Imaging of any tumor type by pH-triggered fluorescence activation using nanoparticles
Current approaches to detection of tumors by imaging are generally tumor type or subtype-specific, so their applicability is limited. Towards the goal of an imaging agent capable of detecting any tumor, numerous research groups have created imaging agents whose signal is activated by the pH characteristic of the tumor extracellular space (6.5-6.8, slightly lower than the normal 7.4). This decreased pH is observed in all tumors as a result of numerous mechanisms, including hypoxia and enhanced H+ efflux by tumor cells. However, previous pH-responsive imaging agents haven’t been promising because their signal gradually increases at decreasing pH, the difference between “on” and “off” states is only a few fold, or they become
activated over many hours, all of which would blur the distinction between normal and tumor tissue.
Jinming Gao’s group at UT Southwestern recently reported a system that overcomes all of these issues, displaying a 300-fold greater fluorescent signal within tumors than in the circulation. This impressive degree of tumor specificity results from a sharp pH response and tumor targeting using a peptide that recognizes newly formed blood vessels, another universal feature of tumors. Though the agent’s overall design, a micelle encapsulating hundreds of dye molecules so that their fluorescence is quenched by energy transfer among them, is not new, the huge difference in signal between the “off” and “on” states is a major advance that results from careful engineering. The agent by its creators, responds to slight changes in pH (<0.25 pH units) with huge changes in fluorescent signal because the material (a block copolymer) composing the micelle ionizes at a specific pH, completely disrupting the structure to release all of the dye molecules within. The ionizable micelle design had been previously reported by the same group; this study tuned pH responsiveness for tumor detection and incorporated the targeting peptide to allow greater accumulation within tumors through cellular uptake.
Most importantly, lead author Yiguang Wang and his team demonstrate the applicability of this approach to numerous tumor types in mice, including a transgenic model of breast cancer and orthotopic (consisting of injected human cancer cells) lung, head and neck, prostate tumors. In all of these cases, the fluorescent signal is clearly restricted to tumors.
These ultra pH-sensitive nanoprobes are an exciting development in the area of smart biomedical imaging materials, and could become a tool to resolve tumor borders during resection. However, tools for that purpose already exist, including the cell-penetrating protease-cleavable peptides developed by Roger Tsien’s group, so the clinical relevance of pH-sensitive nanoprobes depends upon whether they offer brighter signal or allow imaging of a wider variety of tumors than existing technologies. If it could be modified to silence and activate paramagnetic metal particles or ions to enable tumor-specific MRI, this design could one day be relevant to cancer diagnosis and treatment monitoring.