Photodynamic therapy (PDT) has emerged as one promising treatment regimen for several cancer types, with a clinical trial ongoing in pancreatic adenocarcinoma (PDAC). PDT treatment efficacy mainly depends on the combination of light delivery, oxygen availability and photosensitizer uptake, each of which can be limited in pancreas cancer. Therefore, increasing drug uptake in the tumor would make an important impact on treatment outcome. This study was conducted to focus on the issue with drug resistance by examining the relationship between photosensitizer verteporfin and tissue parameters such as collagen and vascular patency. Verteporfin uptake in the tumors was assessed by fluorescence imaging while collagen content and patent vessel area fraction were quantified by evaluating Masson’s Trichrome and Lectin pathology staining images. Two tumor cell lines – AsPC-1 and BxPC-3 – were modeled in nude mice to investigate the impact of different tumor microenvironments. Experimental results highlighted the correlation between vascular patency and verteporfin uptake. Collagen content was found to be an independent factor within each tumor line, but a comparison across two tumor types suggested that collagen area of greater than 10% of tumor cross section reflected a lower verteporfin uptake. It was observed that whole-slice tumor quantifications have showcased some interesting trends which could be greatly enhanced and further supported by regional analysis.
Pancreatic tumors are characterized by large interstitial hypertension from enhanced deposition of extracellular matrix components, resulting in widespread vascular collapse and reduced molecular uptake of systemically delivered therapies. Although the origins of hypoperfusion is debated amongst researchers, spatial distribution of collagen density and hyaluronic acid content have shown to be a key metric in understanding the lack of efficacy for both acute and chronic therapies in these tumors. In this study, the AsPC-1 tumor model was used both subcutaneously and orthotopically to study the measurable factors which are related to this. A conventional piezoelectric pressure catheter was used to measure total tissue pressure (TTP), defined as a combination of solid stress (SS) and interstitial fluid pressure (IFP), TTP = SS + IFP, in multiple locations within the tumor interstitium. Matrix components such as collagen and hyaluronic acid were scored using masson’s trichrome stain and hyaluronic acid binding protein (HABP), respectively, and co-registered with values of TTP. The results show that these key measurements are related to the spatial distribution of verteporfin in the same tumors. Photodynamic treatment with verteporfin is known to ablate large regions of tumor tissue and also allow better permeability for chemotherapies. The study of spatial distribution of verteporfin in relation to stromal content and TTP will help us better control these types of combination therapies.
This paper highlights the methodology in measuring interstitial pressure in pancreatic adenocarcinoma tumors. A Millar
Mikrotip pressure catheter (SPR-671) was used in this study and a system was built to amplify and filter the output signal
for data collection. The Millar pressure catheter was calibrated prior to each experiment in a water column at 37°C, range
of 0 to 60 inH2O (112 mmHg), resulting in a calibration factor of 33 mV / 1 inH2O. The interstitial pressures measured in
two orthotopically grown pancreatic adenocarcinoma tumor were 57 mmHg and 48 mmHg, respectively. Verteporfin
uptake into the pancreatic adenocarcinoma tumor was measured using a probe-based experimental dosimeter.