ECM Depletion Is Required to Improve the Intratumoral Uptake of Iron Oxide Nanoparticles in Poorly Perfused Hepatocellular Carcinoma

Yen Ling Yeow; Jiansha Wu; Xiao Wang; Louise Winteringham; Kirk W Feindel; Janina E E Tirnitz-Parker; Peter J Leedman; Ruth Ganss; Juliana Hamzah

doi:10.3389/fonc.2022.837234

ECM Depletion Is Required to Improve the Intratumoral Uptake of Iron Oxide Nanoparticles in Poorly Perfused Hepatocellular Carcinoma

Front Oncol. 2022 Feb 22:12:837234. doi: 10.3389/fonc.2022.837234. eCollection 2022.

Authors

Yen Ling Yeow¹, Jiansha Wu¹, Xiao Wang¹, Louise Winteringham¹, Kirk W Feindel², Janina E E Tirnitz-Parker³, Peter J Leedman¹, Ruth Ganss¹, Juliana Hamzah^{1

3}

Affiliations

¹ Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Nedlands, WA, Australia.
² Centre for Microscopy, Characterisation and Analysis, The University of Western Australia, Nedlands, WA, Australia.
³ Curtin Medical School and Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.

Abstract

Improving tumor access for drug delivery is challenging, particularly in poorly perfused tumors. The availability of functional tumor blood vessels for systemic access is vital to allow drugs or imaging agents to accumulate in the tumor parenchyma. We subjected mice engineered to develop hepatocellular carcinoma (HCC), to treatment with tumor necrosis factor alpha (TNFα) conjugated to a CSG peptide (CSGRRSSKC). CSG binds to the laminin-nidogen-1 complex of the extracellular matrix (ECM) in HCC. When produced as a recombinant fusion protein, the TNFα-CSG functions as an ECM depletion agent via an immune-mediated mechanism to improve tumor perfusion. Tumor perfusion in HCC was dramatically improved after daily intravenous (i.v.) injection of 5 µg TNFα-CSG for five consecutive days. Following treatment, we assessed the tumor accessibility to accumulate an imaging agent, superparamagnetic iron-oxide nanoparticles (IO-NP). Here, we compared the passive delivery of an i.v. dose of IO-NP in HCC following ECM depletion after TNFα-CSG treatment, to the intratumoral accumulation of a comparable dose of CSG-targeted IO-NP in HCC with intact ECM. Magnetic resonance imaging (MRI) T₂-weighted scans and T₂ relaxation times indicate that when the tumor ECM is intact, HCC was resistant to the intratumoral uptake of IO-NP, even when the particles were tagged with CSG peptide. In contrast, pre-treatment with TNFα-CSG resulted in the highest IO-NP accumulation in tumors. These findings suggest poorly perfused HCC may be resistant to molecular-targeted imaging agents including CSG-IO-NP. We demonstrate that specific ECM depletion using TNFα-CSG improves nanoparticle delivery into poorly perfused tumors such as HCC.

Keywords: extracellular matrix; hepatocellular carcinoma; immune cells; magnetic resonance imaging; nanoparticles; peptide targeting; perfusion; tumor necrosis factor.