Effective new therapies for pancreatic ductal adenocarcinoma (PDAC) are desperately needed as the prognosis of PDAC patients is dismal and treatment remains a major challenge. Gemcitabine (GEM) is commonly used to treat PDAC; however, the clinical use of GEM has been greatly compromised by its low delivery efficacy and drug resistance. Here, we describe a very simple yet cost-effective approach that synergistically combines drug reconstitution, supramolecular nanoassembly, and tumor-specific targeting to address the multiple challenges posed by the delivery of the chemotherapeutic drug GEM. Using our developed PUFAylation technology, the GEM prodrug was able to spontaneously self-assemble into colloidal stable nanoparticles with sub-100 nm size on covalent attachment of hydrophobic linoleic acid via amide linkage. The prodrug nanoassemblies could be further refined by PEGylation and PDAC-specific peptide ligand for preclinical studies. In vitro cell-based assays showed that not only were GEM nanoparticles superior to free GEM but also the decoration with PDAC-homing peptide facilitated the intracellular uptake of nanoparticles and thereby augmented the cytotoxic activity. In two separate xenograft models of human PDAC, one of which was a patient-derived xenograft model, the administration of targeted nanoparticles resulted in marked inhibition of tumor progression as well as alleviated systemic toxicity. Together, these data unequivocally confirm that the hydrophilic and rapidly metabolized drug GEM can be feasibly transformed into a pharmacologically efficient nanomedicine through exploiting the PUFAylation technology. This strategy could also potentially be applied to rescue many other therapeutics that show unfavorable outcomes in the preclinical studies because of pharmacologic obstacles.
Keywords: gemcitabine; pancreatic ductal adenocarcinoma; prodrug; self-assembly; targeted delivery.