pH-titratable superparamagnetic iron oxide for improved nanoparticle accumulation in acidic tumor microenvironments.
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.
Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Samuel H
SH
Crayton
Andrew
A
Tsourkas
D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry; D003911:Dextrans / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007089:Image Enhancement / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D012983:Soft Tissue Neoplasms / Q000737:chemistry* / Q000473:pathology*
D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; C097921:ferumoxtran-10