Room: Karl Dean Ballroom B1
Purpose: Although extensive biological experiments have validated metallic nanoparticles (NPs) as a powerful radiosensitizer, studies have also shown NP delivery through passive enhanced permeability and retention effect is not sufficiently tumor specific and suffers from rapid clearance in vivo. On the imaging side, issues related to the determination of in vivo NP biodistribution for quantitative radiation therapy treatment planning and optimal irradiation timing, and preselecting suitable patients for NP enhancement remain unresolved. To address these difficulties, we developed novel tumor-targeting theranostic gadolinium (Gd) NPs for simultaneous cancer and NP distribution imaging and radiation enhancement.
Methods: We conjugated untargeted conventional GdNPs to pH-Low Insertion Peptides (pHLIPs). pHLIPs actively target solid tumorsâ€™ unavoidable acidic microenvironment, superior to antibody tumor-targeting which often leads to drug-resistant recurrence due to clonal selection against biomarker expression. MR imaging of pHLIP-GdNPs has the potential to pre-screen patients with more acidic (generally more aggressive) tumors, who will likely benefit more from NP radiation enhancement. Another unique advantage of pHLIP is that, in acidic environment, it actively transports cell-impermeable GdNPs across the cell membrane. Because of the very short ranges of radiosensitizing photoelectrons and Auger electrons, delivering NPs into cancer cells is critical for enhancing DNA-damage.
Results: In contrast to conventional GdNPs, MR imaging of tumor-bearing mice showed pHLIP-GdNPs had long retention in tumor (>9 hr) and penetrated into the poorly-vascularized tumor core. The contrast-enhanced regions coincide with the independently measured low tumoral pH. At 0.5 mM Gd incubation concentration in cultured A549 human lung cancer cells, compared to conventional GdNPs, mass spectrometry measured 78-fold more cellular Gd uptake with pHLIP-GdNPs, and clonogenic survival assays showed 44% more radiosensitivity by 5 Gy irradiation with pHLIP-GdNPs at pH6.2.
Conclusion: pHLIP-GdNPs showed great potential to help advance image-guided metallic radiosensitization to the clinic by overcoming several key imaging and therapeutic obstacles.