Robust and Tumor-Environment-Activated DNA Cross-Linker Driving Nanoparticle Accumulation for Enhanced Therapeutics

Abstract

Agglomeration of therapeutic nanoparticles in response to tumor microenvironments is a promising approach to enhance drug accumulation and improve therapeutic efficacy. Cytosine-rich DNA sequences show potential as ideal cross-linkers to drive nanoparticle agglomeration because they can sensitively respond to weak acidity and form interchain folding. However, the in vivo application of DNA is generally limited by its poor biostability; as a consequence, modifications with unprotected DNA cross-linkers can enhance the accumulation of nanoparticles twofold at the tumor site. Facing this challenge, we have designed and developed a protection and tumor-environment activation strategy to enable the in vivo application of a DNA cross-linker. Specifically, reactive oxygen species (ROS)-responsive polyethylene glycol (PEG) was modified on the nanoparticle surface together with the DNA crosslinker, which protects DNA from degradation during the blood circulation; meanwhile, when arriving at the tumor site, the nanoparticles shed the PEG shell as a response to ROS to uncover and activate the DNA cross-linkers. Using this strategy, a sevenfold enhancement in tumor accumulation was achieved owing to both superior pH sensitivity and improved stability of DNA cross-linkers. Finally, significantly improved therapeutic efficacy in in vivo anticancer treatment was realized by using this agglomeration strategy driven by protected and stimuli-activated DNA cross-linkers.

Low-Power Magnetic Resonance-Guided Focused Ultrasound Tumor Ablation upon Controlled Accumulation of Magnetic Nanoparticles by Cascade-Activated DNA Cross-Linkers

“…Next, i-motif DNA and TK-mPEG 5000 were successively grafted to the surface of FS according to the previous method of our group, and the resultant nanoparticle was named FSIP. For i-motif DNA, we chose the optimized C5 sequence with carboxyl functionalization.…”

“…The TK and mPEG 5000 -TK-COOH were synthesized according to the method reported in our previous article, and detailed synthesis procedures could be found in the previous publications without modifications …”

“…When the nanoparticles were delivered into the tumor site through the enhanced permeability and retention (EPR) effect, the particular and complex tumor environment would trigger the transformation of the nanoparticles. First, the labile TK-PEG layer was shed off by the presence of over-expressed ROS. , Next, the cytosine-rich DNA sequences will fold into i-motif structures by C·CH + pairs in response to tumor acidity. − Herein, DNA was selected as the pH-responsive motif because of its superior biocompatibility as well as fast and sensitive responding capability. Also, the pH-responsive sensitivity of the DNA linker can be easily adjusted by the DNA sequence.…”

Hierarchical Chiral Supramolecular Nanoarchitectonics with Molecular Detection: Helical Structure Controls upon Self‐Assembly and Coassembly

“…Among the supramolecular interactions in the assembly systems, the stacking of the hydrophobic phenyl core of the phenylalanine‐based supramolecular system and the hydrogen bonding based on carboxylic acid moieties may provide an approach for efficient coassembly with achiral structural analogues. [ 7 ] So we synthesized the R ‐TDAP‐COOH to explore biological applications (Scheme S2 and Figure S5, Supporting Information). Then we tested its self‐assembly in the H 2 O, which stimulates the biological assembled situation without organic solvents.…”

“…[5] For well-defined chiral architectures, a general strategy has been established to design building blocks based on biologically relevant molecules (such as amino acids or DNA). [6,7] Among these, supramolecular self-assembly, [8] which is an important method in nature to construct chiral ordered structures, opens an efficient way by noncovalent interactions, such as hydrogen-bonding, hydrophobic interactions, and 𝜋-𝜋 stacking to design functional materials with tailored properties. [9] Notably, chirality is also extended to the supramolecular level, and the stereochemical communication or chiral-chiral interaction between various chiral molecules becomes extremely important.…”