Abstract
Background
Pancreatic cancer remains one of the most lethal cancers largely due to the inefficient delivery of therapeutics. Nanomaterials have been extensively investigated as drug delivery platforms, showing improved drug pharmacodynamics and pharmacokinetics. However, their applications in pancreatic cancer have not yet been successful due to limited tumor delivery caused by dense tumor stroma and distorted tumor vasculatures. Meanwhile, smaller-sized nanomaterials have shown improved tumor delivery and retention in various tumors, including pancreatic tumors, suggesting their potential in enhancing drug delivery.
Methods
An ultrafine iron oxide nanoparticle (uIONP) was used to encapsulate 7-ethyl-10-hydroxyl camptothecin (SN38), the water-insoluble active metabolite of chemotherapy drug irinotecan for treating pancreatic cancer in clinic. Insulin-like growth factor 1 (IGF-1) was conjugated to uIONP as a ligand for targeting pancreatic cancer and stromal cells overexpressing IGF-1 receptor (IGF1R). The SN38 loading and release profile were characterized. The cancer cell targeting and induced apoptosis by developed nano-formulationIGF1-uIONP/SN38 were also investigated.
Results
IGF1-uIONP/SN38 demonstrated stable drug loading in physiological pH with the loading efficiency of 68.2 ± 3.5% (SN38/Fe, wt%) and <7% release for 24 hours. In tumor-interstitial- and lysosomal-mimicking pH (6.5 and 5.5), 52.2 and 91.3% of encapsulated SN38 were released over 24 hours. The IGF1-uIONP/SN38 exhibited specific receptor-mediated cell targeting and cytotoxicity to MiaPaCa-2 cells with IC50 of 11.8 ± 2.3 nM, but not to HEK293 human embryonic kidney cells.
Conclusion
The IGF1-uIONP significantly improved the delivery of SN38 to targeted pancreatic cancer cells, holding the potential for in vivo theranostic applications.
IGF-1 Conjugated Sub-5 nm Ultrafine Iron Oxide Nanoparticle Enhances Targeted Drug Delivery and Efficacy of DNA Topoisomerase Inhibitor SN38 for Pancreatic Cancer: An in Vitro Study
