Extracellular pH Mapping as Therapeutic Readout of Drug Delivery in Glioblastoma

Abstract

An acidic extracellular space is a hallmark of the tumor microenvironment. Acidosis has been postulated to promote the aggressive and invasive characteristics of tumors and also inhibit the therapeutic response, particularly in the context of novel immunotherapies. Therefore, methods to quantitatively measure the extracellular pH (pH_e) are needed. Here we describe a magnetic resonance spectroscopic imaging (MRSI) technique termed Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which uses the pH-dependent chemical shifts of nonexchangeable protons of lanthanide-based contrast agents to generate quantitative spatial pH_e maps. We assess this method in the context of evaluating the acidic pH_e and therapeutic response in glioblastoma in rodents, where normalization of the pH_e upon therapy can serve as a quantitative readout of successful drug delivery to the tumor.

Keywords: Acidosis; BIRDS; Glioblastoma; Magnetic resonance imaging; Magnetic resonance spectroscopy; Microenvironment; pH.