Targeting the Tumor Core: Hypoxia-Responsive Nanoparticles for the Delivery of Chemotherapy to Pancreatic Tumors

In
pancreatic ductal adenocarcinoma (PDAC), early onset of hypoxia
triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal
transition, increased cell survival, the formation of cancer stem
cells, and drug resistance. Hypoxia in PDAC is also associated with
the development of collagen-rich, fibrous extracellular stroma (desmoplasia),
resulting in severely impaired drug penetration. To overcome these
daunting challenges, we created polymer nanoparticles (polymersomes)
that target and penetrate pancreatic tumors, reach the hypoxic niches,
undergo rapid structural destabilization, and release the encapsulated
drugs. In vitro studies indicated a high cellular uptake of the polymersomes
and increased cytotoxicity of the drugs under hypoxia compared to
unencapsulated drugs. The polymersomes decreased tumor growth by nearly
250% and significantly increased necrosis within the tumors by 60%
in mice compared to untreated controls. We anticipate that these polymer
nanoparticles possess a considerable translational potential for delivering
drugs to solid hypoxic tumors.