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Tumor-targeting contrast agents promise indispensable value for therapeutic monitoring, image guided therapy, early stage detection, and tumor growth surveillance. Many contrast agents, however, are limited by millimeter-ranged penetration depths, ionizing radiation sources, full-body scan imaging modalities, or a short half-life. Photoacoustic ultrasound offers a chairside and real-time platform for tumor imaging using both endogenous and exogenous sources for optical contrast. In this work, we formulated micelle-inspired nanoparticles via noncovalent intermolecular forces with (1) robust photoacoustic signal and (2) specificity to the tumor microenvironment. The particles are formed by tagging cyclic iRGD peptides with aspartic acid residues and linking them with methylene blue molecules; electrostatic attraction between the negatively charged residues of the peptide and the positively charged dyes enable their controlled assembly into nanoparticles that are stable in 150 mM saline solution on the order of days. The nanoparticles possessed a hydrodynamic diameter of 180 nm based on optimized peptide to dye molar ratios. The tagged iRGD peptides demonstrated targeted uptake in SKOV-3, MCF-7, and A549 cells measured via alpha v beta 3 competitive inhibition. On the other hand, the formulated nanoparticles possessed a photoacoustic peak excitation wavelength of 725 nm, but activatable photodynamic toxicity at 660 nm. The particles induced 9.31, 14.64, and 14.15-fold increase of efficient reactive oxygen species (ROS) generation in cancerous A549, MCF-7, and SKOV-3 cells, respectively, compared to noncancerous HEK 293-T cells. Future work will investigate the half-life and early stage detection capabilities of these nanoparticles in murine cancer models.
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