The targeted delivery of drugs and diagnostic imaging agents to a tumor site can limit off-target toxicities and nonspecific tissue distribution, respectively. A common strategy to achieve this is by appending a targeting ligand that is preferentially taken up by cancer cells relative to surrounding tissue. For instance, rapidly dividing cancer cells will upregulate certain surface proteins such as the folate receptor, which binds to and internalizes folate utilized to synthesize DNA, RNA, as well as other key building blocks for cell division. A notable example that leverages this interaction is CYTALUX™, an FDA approved folate-cyanine conjugate used for imaging-guided ovarian cancer surgery. Likewise, the overexpression of the glucose transporter 1 (GLUT1) is essential in providing cancer cells with fuel via aerobic glycolysis. The reliance on this process for energy is known as the Warburg effect and has been exploited to deliver a variety of cargo. Of note, the attachment of glucose to a molecule imparts additional key benefits such as improved aqueous solubility. This property is of particular interest to the imaging community because dyes suitable for in vivo applications are often large, hydrophobic, and exhibit poor solubility. Our group and others have contributed to the development of activity-based sensing (ABS) probes designed to monitor cancer biomarkers such as hypoxia, reactive oxygen and nitrogen species, enzymes, and thiols via photoacoustic (PA) imaging. This modality is best described as a "light-in, sound out" approach in which absorbed light is converted to ultrasound via the PA effect. Because sound can readily propagate through tissue, it is possible to obtain high resolution images in deep regions of the body. However, the quality (and accuracy) of a PA image relies on a well-resolved in vivo PA spectrum of the imaging agent to deconvolute its signal from that of background. Unfortunately, the spectra of aggregation-prone dyes, which encompass many PA imaging agents, are typically broad, spectrally shifted, and poorly defined. Recently, we attempted to address this by installing 2 glucose residues onto an aza-BODIPY (AB) dye (infra vide, Figure ). While we were able to enhance aqueous solubility, only moderate improvements to the PA spectra were observed, presumably because the dyes are still able to π-stack. This is consistent with reports that have demonstrated that the inclusion of strategically positioned functional groups such as oligoglycerol dendrons, 36 quaternary ammonium centers or PEG shielding arms are required to block dye aggregation. In the present study, we developed a new multivalent glucose targeting moiety (herein named mvGlu) by mimicking Nature's solution to weak binding interactions, which is to display numerous copies of a ligand to maximize receptor contact. mvGlu was designed to: 1) solubilize and 2) prevent π-stacking of the appended dye; and 3) enhance cancer targeting relative to a single glucose residue (Figure ). Using this new aggregation blocking and tumor-seeking motif, we prepared a panel of aza-BODIPY-based contrast agents for in vivo PA cancer imaging. Moreover, we developed a logic-gated acoustogenic probe by integrating this technology to detect elevated labile copper (Cu) in a murine model of breast cancer.