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反义卵泡刺激素肽介导的聚乙烯亚胺复合物用于靶向卵巢癌基因治疗。

Retro-inverso follicle-stimulating hormone peptide-mediated polyethylenimine complexes for targeted ovarian cancer gene therapy.

机构信息

a Obstetrics and Gynecology Hospital , Fudan University , Shanghai , China.

b Department of Gynecology , 411 Military Hospital Affiliated to Changhai Hospital of Shanghai , Shanghai , China.

出版信息

Drug Deliv. 2018 Nov;25(1):995-1003. doi: 10.1080/10717544.2018.1461956.

DOI:10.1080/10717544.2018.1461956
PMID:29667478
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6058519/
Abstract

BACKGROUND

The development of nanoparticle drug delivery systems with targeted ligands has the potential to increase treatment efficiency in ovarian cancer.

METHODS

We developed a 21-amino acid peptide, YTRDLVYGDPARPGIQGTGTF (L-FP21) conjugated to polyethylenimine (PEI) and methoxy polyethylene glycol (mPEG) to prepare a nanoparticle drug vehicle to target follicle-stimulating hormone receptor (FSHR) in ovarian cancer. At the same time, we optimized the ligand of the nanoparticle vehicle using D-peptides, which consist of D-amino acids (D-FP21). Nanoparticle vehicles carrying the therapeutic gene plasmid growth-regulated oncogene alpha (pGRO-α) short hairpin RNA (shRNA) (FP21-PEG-PEI/pGRO-α) were prepared for further investigation.

RESULTS

Compared with L-FP21, D-FP21 exhibited improved biological stability and higher uptake rate for FSHR-expressing ovarian cancer cells. The cytotoxicity of the L, D-FP21-PEG-PEI/pGRO-α complexes were significantly lower than that of the PEI/pGRO-α complex. The nanoparticle drug with the targeted ligand showed higher transfection efficiencies and improved anti-proliferation effects for ovarian cancer cells than that without the targeted ligand (mPEG-PEI/pGRO-α). Furthermore, an in vivo evaluation of an antitumor assay indicated that D-FP21-PEG-PEI/pGRO-α inhibited the growth of tumor spheroids considerably more than L-FP21-PEG-PEI/pGRO-α; their tumor inhibition rates were 58.5% and 33.3%, respectively.

CONCLUSIONS

D-FP21-PEG-PEI/plasmid DNA is a safe and efficient gene delivery vehicle for ovarian cancer targeted therapy.

摘要

背景

开发具有靶向配体的纳米药物递送系统有可能提高卵巢癌的治疗效率。

方法

我们开发了一种由 21 个氨基酸组成的肽，YTRDLVYGDPARPGIQGTGTF（L-FP21），与聚乙烯亚胺（PEI）和甲氧基聚乙二醇（mPEG）偶联，以制备针对卵巢癌细胞中卵泡刺激素受体（FSHR）的纳米药物载体。同时，我们使用由 D-氨基酸组成的 D-肽优化了纳米载体的配体（D-FP21）。为了进一步研究，制备了携带治疗基因质粒生长调节癌基因α（pGRO-α）短发夹 RNA（shRNA）的纳米载体药物（FP21-PEG-PEI/pGRO-α）。

结果

与 L-FP21 相比，D-FP21 表现出更好的生物稳定性和更高的 FSHR 表达卵巢癌细胞摄取率。L、D-FP21-PEG-PEI/pGRO-α 复合物的细胞毒性明显低于 PEI/pGRO-α 复合物。具有靶向配体的纳米药物对卵巢癌细胞的转染效率更高，增殖抑制作用更强，而无靶向配体的纳米药物（mPEG-PEI/pGRO-α）则较弱。此外，体内抗肿瘤试验评估表明，D-FP21-PEG-PEI/pGRO-α 抑制肿瘤球状体生长的效果明显优于 L-FP21-PEG-PEI/pGRO-α；它们的肿瘤抑制率分别为 58.5%和 33.3%。

结论

D-FP21-PEG-PEI/质粒 DNA 是一种安全有效的卵巢癌靶向治疗基因递送载体。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/60a3fe12d79b/IDRD_A_1461956_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/c0da39393f72/IDRD_A_1461956_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/09bcbeb0b2d8/IDRD_A_1461956_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/a26feb9f48ad/IDRD_A_1461956_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/4c7c69dda974/IDRD_A_1461956_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/3a963f4b0ef7/IDRD_A_1461956_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/60a3fe12d79b/IDRD_A_1461956_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/c0da39393f72/IDRD_A_1461956_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/09bcbeb0b2d8/IDRD_A_1461956_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/a26feb9f48ad/IDRD_A_1461956_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/4c7c69dda974/IDRD_A_1461956_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/3a963f4b0ef7/IDRD_A_1461956_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a296/6058519/60a3fe12d79b/IDRD_A_1461956_F0006_C.jpg

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