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Advanced Science Volume 5 ,Issue 12 ,2018-10-29
Deep Tumor‐Penetrated Nanocages Improve Accessibility to Cancer Stem Cells for Photothermal‐Chemotherapy of Breast Cancer Metastasis
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Tao Tan 1 , 2 Hong Wang 1 Haiqiang Cao 1 Lijuan Zeng 2 Yuqi Wang 1 , 2 Zhiwan Wang 1 Jing Wang 1 Jie Li 1 Siling Wang 2 Zhiwen Zhang 1 Yaping Li 1
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DOI:10.1002/advs.201801012
Received 2018-06-29,
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摘要

Abstract Cancer stem cells (CSCs) are proposed to account for the initiation of cancer metastasis, but their accessibility remains a great challenge. This study reports deep tumor‐penetrated biomimetic nanocages to augment the accessibility to CSCs fractions in tumor for anti‐metastasis therapy. The nanocages can load photothermal agent of 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DBN) and chemotherapeutic epirubicin (EBN) to eradicate CSCs for photothermal‐chemotherapy of breast cancer metastasis. In metastatic 4T1‐indcued tumor model, both DBN and EBN can efficiently accumulate in tumor sites and feasibly permeate throughout the tumor mass. These biomimetic nanosystems can be preferentially internalized by cancer cells and effectively accessed to CSCs fractions in tumor. The DBN+laser/EBN treatment produces considerable depression of primary tumor growth, drastically eradicates around 80% of CSCs fractions in primary tumor, and results in 95.2% inhibition of lung metastasis. Thus, the biomimetic nanocages can be a promising delivery nanovehicle with preferential CSCs‐accessibility for effective anti‐metastasis therapy.

关键词

nanocages;drug delivery;deep tumor penetration;cancer stem cells;cancer metastasis

授权许可

© 2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

图表

Schematic illustration of deep tumor penetrated biomimetic nanocages with preferential CSCs‐accessibility for effective anti‐metastasis therapy. The biomimetic nanocages can effectively deliver photothermal agents of DiR and cytotoxic epirubicin to CSCs in tumor mass for photothermal‐chemotherapy of breast cancer metastasis.

Characterization of DBN and EBN. A) Typical TEM images of DBN and EBN, scale bar = 50 nm. B) The particle size distribution of DBN and EBN measured by DLS analysis. C) The thermal images of water, free DiR, and DBN upon their exposure to an 808 nm laser. D) The in vitro temperature variations of water, free DiR, and DBN upon 808 nm laser irradiation. E) The in vitro release profiles of EBN in PBS at different pH values. F) The in vitro release profiles of EBN in PBS (pH 7.4) and PBS (pH 7.4)+10% FBS.

In vitro preferential accessibility to CSCs in 3D tumorsphere. A) The expression of CD44+CD24− markers in 3D tumorsphere and parent 4T1 cells. B) The proportion of ALDHhigh fractions in 3D tumorsphere and parent 4T1 cells. C) The uptake of DBN in CSCs‐enriched 3D tumorsphere cells and parent 4T1 cells under LCSM. By contrast, the nuclei were stained with Hoechst 33 342 for visualization. D) The mean fluorescence intensity of DBN in CSCs‐enriched tumorsphere cells and parent 4T1 cells, **p < 0.01. E) The relative uptake of DBN in ALDHhigh and ALDHlow fractions of 3D tumorsphere cells. F) The expression of Scara5 and TfR in parent 4T1 cells and CSCs‐enriched 3D tumorsphere cells. G) The quantified cellular uptake of DBN in CSCs‐enriched 3D tumorsphere cells in the presence and absence of anti‐Scara5, *p < 0.05.

The in vitro therapeutic efficacy of DBN+L/EBN combination therapy on the viability, sphere‐forming, and ALDHhigh CSCs fractions of tumorsphere cells. A) The inhibitory effects of EBN on the viability of parent 4T1 cells. B) The inhibitory effects of various groups on the viability of parent 4T1 cells, **p < 0.01. C) The inhibition of various groups on the tumorsphere forming ability of 4T1 cells, scale bar = 200 µm. D) The inhibition of various groups on destroying the already existing tumorspheres, scale bar = 200 µm. E) The effects on eliminating ALDHhigh CSCs fractions in 3D tumorsphere model from each treatment.

The in vivo distribution of DBN in 4T1‐induced orthotopic breast cancer model. A) The in vivo imaging of DBN and free DiR in tumor bearing mice at different time points after injection. B) The ex vivo imaging of DBN and free DiR in the major organs at 4 h of injection. C) The quantified distribution of DBN and free DiR in major organs at 4 h postinjection, **p < 0.01. D) The photoacoustic imaging of DBN in tumor at 4 h after injection. E) The reconstructed 3D distribution profiles of DBN in tumor.

The in vivo cellular internalization and preferential CSCs‐accessibility in tumor sites. A) The in vivo internalization of DBN by various cells of CAF, TAM, and 4T1‐GFP cancer cells at tumor sites. By contrast, the nuclei were stained with DAPI for visualization, scale bar = 25 µm. B) The in vivo preferential CSCs‐accessibility of nanocages, wherein CSCs were denoted as cells with high expression of ALDH, SOX‐2, and OCT‐4 markers in tumor mass, scale bar = 20 µm.

The in vivo distribution, deep penetration, and CSCs‐accessibility of EBN in tumor mass after DBN+L treatment. A) The ex vivo distribution of EBN by recording the fluorescence signals of epirubicin. B) The permeation of EBN in the whole tumor mass, wherein the actin and nuclei were respectively stained with phalloidin‐FITC and DAPI for visualization under LCSM, scale bar = 1.0 mm. C) The enlarged in vivo cellular uptake of EBN in tumor sites, scale bar = 25 µm. D) The in vivo accessibility of EBN to ALDHhigh CSCs cells in tumor sites, which was denoted as yellow arrows, scale bar = 25 µm.

The in vivo therapeutic effects on tumor growth and lung metastasis of metastatic breast cancer model. A) The typical thermal images of tumor bearing mice. B) The temperature changes in tumor from each laser‐irradiated group. C) The tumor growth profiles from each group. D) The relative tumor weight from each group, *p < 0.05, **p < 0.01. E) The number of lung metastatic nodules from each group, *p < 0.05, **p < 0.01. F) The inhibition on the incidence of lung metastasis from each treatment, *p < 0.05, **p < 0.01. G) The histological examination of lung tissues from each group, scale bar = 5000 µm.

The in vivo suppression on the proportion of ALDHhigh CSCs in tumor mass. A) Expression of ALDHhigh markers in tumor mass from each group, which was denoted as green fluorescence signals in the captured images, scale bar = 200 µm. B) The quantified results of ALDHhigh CSCs expressions in tumor from each group, **p < 0.01.

通讯作者

1. Siling Wang.School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.wangslsy@163.com
2. Zhiwen Zhang.State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.wangslsy@163.com
3. Yaping Li.State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.wangslsy@163.com

推荐引用方式

Tao Tan,Hong Wang,Haiqiang Cao,Lijuan Zeng,Yuqi Wang,Zhiwan Wang,Jing Wang,Jie Li,Siling Wang,Zhiwen Zhang,Yaping Li. Deep Tumor‐Penetrated Nanocages Improve Accessibility to Cancer Stem Cells for Photothermal‐Chemotherapy of Breast Cancer Metastasis. Advanced Science ,Vol.5, Issue 12(2018)

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