Emory University — Stroma Breaking Theranostic Nanoparticles for Targeted Pancreatic Cancer Therapy
Principal Investigators: Lily Yang, M.D., Ph.D., and Hui Mao, Ph.D.
Co-Investigators: Charles Staley, M.D., David Kooby, M.D., Bassel El-Rayes, M.D., Malgorzata Lipowska, Ph.D., Liya Wang, M.D., and Andrew Wang, Ph.D. (Ocean Nanotech, LLD)
The goal of this project is to develop a dual targeted and stroma breaking theranostic nanoparticle platform to address an unmet, clinical challenge of poor drug delivery efficiency in the application of nanomedicine to cancer therapy. Many types of human cancers, particularly pancreatic cancer, present a dense fibrotic tumor stroma that creates physical barriers against conventional drug delivery approaches. Building upon our understanding of pancreatic cancer biology and expertise in developing theranostic nanoparticles, we are developing a stroma breaking drug delivery system using a new generation of 3-nm ultra-fine magnetic iron oxide nanoparticle (uIONP) coated with an anti-fouling 'stealth' polymer for enhanced tumor penetration and retention, high capacity drug loading, and T1/T2-switchable MRI contrasts for imaging drug delivery. A dual targeting strategy coupling ligands targeting urokinase plasminogen activator receptor (uPAR) and insulin-like growth factor 1 receptor (IGF1R) onto a single nanoparticle is used to maximize both tumor stromal and pancreatic cancer cell targeting, and drug delivery. Additionally, the use of a recombinant MMP14 protease active uPAR targeting ligand should break the extracellular matrix barrier. uIONPs will carry cisplatin and / or SN38, a potent camptothecin analogue, for effective treatment of drug resistant pancreatic cancer cells.
The combination of these unique properties should enable the theranostic uIONPs to break tumor stromal barriers and disrupt the tumor microenvironment leading to improved cancer molecular targeting and drug delivery in treating pancreatic cancer. The efficiency of targeted delivery and intratumoral distribution of the uIONP and therapeutic efficacy will be investigated in orthotopic human pancreatic cancer patient tissue-derived xenograft (PDX) and transgenic mouse pancreatic tumor models using MR and optical imaging, multiphoton microscopy, and histological and chemical analyses. This new generation of theranostic IONPs and our strategy to overcome drug delivery barriers will change the paradigm of future development and translation of image-guided and targeted therapies for the treatment of advanced pancreatic cancer as well as cancer nanotechnology in general.
The team has expertise in targeted cancer therapy, theranostic nanoparticles, image-guided cancer treatment, and animal tumor models as well as extensive experience in the development of magnetic nanoparticles as MRI contrasts / drug carriers and MRI methodology.