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A wide variety of nanoparticle platforms are being developed for the diagnosis and treatment of malignancy. While many of these are passively targeted or rely on receptor-ligand interactions, metabolically directed nanoparticles provide a complementary approach. It is known that both primary and secondary events in tumorigenesis alter the metabolic profile of developing and metastatic cancers. One highly conserved metabolic phenotype is a state of up-regulated glycolysis and reduced use of oxidative phosphorylation, even when oxygen tension is not limiting. This metabolic shift, termed the Warburg effect, creates a "hostile" tumor microenvironment with increased levels of lactic acid and low extracellular pH. In order to exploit this phenomenon and improve the delivery of nanoparticle platforms to a wide variety of tumors, a pH-responsive iron oxide nanoparticle was designed. Specifically, glycol chitosan (GC), a water-soluble polymer with pH-titratable charge, was conjugated to the surface of superparamagnetic iron oxide nanoparticles (SPIO) to generate a T(2)*-weighted MR contrast agent that responds to alterations in its surrounding pH. Compared to control nanoparticles that lack pH sensitivity, these GC-SPIO nanoparticles demonstrated potent pH-dependent cellular association and MR contrast in vitro. In murine tumor models, GC-SPIO also generated robust T(2)*-weighted contrast, which correlated with increased delivery of the agent to the tumor site, measured quantitatively by inductively coupled plasma mass spectrometry. Importantly, the increased delivery of GC-SPIO nanoparticles cannot be solely attributed to the commonly observed enhanced permeability and retention effect since these nanoparticles have similar physical properties and blood circulation times as control agents.

pH-Titratable Superparamagnetic Iron Oxide for Improved Nanoparticle Accumulation in Acidic Tumor Microenvironments