Targeting of an antecedent proteinase by an activatable probe with deep tissue penetration facilitates early visualization and dynamic malignancy evaluation of orthotopic pancreatic ductal adenocarcinoma (PDAC)

摘要

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and most commonly diagnosed at an advanced stage; therefore, early detection with an effective approach is vital. However, due to the anatomical stealthiness and hypovascular features of PDAC, clinically available imaging techniques lack specificity and sensitivity for early detection. As important components of the tumour microenvironment, elevated matrix metalloproteinase (MMP) levels during the early stages of tumour formation lead to tumour invasion and metastases by degrading the extracellular matrix. Thus, in the current study, we hypothesized that MMPs might be promising markers for early visualization and prognosis evaluation of PDAC. An MMP activatable probe, I780BP-PEG12, was synthesized utilizing a long wavelength near-infrared (NIR) fluorophore that could map the dynamic development of orthotopic PDAC in vivo with deep tissue penetration. Elevated MMP activity in tumours was detected as early as 4 days after tumour transplantation. At that time, the tumour diameter was approximately 3 mm, which is much smaller than the size visualized by clinical approaches. Furthermore, much higher levels of MMP activity were detected in PDAC under diabetic conditions, which promote the malignant actions of tumours. By noninvasively monitoring MMP alteration, tumour growth, and prognostic evaluation, we found that malignant actions under diabetic conditions were reversed by inhibition of MMPs. Generally, in addition to earlier visualization of PDAC, a probe targeting MMPs can facilitate dynamic monitoring of tumour progression and inhibitory treatment in vivo, which is beneficial for personal therapeutic strategy planning and optimization of PDAC management, especially for diabetic individuals.