Nanoparticle-based thermal, mechanical and electrical treatment alleviating desmoplasia and improving the therapy of deep-seated tumors – JoulMECT

The overall 5-year survival for pancreatic and hepatic cancer patients has not evolved much over the past decades, indicating that current therapeutic approaches are often inefficient. Poor therapeutic outcomes are due to the impenetrability of the tumor mass to drugs. The tumor is protected by a dense extracellular matrix, including the collagen network, which prevents the penetration of medicines into the tumor. As chemotherapy is poorly efficient, the treatments of such fibrotic (desmoplastic) tumors involve two main strategies. The first is resection surgery, in the rare cases when resection is possible. Alternatively, physical treatments are used to ablate the tumor. Yet, when such tumors lie near vital vessels mentioned strategies cannot be applied. Milder ablative strategies, promoting apoptosis, should be deployed. One of this kind is electroporation. This physical technique relies on the local application of short and intense electric pulses to transiently increase the permeabilization of cell membranes, allowing poorly-penetrating or hydrophilic drugs to be efficiently introduced into cancer cells. However, while efficiently used to treat cutaneous or subcutaneous tumors, this method is currently poorly efficient for treatment of inoperable deep-seated tumors. In such tumors, the electrodes are difficult to position due to anatomical barriers, resulting in an inefficient application of the electric field and consecutively an uneven and insufficient cell permeabilization, which can result in inefficient treatment and cancer relapse. Moreover, as fibrotic tumors are rich in extracellular matrix, even if cells are permeabilized, the local stromal barriers in desmoplastic tumors still prevent the diffusion of chemotherapy into the tumor.
An alternative protocol is thus presented in this project, to prime the extracellular matrix and treat solid deep-seated inoperable tumors in situ, from multiple fronts. My strategy comprises multiaxial approaches involving thermal, mechanical and electrical action, mediated by injectable inorganic -gold and iron oxide nanoparticles submitted to pulsed electric field. The thermal action is enabled by the Joule effect that will result in temperature increase in nanoparticles and their immediate vicinity, resulting in a local destructuration of the collagen matrix, which will decrease desmoplasia. As ionically charged inorganic nanoparticles, submitted to pulsed electric field, align with the lines of the electric field and/or are prone to electrophoretic drag, these mechanical actions could improve local drug diffusion, enabling drug penetration throughout the destructured collagen matrix towards the cells. Finally, the inorganic nanoparticles made of conducting or semiconducting materials, could also act as “injectable antennas”, which could amplify the intensity of externally applied electric pulses via the “lighting rod effect”. This could improve the drug delivery by nanoparticle-enhanced electroporation.
The proposed strategy will be tested and optimized in vitro (in 2D and 3D cellular models, including cellular models with a dense self-secreted collagen matrix) and in vivo in murine desmoplastic cancer models, including orthotopic liver and pancreatic tumors. In these models I will study induced structural and functional effects, such as cell viability, cell growth, cell membrane integrity, generation of reactive oxygen species, protein expression, toxicity as well as study morphological alterations of collagen fibers and concomitant effects on tissue stiffness.
Once mastered, this innovative approach could be translated to clinics and could represent a breakthrough in the treatment of inoperable desmoplastic tumors.