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系统给予载有 siRNA 的中性脂质体纳米粒以实现 mTOR 的治疗性沉默可抑制 DMBA 诱导的乳腺肿瘤发生。

Therapeutic silencing of mTOR by systemically administered siRNA-loaded neutral liposomal nanoparticles inhibits DMBA-induced mammary carcinogenesis.

机构信息

Division of Advanced Pharmacology, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology (BIT), Mesra, Ranchi, Jharkhand, 835 215, India.

Division of Pharmacognosy and Phytochemistry, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology (BIT), Mesra, Ranchi, Jharkhand, 835 215, India.

出版信息

Br J Cancer. 2022 Dec;127(12):2207-2219. doi: 10.1038/s41416-022-02011-1. Epub 2022 Oct 19.

Abstract

BACKGROUND

Mammary carcinogenesis possesses great challenges due to the lack of effectiveness of the multiple therapeutic options available. Gene therapy-based cancer treatment strategy provides more targeting accuracy, fewer side effects, and higher therapeutic efficiency. Downregulation of the oncogene mTOR by mTOR-siRNA is an encouraging approach to reduce cancer progression. However, its employment as means of therapeutic strategy has been restricted due to the unavailability of a suitable delivery system.

METHODS

A suitable nanocarrier system made up of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) has been developed to prevent degradation and for proficient delivery of siRNA. This was followed by in vitro and in vivo anti-breast cancer efficiency analysis of the mTOR siRNA-loaded neutral liposomal formulation (NL-mTOR-siRNA).

RESULTS

In our experiment, a profound reduction in MCF-7 cell growth, proliferation and invasion was ascertained following extensive downregulation of mTOR expression. NL-mTOR-siRNA suppressed tumour growth and restored morphological alterations of DMBA-induced breast cancer. In addition, neutral liposome enhanced accumulation of siRNA in mammary cancer tissues facilitating its deep cytosolic distribution within the tumour, which allows apoptosis thereby facilitating its anti-tumour potential.

CONCLUSION

Hence, the current study highlighted the augmented ground for therapies aiming toward cancerous cells to diminish mTOR expression by RNAi in managing mammary carcinoma.

摘要

背景

由于缺乏有效的多种治疗选择,乳腺肿瘤的发生具有很大的挑战性。基于基因治疗的癌症治疗策略提供了更高的靶向准确性、更少的副作用和更高的治疗效率。通过 mTOR-siRNA 下调致癌基因 mTOR 是一种减少癌症进展的有希望的方法。然而,由于缺乏合适的递送系统,其作为治疗策略的应用受到限制。

方法

开发了由 1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)组成的合适的纳米载体系统,以防止降解并有效地递送 siRNA。随后对负载 mTOR siRNA 的中性脂质体制剂(NL-mTOR-siRNA)进行了体外和体内抗乳腺癌效率分析。

结果

在我们的实验中,广泛下调 mTOR 表达后,MCF-7 细胞的生长、增殖和侵袭明显减少。NL-mTOR-siRNA 抑制肿瘤生长并恢复 DMBA 诱导的乳腺癌的形态改变。此外,中性脂质体增强了 siRNA 在乳腺癌组织中的积累,促进了其在肿瘤内的细胞质分布,从而诱导细胞凋亡,从而增强其抗肿瘤潜能。

结论

因此,本研究强调了通过 RNAi 降低 mTOR 表达以治疗癌症细胞的治疗方法在治疗乳腺肿瘤方面的增强基础。

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