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  • br Anti metastasis e cacy in the MDA MB

    2020-08-07


    3.7. Anti-metastasis efficacy in the MDA-MB-231 back tumor-bearing model
    To compare the anti-metastasis and targeting performances of PMDIs and DINPs, MDA-MB-231 back tumor-bearing nude mice were employed. As shown in Fig. 6A, PMDIs showed 2.5-fold higher accu-mulation within the tumors than did DINPs from 6 h to 48 h, and the fluorescent signals in tumors were highest at 6 h post-injection. The increased tumor accumulation of PMDIs would be attributed to the active targeting ability of PMDIs to CD44 receptor-overexpressed MDA-MB-231 cells. In addition, the distribution of DOX could be used to indicate the level of PMDIs at tumor sites. It was observed that the red fluorescence signal for DOX was stronger for PMDIs relative to DINPs (Fig. 6B), indicating enhanced tumor targeting ability.
    We then explored the photothermal ability of PMDIs. The altera-tions in temperature were recorded using an infrared thermal camera during laser irradiation at 6 h post-injection (Fig. 6C). We observed that the temperatures in tumors of the saline-injected and DINPs-injected mice were only slightly changed when subjected to laser irradiation at similar power densities. The final temperatures reached were lower than 38 °C, which was too low to ablate tumor GSK 3 or adjacent cells (Fig. 6D). By contrast, PMDIs increased the temperature to approxi-mately 45 °C at the tumor site, which was sufficient to inhibit tumor metastasis, due to the ability of PMDIs to accumulate in tumor sites.
    We then explored the in vivo therapeutic efficiency of PMDIs. In vivo chemo-photothermal therapy was performed on MDA-MB-231 back tumor-bearing BALB/c-nu mice after different treatments. We observed that within 20 d, the tumor volumes increased to approxi-mately 921 mm3 and 1106 mm3 from an initial 200 mm3 in mice ad-ministered free DOX and saline, respectively (Fig. 7A and B). For the PMDs group, free ICG + laser group, PMIs + laser group and DOX + ICG group, the tumor volumes were decreased over time from the first 4 d after treatment, and then the tumor growth trend was re-stored and volumes increased to 638 mm3, 498 mm3, 371 mm3 and 305 mm3 during the subsequent 16 d, implying that there was low hy-perpyrexia to ablate the tumor. However, PMDIs plus laser irradiation completely ablated the tumor, and the tumors nearly disappeared after 20 d of treatment, simultaneously displaying good biosafety (Fig. 7E). These results indicated that the strategy used in the experiments was effective and presented no notable side effects.
    To assess the ability of PMDIs to inhibit breast cancer metastasis in vivo, the H&E staining results demonstrated no tumor metastasis in mice administered PMDIs in combination with NIR laser irradiation, relative to the other 6 groups where lung cancer and liver metastases were clearly observed (Fig. 7D). Additionally, as shown in Fig. 7C, the
    Fig. 5. In vivo behavior, PTT efficacy and anti-metastasis treatment in the right hind foot sole of MDA-MB-231-bearing nude mice. (A) In vivo fluorescence imaging of the MDA-MB-231 right hand tumor-bearing nude mice at 20, 40, 60, 90 and 360 min after intratumoral injection with DINPs and PMDIs. (B) In vivo photothermal imaging of lymph node and primary tumor. (C) Images of lymph node at 20 d post-administration Saline, DOX, PMDs, ICG + L, DINPS + L, PMIs + L, DOX + ICG + L, PMDIs + L treatment for 5 times. (D) Quantitative analysis of in vivo photothermal efficacy. (E) Volume of lymph node. (F) Photos of India-ink staining of whole lungs and H&E staining of the lung and liver sections prepared from mice groups after treatments. White arrows indicate the visible metastatic nodules. Yellow and red arrows indicate the lung and liver metastases, respectively. Scale bar: 1 mm. (G) Mice morbidity-free survival results following different treatments (5 mice per group). *p < 0.05, ** p < 0.01 versus the control. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
    mice treated with PMDIs demonstrated a longer survival period within 62 d, as 1 out of 5 mice died. Therefore, PMDIs displayed excellent potential to serve as a chemo/photothermal delivery platform for breast cancer anti-metastasis.
    3.8. Studies on the MDA-MB-231 orthotopic breast tumor-bearing model
    To compare the behavior of PMDIs and DINPs in blood circulation 
    and lymphatic circulation, as well as their tumor targeting capabilities, PMDIs and DINPs were injected through the tail vein into orthotopic MDA-MB-231-luc tumor-bearing nude mice. Four hours after injection, high fluorescence intensity of PMDIs was observed at the tumor site (Fig. 8A), which was sustained at a high level for over 2 h. These results demonstrated a favorable targeting capacity of PMDIs, because PMDIs specifically bind to the CD44 receptors overexpressed on MDA-MB-231 cell surfaces. Moreover, the fluorescence intensity continued to