Engineered exosome mimetics as targeted biological nanomedicines for pancreatic cancer

Project Summary/Abstract Pancreatic cancer (PC) is one of the most lethal forms of cancer in the United States (5-year survival rate below 10%). PC patients are usually diagnosed with a non-resectable disease (80-85%) and have a dismal prognosis with a survival period of only 3-6 months after the diagnosis. Nucleoside analogs (e.g., gemcitabine

and fluorouracil) and platinum-based antineoplastics (e.g., oxaliplatin) are commonly used as chemotherapy for PC. When administered as free drugs, gemcitabine (Gem), fluorouracil (5-FU) and oxaliplatin (Oxa) display significant off-target toxicity causing life-threatening adverse effects in many patients. There is an urgent need

to develop new therapeutic strategies consisting of delivery vehicles able to target PC cells, limit Gem, 5-FU and Oxa off-target toxicity and improve the overall anticancer response. We have recently patented a platform that uses an unbiased and quantitative screening algorithm for the discovery and validation of cancer-specific surface antigens. Our recently published results show that

Intercellular Adhesion Molecule 1 (ICAM1), a transmembrane glycoprotein of the immunoglobulin superfamily, is aberrantly overexpressed in PC and can serve as a PC-specific target. Our results suggest that developing a novel ICAM1-based precision nanomedicine can be successfully utilized to treat PC patients.

We have recently developed a magnetic extrusion technique to synthesize endosome-derived vesicles called exosome mimetics (EMs) in a highly efficient and reproducible manner. Our EMs share the same biological origin, morphology, nanosize and composition with exosomes, a class of natural cell-secreted

extracellular vesicles. Our EM synthesis outperforms conventionally used exosome isolation and loading protocols in terms of particle yield, batch-to-batch consistency, reproducibility and loading efficiency. In this proposal,we leverage our expertise in cancer-specific antigen discovery and validation, bio-

nanomaterial engineering, and exosome biology to test the novel hypothesis that EMs expressing ICAM1 nanobody and loaded with Gem, 5-FU and Oxa can be used as a novel delivery vehicle for PC therapy. We will synthesize EMs engineered with ICAM1 nanobodies that recognize and kill ICAM1-expressing PC cells

and load them with Gem, 5-FU and Oxa. ICAM1-EM will exhibit increased tumor specificity and reduce Gem, 5FU and Oxa off-target delivery and toxicity. These innovative studies have the potential to lead to the development of novel EM-based therapies that can improve the efficacy of current cancer drug delivery.

With key experimental tools, in vivo models and extensive experience in place, we will address the following Specific Aims: 1. To engineer ICAM1-targeted exosome mimetics (ICAM1-EMs) using magnetic extrusion method 2. To determine the efficacy of loaded ICAM1-Chemo-EMs in inhibiting PC growth and progression

3. To determine the pharmacokinetics (PK) and biodistribution of loaded ICAM1-Chemo-EMs