Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies having an overall 5-year survival rate less than 10%. Abundant fibrotic stroma and poor vascularization are the typical features of PDAC in humans limiting the delivery of chemotherapeutics to the tumor site. Herein, we have proposed to deliver VEGFR kinase inhibitor & HH pathway inhibitor simultaneously through a ZnO-based molecularly targeted and smart drug carrier to deplete tumor stroma, normalize tumor vascularity and show synergism to improve standard pancreatic cancer treatment by modulating tumor microenvironment.
Despite various nanomaterials were developed so far in particular against cancer, very little attention was paid to their potential immunogenicity, to their final destiny at the end of their functions, as well as to the off-target zero-delivery. Thus, there is still a huge disproportion between these nanotherapeutic treatments and the conventional ones proposed to patients (i.e. surgery, chemotherapy, radiotherapy, immunotherapy or their combinations). To address these important challenges and cover the gap between the present nanomedicine tools and the clinical requirements, a phospholipidic coating based on lipids derived from autologous extracellular vesicles (EVs) has been proposed, obtaining highly stable and non-immunogenic theranostic lipid coated ZnO nanocrystals (LZnO-NCs). Targeting is then accomplished by functional peptides, able to direct the drug-loaded nanoconstruct to the right site of action.
Successful delivery of these LZnO-NCs to target site can modulate tumor microenvironment and inhibit proliferation & migration of the tumor and stromal cells. This therapeutic outcome will have a significant impact on the standard treatment of PDAC and other stroma-rich cancers. Moreover, LZnO-NCs doped with transition elements is an increasingly attractive theranostic nanoparticle with the combined capabilities of contrast enhancement in magnetic resonance imaging (MRI) and as a drug carrier for therapeutics.
The main research objective of the present research project is to develop novel theranostic immunocompatible nanoparticles to target pancreatic tumor stroma as well as neoplastic cells, enable intracellular release of drugs and also provide contrast enhancement in MRI scanning for treatment monitoring. Therefore, it is articulated into two parts- i) Design of novel theranostic immunocompatible LZnO-NCs, ii) Evaluation of the therapeutic and imaging (theranostic) capabilities of the nanoconstruct (VEGFR inhibitor and Hh pathway inhibitor loaded doped ZnO-NCs coated with lipid bilayer) by performing various cellular functional assays with or without treatment of standard chemotherapy (Gemcitabine).
