would protect the DNA from degradation during the blood circulation, and the nanoparticles would shed their PEG shell at the tumor site. It would be in response to ROS to uncover and activate the DNA crosslinkers.

This strategy resulted in a significant enhancement owing to both the superior pH sensitivity and improved stability of DNA crosslinkers. There was also a significantly improved therapeutic efficacy of in vivo anti-cancer treatment through the use of this strategy.

Research Assistant Zhicong Chao is the first author of this paper. Associate Professor Leilei Tian is the corresponding author, and SUSTech is the only contributing institution.

Paper link: https://doi.org/10.31635/ccschem.020.202000134

For both papers, the authors acknowledge financial support by grants from the National Natural Science Foundation of China, Shenzhen Fundamental Research Programs, Shenzhen Science and Technology Innovation Commission, and Guangdong Innovative and Entrepreneurial Research Team Program.