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Polyoxazoline multivalently conjugated with indocyanine green for sensitive in vivo photoacoustic imaging of tumors

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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.

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Influence of POZ hydrolysis ratios and numbers of ICG molecules on in vivo biodistribution.(A) In vivo fluorescence imaging of tumor-bearing mice administered with POZ-ICG (25 kDa) (left to right; P8-ICG1.5, P9-ICG0.6, P10-ICG0.6, P11-ICG0.7, and P12-ICG1.9, as shown in Table 2). (B) In vivo fluorescence imaging of tumor-bearing mice administered with POZ-ICG (50 kDa) (left to right; P13-ICG1.7, P14-ICG0.5, P15-ICG1.0, P16-ICG1.1 and P17-ICG1.9, as shown in Table 2). Dotted circles indicated tumor regions. Scale bar units: photons/sec/cm2/steradian. (C) Tumor accumulation of POZ-ICG (%ID/g) (Blue; 25 kDa, Red; 50 kDa). (D) Tumor accumulation of POZ-ICG with molecular weight of 25 kDa (blue) and 50 kDa (red). Circles, squares, and triangles indicate hydrolysis ratios of 2.5, 5, and 10%, respectively. (E) In vivo fluorescence images of tumor bearing mice at 24 h (upper) and 1 h (lower) after administration of POZ-ICG. Left to right; P14-ICG1.9, P14-ICG4.7, P14-ICG7.8, P14-ICG10.3, and P10-ICG8.6. Dotted circles and white arrows indicate the tumor and liver regions, respectively. (F) Fluorescence intensity of liver and kidneys isolated from the mice at 24 h after administration of POZ-ICG (*P < 0.05).
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f3: Influence of POZ hydrolysis ratios and numbers of ICG molecules on in vivo biodistribution.(A) In vivo fluorescence imaging of tumor-bearing mice administered with POZ-ICG (25 kDa) (left to right; P8-ICG1.5, P9-ICG0.6, P10-ICG0.6, P11-ICG0.7, and P12-ICG1.9, as shown in Table 2). (B) In vivo fluorescence imaging of tumor-bearing mice administered with POZ-ICG (50 kDa) (left to right; P13-ICG1.7, P14-ICG0.5, P15-ICG1.0, P16-ICG1.1 and P17-ICG1.9, as shown in Table 2). Dotted circles indicated tumor regions. Scale bar units: photons/sec/cm2/steradian. (C) Tumor accumulation of POZ-ICG (%ID/g) (Blue; 25 kDa, Red; 50 kDa). (D) Tumor accumulation of POZ-ICG with molecular weight of 25 kDa (blue) and 50 kDa (red). Circles, squares, and triangles indicate hydrolysis ratios of 2.5, 5, and 10%, respectively. (E) In vivo fluorescence images of tumor bearing mice at 24 h (upper) and 1 h (lower) after administration of POZ-ICG. Left to right; P14-ICG1.9, P14-ICG4.7, P14-ICG7.8, P14-ICG10.3, and P10-ICG8.6. Dotted circles and white arrows indicate the tumor and liver regions, respectively. (F) Fluorescence intensity of liver and kidneys isolated from the mice at 24 h after administration of POZ-ICG (*P < 0.05).

Mentions: Prior to conjugation of multiple ICG molecules into POZ, we evaluated the influence of POZ hydrolysis ratios (percentage of secondary amino groups per POZ polymer) on in vivo biodistribution. The accumulation of the POZ series labeled with ICG (ICG/POZ = 0.5–1.9) (Table 2) in the tumor was investigated using colon 26 tumor-bearing mice. Independent of molecular weights of POZ (25 and 50 kDa), the tumor uptake was reduced as the hydrolysis ratios were increased (Fig. 3A–C). Moreover, increase in hydrolysis ratios was accompanied by rapid clearance of POZ from the blood, and the half-life of POZ in the blood was correlated with electrical conductivity, as shown in Table 2.


Polyoxazoline multivalently conjugated with indocyanine green for sensitive in vivo photoacoustic imaging of tumors
Influence of POZ hydrolysis ratios and numbers of ICG molecules on in vivo biodistribution.(A) In vivo fluorescence imaging of tumor-bearing mice administered with POZ-ICG (25 kDa) (left to right; P8-ICG1.5, P9-ICG0.6, P10-ICG0.6, P11-ICG0.7, and P12-ICG1.9, as shown in Table 2). (B) In vivo fluorescence imaging of tumor-bearing mice administered with POZ-ICG (50 kDa) (left to right; P13-ICG1.7, P14-ICG0.5, P15-ICG1.0, P16-ICG1.1 and P17-ICG1.9, as shown in Table 2). Dotted circles indicated tumor regions. Scale bar units: photons/sec/cm2/steradian. (C) Tumor accumulation of POZ-ICG (%ID/g) (Blue; 25 kDa, Red; 50 kDa). (D) Tumor accumulation of POZ-ICG with molecular weight of 25 kDa (blue) and 50 kDa (red). Circles, squares, and triangles indicate hydrolysis ratios of 2.5, 5, and 10%, respectively. (E) In vivo fluorescence images of tumor bearing mice at 24 h (upper) and 1 h (lower) after administration of POZ-ICG. Left to right; P14-ICG1.9, P14-ICG4.7, P14-ICG7.8, P14-ICG10.3, and P10-ICG8.6. Dotted circles and white arrows indicate the tumor and liver regions, respectively. (F) Fluorescence intensity of liver and kidneys isolated from the mice at 24 h after administration of POZ-ICG (*P < 0.05).
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f3: Influence of POZ hydrolysis ratios and numbers of ICG molecules on in vivo biodistribution.(A) In vivo fluorescence imaging of tumor-bearing mice administered with POZ-ICG (25 kDa) (left to right; P8-ICG1.5, P9-ICG0.6, P10-ICG0.6, P11-ICG0.7, and P12-ICG1.9, as shown in Table 2). (B) In vivo fluorescence imaging of tumor-bearing mice administered with POZ-ICG (50 kDa) (left to right; P13-ICG1.7, P14-ICG0.5, P15-ICG1.0, P16-ICG1.1 and P17-ICG1.9, as shown in Table 2). Dotted circles indicated tumor regions. Scale bar units: photons/sec/cm2/steradian. (C) Tumor accumulation of POZ-ICG (%ID/g) (Blue; 25 kDa, Red; 50 kDa). (D) Tumor accumulation of POZ-ICG with molecular weight of 25 kDa (blue) and 50 kDa (red). Circles, squares, and triangles indicate hydrolysis ratios of 2.5, 5, and 10%, respectively. (E) In vivo fluorescence images of tumor bearing mice at 24 h (upper) and 1 h (lower) after administration of POZ-ICG. Left to right; P14-ICG1.9, P14-ICG4.7, P14-ICG7.8, P14-ICG10.3, and P10-ICG8.6. Dotted circles and white arrows indicate the tumor and liver regions, respectively. (F) Fluorescence intensity of liver and kidneys isolated from the mice at 24 h after administration of POZ-ICG (*P < 0.05).
Mentions: Prior to conjugation of multiple ICG molecules into POZ, we evaluated the influence of POZ hydrolysis ratios (percentage of secondary amino groups per POZ polymer) on in vivo biodistribution. The accumulation of the POZ series labeled with ICG (ICG/POZ = 0.5–1.9) (Table 2) in the tumor was investigated using colon 26 tumor-bearing mice. Independent of molecular weights of POZ (25 and 50 kDa), the tumor uptake was reduced as the hydrolysis ratios were increased (Fig. 3A–C). Moreover, increase in hydrolysis ratios was accompanied by rapid clearance of POZ from the blood, and the half-life of POZ in the blood was correlated with electrical conductivity, as shown in Table 2.

View Article: PubMed Central - PubMed

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&thinsp;kDa) conjugated with ICG (ICG/polyoxazoline&thinsp;=&thinsp;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&thinsp;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.

No MeSH data available.


Related in: MedlinePlus