|
Pancreatic ductal adenocarcinoma (PDAC) has the poorest five-year survival rate of any cancer. Surgical resection is the only curative treatment but, is only possible in 15-20% of cases. Systemic therapies that demonstrate some efficacy are limited to chemotherapeutics, such as Gemcitabine, Abraxane (nab-Paclitaxel) and FOLFIRINOX, a multidrug chemotherapy regimen. Numerous studies have tried to apply multi-agent therapies to advance standard of care for metastatic PDAC. However, consistent improvement in survival remains poor. Of broader interest, there is an urgent need for improved treatment selection and early assessment of therapeutic responses as mean survival time following diagnosis is less than one year. Paired agent imaging (PAI) is a spatially-resolved, quantitative imaging methodology, which enables quantification of bound and unbound drugs on a cell by cell basis, using a targeted and control (untargeted) imaging agent. PAI has the potential to provide a spatially resolved map of drug engagement and treatment efficacy for PDAC. Herein, we have developed fluorescently labeled, paired targeted and control Gemcitabine, which have been characterized for their similarity to the parent Gemcitabine using competitive binding, liquid chromatography mass spectroscopy based uptake and pharmacokinetic studies, and cytotoxicity assays. Using our validated targeted and control agents, we have generated maps of targeted and untargeted Gemcitabine in murine models of PDAC, demonstrating that therapeutic efficacy is correlated to the bound drug fractions. We anticipate that PAI using fluorescently labeled targeted and control drug derivatives will be useful for future studies to prediction therapy combinations for personalized PDAC therapy.
|
