Abdullah Mahmud
Nanotechnology Characterization Lab, USA
Title: CCK-B targeted PEG-poly (L-Lysine) polyplex micelle for the effective delivery of gastrin siRNA to the pancreatic cancer
Biography
Biography: Abdullah Mahmud
Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with late detection, rapid progression, high metastasis rate and poor treatment options culminating in the worst 5-year survival of all gastrointestinal malignancies. Two of the major obstacles in treating PDAC are the inefficient delivery of therapeutic agents to the tumor and profound drug resistance that necessitates development of novel delivery and treatment strategies. One such novel approach is the targeted delivery of gene therapies to PDAC. The cholecystokinin-B (CCK-B) receptor and its ligand gastrin are both overexpressed in PDAC, and contribute to PDAC development and proliferation through an autocrine mechanism. We have developed a novel gastrin targeted polyethylene glycol-block-poly (L-Lysine) (PEG-PLL) polyplex (Ga-polyplex), selective for the CCK-B receptor, in order to deliver gastrin siRNA (Figure 1) to PDAC and disrupt proliferation.
Methods: The targeted polyplex micelle (Ga-polyplex) was prepared by complexing gastrin-10 (Ga-10) conjugated PEG-poly (L-lysine) polymer, Ga-PEG-PLL, with gastrin siRNA (Figure1). Ga-polyplex was characterized for hydrodynamic size and stability in serum. The Ga-polyplex was then assessed for targeting ability, gastrin mRNA knockdown, and tumor growth inhibition, both in vitro and in vivo.
Results: The Ga-polyplex micelle formation was confirmed from its monodisperse hydrodynamic size (~44.3 nm). The Ga-polyplex demonstrated 7h serum stability, selective tumor uptake, superior mRNA knockdown and tumor growth inhibition compared to untargeted and scrambles siRNA polyplex both in vitro and in PDAC bearing mice. Furthermore, the targeted gastrin siRNA polyplex micelle prevented metastasis in pancreatic tumor bearing mice.
Conclusion: The CCK-B receptor targeted polyplex micelle was successfully developed, characterized and evaluated for selective delivery of gastrin siRNA to the PDAC. This targeted platform has tremendous potential for oligonucleotide therapeutic delivery to pancreatic cancer.