Extracellular acidosis (i.e., low pHe) is a tumor microenvironment hallmark, caused by atypical metabolism and perfusion. Acidic pHe enhances cancer growth, proliferation, and builds therapy resistance. The prognosis remains dismal for most brain tumor patients. Malignant gliomas, including glioblastoma multiforme (GBM), fail treatments because gliomas invade outside tumor boundaries conventionally demarked by MRI contrast and the blood-brain barrier (BBB) blocks most drugs. Furthermore conventional MRI methods are insensitive to physicochemical parameters like pHe and mainly track intratumoral volume. Among the primary MRI methods are paramagnetic agents for longitudinal (T1) contrast, where assessment of treatment response involves 2D or 3D measurement with Gd3+ enhanced MRI contrast. However, such methods are not reliable in distinguishing pseudoprogression and pseudoresponse from actual changes in tumor status. Thus there is an urgent need for alternative MR techniques sensitive to metabolic changes, which can aid in effective monitoring of therapeutic response in addition to measuring the tumor size. Because acidic pHe milieu is conducive to tumor growth and builds resistance to therapies, simultaneous mapping of pHe inside and outside the tumor (i.e., intratumoral-peritumoral pHe gradient) is an important cancer imaging need. A novel way to map intratumoral-peritumoral pHe gradient is using lanthanide III (Ln3+) agents with BIRDS methods, where physicochemical factors like pHe contribute to shifts of non-exchangeable protons. To meet the need for MR readouts of the tumor physicochemical state, we developed BIRDS to map the intratumoral-peritumoral pHe gradient, and found that it is a sensitive readout of cancer growth and treatment. Based on preliminary data obtained from GBM models (e.g., U251), including patient-derived xenograft (PDX) models, we will validate high-resolution pHe mapping with BIRDS as therapeutic readout of chemotherapy drugs delivered into human GBM models. Although we detected 1-2 mm diameter tumors with BIRDS using non-methylated agents, higher resolution mapping of intratumoral-peritumoral pHe gradients will be reached with a novel methylated multiplexed agent in Aim 1.
In Aim 2 we will validate intratumoral-peritumoral pHe gradient mapping by BIRDS with fluorescent pHe probes. We will use BIRDS to examine how intratumoral-peritumoral pHe gradients change with tumor aggression (Aim 3). We will also test compatibility of pHe mapping with BIRDS for tracking response to chemotherapy drugs (e.g., Temozolomide and Sorafenib) being used to treat GBMs (Aim 4). Both of these drugs are known to cross the BBB and are used in GMB therapy. Temozolomide activates apoptosis by alkylating DNA to stall cell replication and Sorafenib is a multiple kinase inhibitor targeting several oncogenic pathways and enhances glycolysis. If successful, pHe mapping by BIRDS will enable monitoring of therapeutic response of various chemotherapy drugs for preclincal PDX models to potentially be translated clinically.

Public Health Relevance

Because acidic extracellular pH (pHe) milieu is conducive to tumor growth and builds resistance to tumor therapies, mapping pHe inside and outside glioblastoma multiforme (GBM) is an important cancer imaging need. We will develop and validate a high-resolution pHe mapping method called BIRDS to obtain readout of chemotherapy drug treatment (e.g., Temozolomide and Sorafenib) into human GBM models. If successful, pHe mapping by BIRDS will enable monitoring therapeutic response of drug delivery to human GBMs in addition to measuring the tumor size.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Liu, Guoying
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Rao, Jyotsna U; Coman, Daniel; Walsh, John J et al. (2017) Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH. Sci Rep 7:7865
Hyder, Fahmeed; Manjura Hoque, S (2017) Brain Tumor Diagnostics and Therapeutics with Superparamagnetic Ferrite Nanoparticles. Contrast Media Mol Imaging 2017:6387217