Heritable modifiers of the tumor microenvironment influence nanoparticle uptake, distribution and response to photothermal therapy

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 3(rd) chromosome. These strains were based on immunocompromised Salt-sensitive or SS(IL2Rγ-) (DLL4-high) and SS.BN3(IL2Rγ-) (DLL4-low) rats with 3rd chromosome substituted from Brown Norway rat. We further constructed three novel SS.BN3(IL2Rγ-) congenic strains by introgressing varying segments of BN chromosome 3 into the parental SS(IL2Rγ-) strain to localize the role of SS(IL2Rγ-) 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.