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一种无载体的叶酸受体靶向熊果酸/甲氨蝶呤纳米递药系统用于协同抗癌治疗。

A Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy.

机构信息

Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.

出版信息

Int J Nanomedicine. 2021 Mar 3;16:1775-1787. doi: 10.2147/IJN.S287806. eCollection 2021.

DOI:10.2147/IJN.S287806
PMID:33692622
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7938229/
Abstract

PURPOSE

To avoid undefined metabolic mechanisms and to eliminate potential side effects of traditional nanocarriers, new green carriers are urgently needed in cancer treatment. Carrier-free nanoparticles (NPs) based on ursolic acid (UA) have attracted significant attention, but the UA NPs targeting the folate receptor have never been explored. We designed a novel self-assembled UA-Methotrexate (MTX) NPs targeting the folate-receptor and its synergetic anticancer activity was studied in vitro and in vivo.

METHODS

UA-MTX NPs were prepared using the solvent precipitation method. Characterization of the UA-MTX NPs preparation was performed using a size analyzer, transmission electron microscopy, and UV-vis spectrophotometry. The in vitro pH-responsive drug release capability of UA-MTX NPs was tested at different pH values. The UA-MTX NPs targeting of folates was determined by comparing the endocytosis rates of cell lines with low or overexpression of the folate receptor (A549 and MCF-7 cells). The cytotoxicity and cell apoptosis of UA-MTX NPs were also studied to determine the in vitro synergistic effects. Combination chemotherapy of UA-MTX NPs in vivo was evaluated using MCF-7 xenografted tumor models.

RESULTS

Compared with free UA or MTX, the water solubility of UA-MTX NPs improved significantly. Drug-release from the UA-MTX NPs was faster at pH 5.0 than pH 7.4, suggesting MTX-UA NPs could rapidly release MTX in the acidic conditions of the tumor microenvironment. Confocal laser scanning microscopy revealed the excellent folate receptor targeting of UA-MTX NPs in MCF-7 cells. Cytotoxicity and cell apoptosis results demonstrated greater antiproliferative capacity of UA-MTX NPs than that of free drug in folate receptor overexpressing MCF-7 cells. Anticancer effects in vivo suggested MTX-UA NPs exhibited good biological safety and could enhance antitumor efficacy due to the combination therapy.

CONCLUSION

Our findings indicate that the UA-MTX NPs targeting folate-receptors is an efficient strategy for combination chemotherapy.

摘要

目的

为避免传统纳米载体的代谢机制不明确和消除潜在的副作用，癌症治疗中急需新的绿色载体。基于熊果酸（UA）的无载体纳米粒子（NPs）引起了广泛关注，但针对叶酸受体的 UA NPs 从未被探索过。我们设计了一种新型的叶酸受体靶向自组装 UA-甲氨蝶呤（MTX） NPs，并研究了其在体外和体内的协同抗癌活性。

方法

采用溶剂沉淀法制备 UA-MTX NPs。采用粒径分析仪、透射电子显微镜和紫外可见分光光度计对 UA-MTX NPs 制剂进行表征。在不同 pH 值下测试 UA-MTX NPs 的体外 pH 响应性药物释放能力。通过比较叶酸受体低表达和过表达的细胞系（A549 和 MCF-7 细胞）的内吞率，确定 UA-MTX NPs 的叶酸靶向性。还研究了 UA-MTX NPs 的细胞毒性和细胞凋亡，以确定体外协同作用。采用 MCF-7 异种移植瘤模型评价 UA-MTX NPs 的体内联合化疗。

结果

与游离 UA 或 MTX 相比，UA-MTX NPs 的水溶性显著提高。UA-MTX NPs 在 pH 5.0 下的药物释放速度快于 pH 7.4，提示 MTX-UA NPs 可在肿瘤微环境的酸性条件下快速释放 MTX。共聚焦激光扫描显微镜显示 UA-MTX NPs 对 MCF-7 细胞具有良好的叶酸受体靶向性。细胞毒性和细胞凋亡结果表明，UA-MTX NPs 在叶酸受体过表达的 MCF-7 细胞中的增殖抑制能力大于游离药物。体内抗癌作用表明，由于联合治疗，MTX-UA NPs 具有良好的生物安全性，并能增强抗肿瘤疗效。

结论

我们的研究结果表明，靶向叶酸受体的 UA-MTX NPs 是联合化疗的有效策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/8aef9e3e9c0c/IJN-16-1775-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/06e19c6d5a98/IJN-16-1775-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/f33751bbe2a7/IJN-16-1775-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/1dddf4270346/IJN-16-1775-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/4ae0e23cee61/IJN-16-1775-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/e630752f67ce/IJN-16-1775-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/8aef9e3e9c0c/IJN-16-1775-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/06e19c6d5a98/IJN-16-1775-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/f33751bbe2a7/IJN-16-1775-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/1dddf4270346/IJN-16-1775-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/4ae0e23cee61/IJN-16-1775-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/e630752f67ce/IJN-16-1775-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de60/7938229/8aef9e3e9c0c/IJN-16-1775-g0006.jpg

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