Molecular Engineering of Aptamer to Solubilize Hydrophobic Near-Infrared Photosensitizer for Enhanced Cancer Photodynamic Therapy

Photodynamic therapy (PDT) is a clinically representative treatment strategy for cancer. However, conventional photosensitizers (PSs) are usually hampered by poor water solubility and low targeting capacity. Here, we report the precise molecular engineering of aptamer oligonucleotides to solubilize hydrophobic near-infrared (NIR) PSs for enhanced cancer PDT. Hydrophobic pyropheophorbide A (PA) is precisely conjugated to aptamer oligonucleotides by combing DNA solid-phase synthesis technology and Cu-free click chemistry. Precise coupling of insoluble PA to hydrophilic aptamer oligonucleotides vastly improves its solubility to as high as 750 mu M in water without any cosolvent, resulting in an enhanced NIR fluorescence property (quantum yield = 23%) and photoactivity. Moreover, the targeting ability of aptamer oligonucleotides is not affected by our molecular engineering strategy. Abundant reactive oxygen species (ROS) are produced intracellularly with 660 nm laser irradiation, eliciting mitochondria damage and cell death. Tumor growth is effectively inhibited with a single dose of aptamer-PA conjugates without in vivo toxicity. Their therapeutic effect is more than 20-fold higher than that of PA. Compared with traditional formulation, using aptamer oligonucleotides as functional carriers to solubilize hydrophobic NIR PSs is more precise and operable. Our DNA molecular engineering strategy paves a way for the rational design of molecularly targeted medicine for future clinical cancer therapy. [GRAPHICS] .