Abstract

The evaluation of therapeutic response to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer currently relies on anatomical imaging, which suffers from significant delays. To enable early and direct visualization of drug activity, we developed a near-infrared-II (NIR-II) fluorescent molecular probe, HSA-ICi, by conjugating a CDK4/6 inhibitor (Palbociclib or Ribociclib) with ICG and facilitating its self-assembly with human serum albumin. This probe demonstrated specific targeting to the CDK4/6-cyclin D complex, excellent biocompatibility, and high tumor accumulation in preclinical models. Crucially, HSA-ICi allowed non-invasive monitoring of pharmacodynamic response: a significant decrease in tumor fluorescence signal was detected via NIR-II imaging as early as one week after treatment initiation, preceding any measurable change in tumor volume by caliper or magnetic resonance imaging (MRI). This early signal reduction correlated with decreased pRB and Ki-67 expression in tumor tissues. Furthermore, the probe could distinguish between CDK4/6 inhibitor-sensitive and -resistant tumors, with resistant models showing a consistently low baseline signal. Our findings establish HSA-ICi as a promising tool for the early assessment of therapeutic efficacy and the identification of resistance, potentially facilitating timely treatment adaptation for patients with HR+/HER2- breast cancer.