Abstract
Here we report a novel assembly structure of near-infrared plasmonic gold nanoparticles (AuNPs), possessing both photoacoustic (PA) and photothermal (PT) properties. The template for the plasmonic AuNP assembly is a bioconjugate between short double-strand DNA (sh-dsDNA) and human methyl binding domain protein 1 (MBD1). MBD1 binds to methylated cytosine-guanine dinucleotides (mCGs) within the sequence of sh-dsDNA. Hexahistidine peptides on the engineered MBD1 function as a nucleation site for AuNP synthesis, allowing the construction of hybrid conjugates, sh-dsDNA-MBD1-AuNPs (named DMAs). By varying the length of sh-dsDNA backbone and the spacer between two adjacent mCGs, we synthesized three different DMAs (DMA_5mCG, DMA_9mCG, and DMA_21mCG), among which DMA_21mCG exhibited a comparable photothermal and surprisingly a higher photoacoustic signals, compared to a plasmonic gold nanorod. Further, epidermal growth factor receptor I (EGFR)-binding peptides are genetically attached to the MBD1 of DMA_21mCG, enabling its efficient endocytosis into EGFR-overexpressing cancer cells. Notably, the denaturation of MBD1 disassembled the DMA and accordingly released the individual small AuNPs (<5 nm) that can be easily cleared from the body through renal excretion without causing accumulation/toxicity problems. This DMA-based novel approach offers a promising platform for targeted cancer theragnosis based on simultaneous PA imaging and PT therapy.
Highlights
One problem to hamper the clinical application of assembly structure of near-infrared plasmonic gold nanoparticles (AuNPs), is the accumulation of AuNPs inside the body, which causes nanotoxicity[11,12]
This method is typically based on thiol-linked conjugation between the template and small AuNPs (1 to 5 nm) that are formerly synthesized through the reduction of gold salts in the presence of thiol capping ligands, leaving the capping ligands on the AuNP surface, which may interfere with further surface modification and/or functionalization of the AuNPs33,34
The multi-functional agents with cancer targeting, imaging, and therapeutic capabilities are essential to the cancer theragnosis, and here we report a new type of cancer theragnostic agent based on photothermal and photoacoustic activies of AuNPs
Summary
Synthesis and assembly of small AuNPs using DNA-protein conjugate as a template. As shown in Fig. 1a, an MBD1 variant that is genetically engineered to have N- and C-terminal polyhistidine tags (H6) and C-terminal affibodies binds to the mCG sites of a sh-dsDNA backbone. DMA_21mCG (aff+) that contains the highest number of mCG and MBD1 (aff+) exhibited the highest-level endocytic uptake by A431 cells among the three DMAs, and its uptake was almost 8-times higher than that of MBD1 (aff+) only (Fig. 5b), indicating that the cellular uptake of DMA increased as the number of MBD1 (aff+) per DMA (i.e. the number of mCG per DMA) increased This result is in agreement with the previous. These results suggest that DMA_21mCG (aff+) is a promising functional material for targeted cancer therapy
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