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, 8 (16), 27177-27188

Simultaneous Sentinel Lymph Node Computed Tomography and Locoregional Chemotherapy for Lymph Node Metastasis in Rabbit Using an Iodine-Docetaxel Emulsion

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Simultaneous Sentinel Lymph Node Computed Tomography and Locoregional Chemotherapy for Lymph Node Metastasis in Rabbit Using an Iodine-Docetaxel Emulsion

Honsoul Kim et al. Oncotarget.

Abstract

Purpose: A sentinel lymph node (SLN) tracer can gain multi-functionality by combining it with additional components. We developed a SLN tracer consisting of iodine and docetaxel and applied it as a theragnostic nanoparticle to simultaneously perform SLN computed tomography (CT) lymphography and locoregional chemotherapy of the draining lymphatic system.

Results: Docetaxel could be loaded in iodine emulsions at a drug-to-surfactant weight ratio as high as that in the drug formulation Taxotere®. The particle size and drug concentration were stable during storage for up to 3 months in optimized nanoemulsions. Popliteal LN enhancement on CT was observed in all healthy rabbits (n=3) and VX2 tumor-implanted rabbits (n=6) 12 hours after injection. The rate of SLN metastasis was significantly lower in the treatment group (29.4%, 5/17) than in the non-treatment group (70.6%, 12/17) (P=0.038).

Material and methods: We prepared a nanoemulsion carrying both iodine and docetaxel in a single structure by optimizing the composition of surfactants surrounding the inner iodized oil core. CT was performed 12 hours after subcutaneous injection of the emulsion in healthy rabbits (n=3) and VX2 tumor-implanted rabbits (n=6) for SLN imaging. Next, we tested the effect of treatment by histopathologically assessing the popliteal LN metastasis rate in VX2 tumor-implanted rabbits 7 days after subcutaneous injection of the emulsion (treatment group, n=17) and comparing it with that of non-treatment group rabbits (n=17).

Conclusions: We developed an iodine-docetaxel emulsion and demonstrated that it can be applied to simultaneously achieve CT SLN imaging and local chemotherapy against nodal metastasis.

Keywords: computed tomography (CT); iodine-docetaxel emulsion; locoregional chemotherapy; lymph node metastasis; sentinel lymph node.

Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no potential conflicts of interest.

Figures

Figure 1
Figure 1
Emulsion stability assessed by changes in (A) loaded docetaxel concentration and (B) mean particle size of emulsions. The loaded docetaxel concentration of emulsions stored at 4°C was determined by HPLC analysis and change in droplet size was measured using a dynamic light scattering method. Data are presented as mean ± S.D. (n=3). (C) Representative TEM image of an iodine-docetaxel emulsion obtained with an 87:13 mixture of Tween 80:Span 85.
Figure 2
Figure 2. CT lymphography after subcutaneous injection of an iodine-docetaxel emulsion for sentinel lymph node (SLN) imaging in rabbit models
Lower extremity CT of a (A) healthy control rabbit performed 12 hours after iodine-docetaxel emulsion injection. Multiphasic CT lymphography images of a VX2 tumor-implanted rabbit model obtained (B) before, (C) 12 hours after, and (D) 7 days after iodine-docetaxel emulsion injection. Focal intra-nodal contrast enhancement (arrow) within the popliteal LN (arrowheads) caused by the subcutaneously injected iodine-docetaxel emulsion (small arrows) was observed. Magnified images of the ipsilateral popliteal images showing focal uptake of iodine-docetaxel emulsion (Inset) are provided.
Figure 3
Figure 3. CT volumetry of the popliteal LNs of VX2-implanted rabbits performed before (pre-treatment CT) and 7 days after (post-treatment CT) injection
The rabbits were divided into the treatment group (n=17), which received subcutaneous injection of the iodine-docetaxel emulsion, or the non-treatment (control) group (n=17).
Figure 4
Figure 4. A non-treatment (control) group VX2-implanted rabbit
Images obtained during (A) the pre-treatment CT session (10 days after tumor implantation) and (B) the post-treatment CT session (17 days after tumor implantation). The popliteal LN (arrowhead) ipsilateral to the implanted tumor increased in size from 0.4 to 0.9 cm3. (C) Gross image of the dissected popliteal LNs at the ipsilateral (arrow) and contralateral (arrowheads) side of the tumor. Microscopic images of (D) hematoxylin and eosin staining (40×) and (E) anti-cytokeratin (AE1+AE3 antibody) immunohistochemistry staining (40×) of the ipsilateral popliteal LN demonstrated tumor metastasis (arrows).
Figure 5
Figure 5. A treatment group VX2-implanted rabbit
Images obtained during (A) the pre-treatment CT (10 days after tumor implantation) and (B) the post-treatment CT (17 days after tumor implantation, 7 days after iodine-docetaxel emulsion injection). The popliteal LN (arrowheads) ipsilateral to the implanted tumor increased in size from 0.3 to 0.6 cm3, and focal intra-nodal contrast enhancement (arrow) by uptake of the injected iodine-docetaxel emulsion (small arrows) was observed. Magnified image of the ipsilateral popliteal images showing focal uptake of iodine-docetaxel emulsion (Inset) is provided. (C) Gross image of the dissected popliteal LNs at the ipsilateral (arrow) and contralateral (arrowhead) side of the tumor. Microscopic images of (D) hematoxylin and eosin staining (40×) and (E) anti-cytokeratin (AE1+AE3 antibody) immunohistochemistry staining (40×) of the ipsilateral popliteal LN revealed no evidence of tumor metastasis.
Figure 6
Figure 6. The rate of popliteal LN metastasis in VX2 tumor-implanted rabbits as detected by microscopic examination 17 days after tumor implantation (or 7 days after iodine-docetaxel emulsion injection in the treatment group)
The rate of popliteal LN metastasis was 29.4% (n=5/17) in the treatment group versus 70.6% (n=12/17) in the non-treatment group, indicating that LN metastasis occurred less frequently in the treatment group (*P=0.038).

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