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Heritable modifiers of the tumor microenvironment influence nanoparticle uptake, distribution and response to photothermal therapy. Theranostics 2020;10(12):5368-5383

Date

05/07/2020

Pubmed ID

32373218

Pubmed Central ID

PMC7196309

DOI

10.7150/thno.41171

Scopus ID

2-s2.0-85084328678   11 Citations

Abstract

We report the impact of notch-DLL4-based hereditary vascular heterogeneities on the enhanced permeation and retention (EPR) effect and plasmonic photothermal therapy response in tumors. Methods: We generated two consomic rat strains with differing DLL4 expression on 3rd chromosome. These strains were based on immunocompromised Salt-sensitive or SSIL2Rγ- (DLL4-high) and SS.BN3IL2Rγ- (DLL4-low) rats with 3rd chromosome substituted from Brown Norway rat. We further constructed three novel SS.BN3IL2Rγ- congenic strains by introgressing varying segments of BN chromosome 3 into the parental SSIL2Rγ- strain to localize the role of SSIL2Rγ- DLL4 on tumor EPR effect with precision. We synthesized multimodal theranostic nanoparticles (TNPs) based on Au-nanorods which provide magnetic resonance imaging (MRI), X-ray, and optical contrasts to assess image guided PTT response and quantify host specific therapy response differences in tumors orthotopically xenografted in DLL4-high and -low strains. We tested recovery of therapy sensitivity of PTT resistant strains by employing anti-DLL4 conjugated TNPs in two triple negative breast cancer tumor xenografts. Results: Host strains with high DLL4 allele demonstrated slightly increased tumor nanoparticle uptake but consistently developed photothermal therapy resistance compared to tumors in host strains with low DLL4 allele. Tumor micro-environment with low DLL4 expression altered the geographic distribution of nanoparticles towards closer proximity with vasculature which improved efficacy of PTT in spite of lower overall TNP uptake. Targeting TNPs to tumor endothelium via anti-DLL4 antibody conjugation improved therapy sensitivity in high DLL4 allele hosts for two triple negative human breast cancer xenografts. Conclusions: Inherited DLL4 expression modulates EPR effects in tumors, and molecular targeting of endothelial DLL4 via nanoparticles is an effective personalized nanomedicine strategy.

Author List

Sharma G, Jagtap JM, Parchur AK, Gogineni VR, Ran S, Bergom C, White SB, Flister MJ, Joshi A

Authors

Venkateswara R. Gogineni PhD Assistant Professor in the Radiology department at Medical College of Wisconsin
Amit Joshi PhD Associate Professor in the Biomedical Engineering department at Medical College of Wisconsin
Sarah B. White MD, MS, FSIR, FCIRSE Vice Chair, Professor in the Radiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Breast Neoplasms
Cell Line, Tumor
Female
Humans
Nanomedicine
Nanoparticles
Rats
Tumor Microenvironment