Targeted Co-delivery of the Iron Chelator Deferoxamine and a HIF1α Inhibitor Impairs Pancreatic Tumor Growth.

Abstract

Rapidly growing cancer cells exhibit a strong dependence on iron for their survival. Thus, iron-removing drugs, iron chelators, have potential applications in cancer treatment. Deferoxamine (DFO) is an efficient iron chelator, but its short circulation half-life and ability to induce hypoxia-inducible factor 1α (HIF1α) overexpression restricts its use as an antitumor agent. In the present study, we first found that a pattern of iron-related protein expression favoring higher intracellular iron closely correlates with shorter overall and relapse-free survival in pancreatic cancer patients. We subsequently found that a combination of DFO and the HIF1α inhibitor, lificiguat (also named YC1), significantly enhanced the antitumor efficacy of DFO in vitro. We then employed transferrin receptor 1 (TFR1) targeting liposomes to codeliver DFO and YC1 to pancreatic tumors in a mouse model. The encapsulation of DFO prolonged its circulation time, improved its accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect, and facilitated efficient uptake by cancer cells, which express high level of TFR1. After entering the tumor cells, the encapsulated DFO and YC1 were released to elicit a synergistic antitumor effect in subcutaneous and orthotopic pancreatic cancer xenografts. In summary, our work overcame two major obstacles in DFO-based cancer treatment through a simple liposome-based drug delivery system. This nanoencapsulation and targeting paradigm lays the foundation for future application of iron chelation in cancer therapy.

• Authors: Jiayan Lang, Xiao Zhao, Xiuchao Wang, Ying Zhao, Yiye Li, Ruifang Zhao, Keman Cheng, Yao Li, Xuexiang Han, Xiaowei Zheng, Hao Qin, Marzieh Geranpayehvaghei, Jian Shi, Gregory J Anderson, Jihui Hao, He Ren, Guangjun Nie
• Journal: ACS nano (ACS Nano) Vol. 13 Issue 2 Pg. 2176-2189 (02 26 2019) ISSN: 1936-086X [Electronic] United States
• PMID: 30676731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Iron Chelating Agents
• Deferoxamine

Topics

• Administration, Oral
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Deferoxamine (administration & dosage, chemistry, pharmacology)
• Drug Delivery Systems
• Drug Screening Assays, Antitumor
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Iron Chelating Agents (administration & dosage, chemistry, pharmacology)
• Nanoparticles (administration & dosage, chemistry)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)