Proceedings Article | 4 March 2019
KEYWORDS: Tumors, Nanoparticles, Therapeutics, Breast cancer, Solids, Phototherapy, Liver, Magnetic resonance imaging, Veins, Gold
Optically triggered nanoparticles can provide safe and tumor specific thermal or chemical ablation methods for treating solid tumors. Nanoparticles trap in tumors with aberrant and leaky vasculature via enhanced permeation and retention effect. Theranostic nanoparticles (TNPs) which combine cross-sectional imaging with a therapeutics such as photothermal gold nanoconstructs, or photosensitizers allows for non-invasive tracking of nanoparticle transport to tumors and therapy planning for optimal spatio-temporal control of light triggered ablation. However, systemic delivery of TNPs leads to variable and often low tumor uptake, reducing phototherapy efficacy. We propose two strategies for personalizing optically triggered nanoparticle therapies to tumors for improving therapy outcomes. The first approach piggybacks the interventional radiology workflows for chemoembolization of liver cancer and metastasis for image guided local vascular delivery of TNPs and therapeutic light, while the second approach identifies the genetically inherited factors which control the tumor vascular micro-environment and affect nanoparticle delivery and response to photothermal and other therapies. Both approaches are studied with recently developed theranostic nanoparticles (TNPs) based on gold nanorods coated with Gadolinium oxide doped with rare earth elements to produce native X-ray, MRI, and 2nd NIR window (~1500 nm) optical luminescent contrasts and photothermal action upon 808 nm light illumination. While these results are reported in a photothermal therapy (PTT) context, they are valid for nanoparticle mediated photodynamic therapies as well.
NIR (808nm) resonant Au-rods (10 nm dia, 50 nm length) were encapsulated with Gd2O3 shell doped with Yb and Er and terminated with 5000 mw PEG chains to result in 75nm TNPs with -4.8mV zeta potential, dose dependent X-ray and T1-weighted MR contrast. To validate the tumor delivery benefits via interventional radiology methods, Six ~400g immunocompetent Wistar rats were implanted with colorectal liver metastasis (CC-531) tumors. The animals were injected with TNPs (0.5 mL, 1013 NP/mL) either locally into the liver via portal vein and navigating to tumor site or systemically via tail vein. Rats were imaged with T1 MR scans immediately after injection for portal vein group, and at 4, 24, and 72 h for the tail vein group. DynaCT imaging was acquired by injecting 0.5 mL of TNP (3x1014 NP/mL). Uptake of the TPN into the liver vis site-selective vs IV- methods was compared via analysis of cross-sectional MR images. Local delivery resulted in ~3.2 times increase tumor dose. DynaCT images clearly shows the CT enhancement (HU) for both Post-NP and Post-PTT treated rats, as compared to Pre-NP rats. Furthermore, the ex vivo TEM images of CRLM tumor tissue indicated TPN uptake in tumor cells following site-selective delivery, as well as consistency in TNP shape and lack of aggregation, which in turn resulted in superior response to photothermal therapy and tripling of survival duration in a separate group of animals. Thus, patient specific interventional image guided local vascular injections are superior to systemic injections for nanoparticle and therapeutic light delivery to interior organ malignancies such as liver metastasis. [1]
The second personalization strategy investigated the role of inherited factors governing tumor vascular microenvironment in a breast cancer setting. Breast and many other cancers are highly heritable, yet most causative variants are unknown. Of the known risk variants, most are considered tumor cell-autonomous, with far less emphasis placed on testing germline variants that impact the tumor microenvironment, that is expected to play a major role both in tumor cell proliferation but also in chemo or radiotherapy delivery and response. We observed that germline host microenvironment variation in vascular perfusion, and tumor architecture play a critical role in both TNP uptake and response to nanoparticle mediated photothermal ablation of breast cancer. We used our recently developed Consomic Xenograft Model (CXM), which maps TME-specific genetic modifiers to single chromosomes [2, 3]. In CXM, human breast cancer cells are orthotopically implanted into consomic xenograft host strains that differ from the parental xenograft host strain by one substituted chromosome. Because the host backgrounds genetically differ by one chromosome, whereas the tumor cells are unvaried, any observed phenotypic changes are due to TME modifier(s) and can be linked to a single chromosome. Thus, CXM offers for the first time, an experimental platform for mapping the host TME modifiers that potentially impact NP delivery and efficacy in BC. Using the CXM strategy, we recently localized vascular-specific DLL4 function as a heritable host TME modifier of enhanced permeability and retention (EPR). Notably, DLL4 is a master regulator of angiogenic vascular patterning and inhibition of DLL4 attenuates tumor growth and progression by eliciting nonproductive angiogenesis yet the explicit role of DLL4 in EPR and its influence on nanoparticle delivery and efficacy remains untested. Even less understood is the potential impact that inheritance of functionally distinct DLL4 alleles might have on the patient-to-patient variability in response to nanomedicine therapy, which ultimately leads to the failure of NP in clinical trials. Here, we used the triple negative breast cancer MDA-MB-231luc+ orthotopic implanted Consomic models (SSIL2Rg- and SS.BN3IL2Rg-) models to determine the impact of vascular organization on TNP uptake and accumulation in tumor, photothermal response to NIR radiation and treatment efficacy. The bio distribution study with inductive coupled plasma-mass spectroscopy (ICP-MS) and MR imaging with TNPs revealed almost equal distribution of NPs in breast tumors of SSIL2Rg- and SS.BN3IL2Rg- . Interestingly, microscopic examination of distribution of NPs in the tissue sections of tumor revealed that TNPs are more closely arranged on and near the blood vessels in SS.BN3IL2Rg tumors which disrupted tumor vasculature with PTT and subsequent loss of tumor with no recurrence, whereas in SSIL2Rg hosts, photothermal therapy response was transient and tumor relapse was observed in most treated animals. This suggests that pattern of distribution of nanoparticles, governed by inherited vascular factors can lead to dramatic difference in the therapy response for the same tumor, and provides vascular targets for nanoparticle therapies in patients prone to aggressive and therapy resistant tumors. DLL4 targeted TNPs were developed and validated for preferential endothelial targeting in tumor promoting SSIL2Rg- hosts.
1. Parchur, A.K., et al., Vascular Interventional Radiology Guided Photothermal Therapy of Colorectal Cancer Liver Metastasis with Theranostic Gold Nanorods. ACS Nano, 2018.
2. Flister, M.J., et al., Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer. Breast Cancer Res Treat, 2017. 165(1): p. 53-64.
3. Jagtap, J., et al., Methods for detecting host genetic modifiers of tumor vascular function using dynamic near-infrared fluorescence imaging. Biomed Opt Express, 2018. 9(2): p. 543-556.
