Info
Background:
Albumin-bound paclitaxel and gemcitabine (AG) chemotherapy is a mainstay in treatment of pancreatic ductal adenocarcinoma (PDAC). Unfortunately, not all patients respond to this treatment[1]. Clinical imaging techniques are not able to precisely evaluate and predict the response to AG therapies over several weeks. A strong fibrotic reaction is a hallmark of drug-resistance while depletion of fibrosis is a positive response of AG. Extradomain-B fibronectin (EDB-FN) is an important element of fibrosis in PDAC. Herein, we prepared EDB-FN targeted Gd-based contrast agent (EDB-Gd) to perform molecular MRI for early, noninvasive and quantitative risk screening, accurate prediction, and precise evaluation of treatment response in PDAC.
Hypothesis/Objective:
We hypothesized that EDB-FN-targeted molecular MRI using a low-dose EDB-Gd contrast agent could serve as a noninvasive imaging strategy for risk stratification, accurate prediction, and precise evaluation of AG chemotherapy response in PDAC. The objective of this study was to investigate whether quantitative assessment of fibrogenesis via EDB-Gd-enhanced MRI enables early identification of drug-resistant tumors, stratifies patients by treatment risk, and provides precise monitoring of therapeutic efficacy, thereby overcoming the limitations of conventional imaging techniques.
Methods:
BxPC-DR, Human PDAC cell line, was treated with AG to establish acquired drug-resistance. subcutaneous and orthotopic models with BxPC-DR or BxPC were established. Mice were intravenously injected with EDB-Gd or Gd-DOTA. The ratio of T1 value reduction (T1d%) were compared quantitatively. For chemotherapy monitoring, mice were treated with AG regimens. MRI were performed before and after treatments. Histological analyses were used as references for validation.
Results:
Molecular MRI with EDB-FN could specifically detect and quantify fibrogenesis in PDAC xenografts at a low dose 0.05mmol/kg, which is half of clinical dosage of Gd. The optimal imaging time point was 30min after injection of EDB-Gd. In addition, the targeted probe generated more robust contrast-enhanced and longer retention compared to traditional Gd-DOTA. For chemotherapy monitoring, T1d% were significantly increased 2.5-fold in drug-resistance xenografts group in fibrotic tumor areas compared to AG-sensitive group (p < 0.05). EDB-FN-targeted probe is capable of effectively distinguishing between animal models that are resistant or sensitive to AG chemotherapy. Comparing the T1d% before and 5 days after AG predicted treatment response and enabled risk stratification.
Conclusion:
This study indicates EDB-FN-targeted molecular MRI possesses clinical applications in risk stratification, accurate prediction, and precise evaluation of AG chemotherapy efficacy.
Author
Wenjia Zhang
Peking University People’s Hospital