Photodynamic Stromal Depletion Enhances Therapeutic Nanoparticle Delivery in 3D Pancreatic Ductal Adenocarcinoma Tumor Models

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human malignancies. PDAC is characterized by dense fibrous stroma which obstructs drug delivery and plays complex tumor-promoting roles. Photodynamic therapy (PDT) is a light-based modality which has been demonstrated to be clinically feasible and effective for tumors of the pancreas. Here, we use in vitro heterocellular 3D co-culture models in conjunction with imaging, bulk rheology and microrheology to investigate photodegradation of non-cellular components of PDAC stroma (photodynamic stromal depletion, PSD). By measuring the rheology of extracellular matrix (ECM) before and after PDT we find that softening of ECM is concomitant with increased transport of nanoparticles (NPs). At the same time, as shown by us previously, photodestruction of stromal fibroblasts leads to enhanced tumor response to PDT. Here we specifically evaluate the capability of PSD to enhance RNA nanomedicine delivery, using a NP carrying an inhibitor of miR-21-5P, a PDAC oncomiR. We confirm improved delivery of this therapeutic NP after PSD by observation of increased expression of PDCD4, a protein target of miR-21-5P. Collectively, these results in 3D tumor models suggest that PSD could be developed to enhance delivery of other cancer therapeutics and improve tumor response to treatment.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with obstructed drug delivery and tumor-promoting fibrous stroma. Photodynamic therapy (PDT) has been shown to be feasible and effective for PDAC. This study investigates the ability of photodynamic stromal depletion (PSD) to enhance RNA nanomedicine delivery, and finds that PSD improves the transport of therapeutic nanoparticles and enhances the tumor response to treatment. These findings suggest that PSD could be developed to enhance the delivery of other cancer therapeutics.