Abstract
Photoacoustic imaging, which enables high-resolution imaging in deep tissues, has lately attracted considerable attention. For tumor imaging, photoacoustic probes have been proposed to enhance the photoacoustic effect to improve detection sensitivity. Here, we evaluated the feasibility of using a biocompatible hydrophilic polymer, polyoxazoline, conjugated with indocyanine green (ICG) as a tumor-targeted photoacoustic probe via enhanced permeability and retention effect. ICG molecules were multivalently conjugated to partially hydrolyzed polyoxazoline, thereby serving as highly sensitive photoacoustic probes. Interestingly, loading multiple ICG molecules to polyoxazoline significantly enhanced photoacoustic signal intensity under the same ICG concentration. In vivo biodistribution studies using tumor bearing mice demonstrated that 5% hydrolyzed polyoxazoline (50 kDa) conjugated with ICG (ICG/polyoxazoline = 7.8), P14-ICG7.8, showed relatively high tumor accumulation (9.4%ID/g), resulting in delivery of the highest dose of ICG among the probes tested. P14-ICG7.8 enabled clear visualization of the tumor regions by photoacoustic imaging 24 h after administration; the photoacoustic signal increased in proportion with the injected dose. In addition, the signal intensity in blood vessels in the photoacoustic images did not show much change, which was attributed to the high tumor-to-blood ratios of P14-ICG7.8. These results suggest that polyoxazoline-ICG would serve as a robust probe for sensitive photoacoustic tumor imaging.
Highlights
PEG = 1 in our previous study[12])
In order to determine the optimal molecular weight of POZ taken up by the tumor via the EPR effect, a series of POZ molecules conjugated with an ICG molecule were synthesized according to Supplementary Fig. S1A or S1B
Tumor-to-blood (T/B) ratios at 24 h after injection were more than three when the molecular weight of POZ was less than 50 kDa, which was significantly higher than those of PEG conjugated with ICG (PEG-ICG) we have previously examined (T/B ratios; 1.2 and 0.7 at 24 h post-injection for PEG-ICG (20 kDa) and PEG-ICG (40 kDa), respectively)
Summary
PEG = 1 in our previous study[12]) To overcome this problem, we selected polyoxazoline (POZ) as a novel carrier of PA signal emitters. No study has utilized POZ itself as a carrier of diagnostic probes. In this study, the feasibility of using POZ labeled with ICG as a contrast agent for PA tumor imaging via the EPR effect was evaluated. After partial hydrolysis of propionyl groups in POZ, the effect of hydrolysis ratio on tumor uptake was assessed (Fig. 1B). We verified the relationship between the amount of ICG conjugated to POZ and tumor accumulation (Fig. 1C). We evaluated the feasibility of POZ multivalently conjugated with ICG (POZ-ICG) as a tumor-targeted probe for sensitive in vivo PA imaging
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