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调制式电温热疗增强载多柔比星的溶酶体热敏脂质体在 4T1 荷瘤小鼠中的肿瘤递送并提高抗癌活性。

Modulated Electro-Hyperthermia Accelerates Tumor Delivery and Improves Anticancer Activity of Doxorubicin Encapsulated in Lyso-Thermosensitive Liposomes in 4T1-Tumor-Bearing Mice.

机构信息

Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary.

HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, 1094 Budapest, Hungary.

出版信息

Int J Mol Sci. 2024 Mar 7;25(6):3101. doi: 10.3390/ijms25063101.


DOI:10.3390/ijms25063101
PMID:38542073
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10970314/
Abstract

Modulated electro-hyperthermia (mEHT) is an adjuvant cancer therapy that enables tumor-selective heating (+2.5 °C). In this study, we investigated whether mEHT accelerates the tumor-specific delivery of doxorubicin (DOX) from lyso-thermosensitive liposomal doxorubicin (LTLD) and improves its anticancer efficacy in mice bearing a triple-negative breast cancer cell line (4T1). The 4T1 cells were orthotopically injected into Balb/C mice, and mEHT was performed on days 9, 12, and 15 after the implantation. DOX, LTLD, or PEGylated liposomal DOX (PLD) were administered for comparison. The tumor size and DOX accumulation in the tumor were measured. The cleaved caspase-3 (cC3) and cell proliferation were evaluated by cC3 or Ki67 immunohistochemistry and Western blot. The LTLD+mEHT combination was more effective at inhibiting tumor growth than the free DOX and PLD, demonstrated by reductions in both the tumor volume and tumor weight. LTLD+mEHT resulted in the highest DOX accumulation in the tumor one hour after treatment. Tumor cell damage was associated with cC3 in the damaged area, and with a reduction in Ki67 in the living area. These changes were significantly the strongest in the LTLD+mEHT-treated tumors. The body weight loss was similar in all mice treated with any DOX formulation, suggesting no difference in toxicity. In conclusion, LTLD combined with mEHT represents a novel approach for DOX delivery into cancer tissue.

摘要

调制的电加热疗法(mEHT)是一种辅助癌症治疗方法,可实现肿瘤选择性加热(+2.5°C)。在这项研究中,我们研究了 mEHT 是否能加速溶酶体热敏脂质体阿霉素(LTLD)中阿霉素(DOX)的肿瘤特异性释放,并提高携带三阴性乳腺癌细胞系(4T1)的小鼠的抗癌疗效。将 4T1 细胞原位注射到 Balb/C 小鼠中,并在植入后第 9、12 和 15 天进行 mEHT。进行 DOX、LTLD 或聚乙二醇化脂质体 DOX(PLD)给药以进行比较。测量肿瘤大小和肿瘤内 DOX 积累。通过 cC3 或 Ki67 免疫组化和 Western blot 评估裂解的半胱天冬酶-3(cC3)和细胞增殖。LTLD+mEHT 组合比游离 DOX 和 PLD 更能有效抑制肿瘤生长,表现为肿瘤体积和肿瘤重量均降低。LTLD+mEHT 在治疗后一小时导致肿瘤内 DOX 积累最高。肿瘤细胞损伤与受损区域中的 cC3 相关,与活区中的 Ki67 减少相关。这些变化在 LTLD+mEHT 治疗的肿瘤中最强。所有接受任何 DOX 制剂治疗的小鼠的体重减轻相似,表明毒性无差异。总之,LTLD 与 mEHT 联合代表了一种将 DOX 递送到癌症组织的新方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/0b8b0688cc47/ijms-25-03101-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/906c23842da2/ijms-25-03101-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/64bd2c06d2fe/ijms-25-03101-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/70e0f0e734ff/ijms-25-03101-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/9a3d453acbac/ijms-25-03101-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/b8493296eab7/ijms-25-03101-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/9149ec858c34/ijms-25-03101-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/cdd8bfce2753/ijms-25-03101-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/aecfce07108e/ijms-25-03101-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/0b8b0688cc47/ijms-25-03101-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/906c23842da2/ijms-25-03101-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/64bd2c06d2fe/ijms-25-03101-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/70e0f0e734ff/ijms-25-03101-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/9a3d453acbac/ijms-25-03101-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/b8493296eab7/ijms-25-03101-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/9149ec858c34/ijms-25-03101-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/cdd8bfce2753/ijms-25-03101-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/aecfce07108e/ijms-25-03101-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfb4/10970314/0b8b0688cc47/ijms-25-03101-g009.jpg

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引用本文的文献

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A Comprehensive Review of Smart Thermosensitive Nanocarriers for Precision Cancer Therapy.

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[2]
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本文引用的文献

[1]
The Clinical Validation of Modulated Electro-Hyperthermia (mEHT).

Cancers (Basel). 2023-9-15

[2]
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World J Clin Oncol. 2023-6-24

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Cells. 2023-2-19

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Cell Rep Med. 2022-11-15

[7]
Effects of Modulated Electro-Hyperthermia (mEHT) on Two and Three Year Survival of Locally Advanced Cervical Cancer Patients.

Cancers (Basel). 2022-1-27

[8]
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Nanotheranostics. 2022

[9]
Turning down the heat: The case for mild hyperthermia and thermosensitive liposomes.

Nanomedicine. 2022-2

[10]
Drug development of lyso-thermosensitive liposomal doxorubicin: Combining hyperthermia and thermosensitive drug delivery.

Adv Drug Deliv Rev. 2021-11

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