Theranostic Nanoparticle Uptake in Patient Brain Tumors as Quantified by MP2RAGE T1 Mapping

Abstract

Modern radiation therapy techniques provide effective treatments for solid tumors, but there remain challenges with delivering high doses to elusive tumors without causing toxicity to surrounding normal tissue. Pre-clinical trials have demonstrated the theranostic properties of a recently developed gadolinium-based nanoparticle (Gd-NP). The first in-human clinical trial was conducted to assess the safety and dose tolerance of intravenous Gd-NPs in combination with whole brain radiotherapy and showed favorable results, including a significant correlation between tumor uptake and therapeutic response. The second, double-blinded, in-human clinical trial is underway in the US and aims to evaluate if brain-directed stereotactic radiation in conjunction with NPs will improve local tumor control compared to radiation alone. The current work investigates uptake patterns in brain tumors of 23 patients as quantified by magnetization prepared 2 rapid gradient echo (MP2RAGE) T1 mapping. A phantom containing eight vials of NP-saline solutions at varying concentrations was created to examine the relationship between NP concentration and longitudinal relaxation (T1, in seconds). This relationship is known as relaxivity and is dependent on the contrast agent, field strength and T1 mapping sequence. A 3T MAGNETOM Vida scanner and MP2RAGE sequence were used to image the phantom and MP2RAGE T1 maps were calculated using Bloch equations (QMRLab software). Relaxivity was determined and applied to 23 patient T1 maps (pre- and post- Gd-NP administration) to calculate uptake on an individual tumor basis. Theranostic NP uptake was calculated for every voxel in each of 129 brain metastases and examined for patterns in quantity and distribution. Average individual tumor uptake ranged from 0.02-0.12 mg/ml, where average overall uptake was equal to 0.05 mg/ml. A relationship between tumor diameter and mean NP concentration was observed and best represented by a power-based curve (R2 = 0.92). In contrast, patients with suspected placebo administration appeared to have no uptake and therefore no relationship with tumor diameter. The distribution of NP concentration within the tumor was also examined; on average, linear uptake profiles through tumor centroids (ant-post, left-right) demonstrated roughly gaussian patterns of uptake with lower concentrations at the tumor edges and higher concentrations at the tumor center. This pattern indicates robust tumor penetration and may have implications for amplifying radiation dose to hypoxic tumors. Gd-NP uptake in brain metastases can be quantified using MP2RAGE T1 mapping. Uptake was determined for each voxel in each tumor volume, where a gaussian pattern of spatial concentrations was observed. This analysis procedure will be applied to the full data set, when available, to evaluate the impact of NP uptake (in conjunction with radiation therapy) within individual patients and individual tumors.