A Molecular Shielding Strategy to Develop Low Protein Binding, Renal Clearable Pan‐Cancer Near‐Infrared Probes

ABSTRACT

Near‐infrared (NIR) fluorescent heptamethine cyanine (HMC) dyes with intrinsic tumor‐targeting ability are promising probes for solid tumor detection. However, HMC dyes are typically amphiphilic molecules, leading to non‐specific binding to blood proteins, primarily albumin, following systemic administration. While albumin binding can extend blood circulation time and enhance tumor accumulation, it can also lead to significant healthy tissue uptake, resulting in low tumor‐to‐background signal ratios (TBR) and potential toxicity. Here, we report a molecular shielding strategy to prevent non‐specific protein binding of tumor‐targeting HMC dyes. We develop a rationally designed library of molecularly shielded NIR fluorescent probes based on a clinically approved HMC dye, indocyanine green (ICG). To shield non‐specific protein interactions of ICG, its sidechain is modified with varying numbers of charged amino acid residues, which transformed ICG into a low protein binding, renal‐clearable pan‐cancer targeting probe. These shielded ICG molecules showed strong tumor accumulation and optimal tissue clearance in a few days, enabling high‐contrast tumor imaging with TBR values reaching 8 and clear tumor margins in orthotopic rodent tumor models. These new tumor‐targeting NIR probes represent a clinically translatable platform for cancer detection and therapy with a modular molecular structure composed of non‐toxic, FDA‐approved components.