PTEN restoration and CXCR2 depletion synergistically enhance the effect of enzalutamide and inhibit bone metastatic CRPC.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-07-25 eCollection Date: 2025-01-01 DOI:10.7150/thno.114534
Jiyuan Chen, Luyao Gong, Simeng Cao, Guanshan Song, Yeheng Peng, Yuanyuan Wang, Yan-Ru Lou, Teemu J Murtola, Yao Wu, Ganjun Yu, Yuan Gao
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引用次数: 0

Abstract

Rationale: Enzalutamide (Enz) is the first-line therapy for castration-resistant prostate cancer (CRPC). However, drug resistance has hindered its further application. Moreover, CRPC is frequently prone to metastasis, particularly to bone (BmCRPC). Methods: To investigate the involvement of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deletion and C-X-C motif chemokine receptor 2 (CXCR2) overexpression in Enz-resistant CRPC and BmCRPC, we constructed a bisphosphonate (BP) lipid-like material with high bone affinity (GB4-BPL) for the codelivery of a PTEN plasmid (pPTEN) and CXCR2 siRNA (siCXCR2) to BmCRPC. Results: GB4-BPL demonstrated twice the bone metastasis-targeting ability of GB4-lipo (which lacks bisphosphonate modification) while maintaining a gene transfection efficiency comparable to that of Lipo8000 and exhibiting significantly lower cytotoxicity. Moreover, siCXCR2 and pPTEN loaded in GB4-BPL (GB4-BPL@siCXCR2/pPTEN) synergistically inhibited tumor growth and metastasis, highly enhancing the effect of Enz by 69.45% in the Enz-resistant model. Furthermore, GB4-BPL@siCXCR2/pPTEN significantly reduced the numbers of MDSCs, Tregs, and M2-like TAMs by 55.01%, 64.75%, and 52.53%, respectively, while increasing the proportions of M1 macrophages, NK cells, and CD8+ T cells by 1.65-, 1.40-, and 4.60-fold, respectively. In addition, this nanosystem reduced skeletal-related events. Conclusions: Our studies demonstrated the potential of GB4-BPL for delivering siCXCR2/pPTEN to tumor and bone metastatic sites. GB4-BPL@siCXCR2/pPTEN alone or in combination with Enz could provide a new strategy for the treatment of drug-resistant BmCRPC.

PTEN修复和CXCR2缺失协同增强恩杂鲁胺的作用,抑制骨转移性CRPC。
理由:恩杂鲁胺(Enzalutamide)是去势抵抗性前列腺癌(CRPC)的一线治疗药物。然而,耐药问题阻碍了其进一步应用。此外,CRPC极易发生转移,尤其是骨转移(BmCRPC)。方法:为了研究enz耐药CRPC和BmCRPC中10号染色体上磷酸酶和紧张素同源物缺失(PTEN)和C-X-C基元趋化因子受体2 (CXCR2)过表达与PTEN质粒(pPTEN)和CXCR2 siRNA (siCXCR2)在BmCRPC中的作用,我们构建了一种高骨亲和力的双磷酸盐(BP)脂质样材料(GB4-BPL),用于PTEN质粒(pPTEN)和CXCR2 siRNA (siCXCR2)的共递送。结果:GB4-BPL表现出两倍于GB4-lipo(缺乏双膦酸盐修饰)的骨转移靶向能力,同时保持与Lipo8000相当的基因转染效率,并表现出明显较低的细胞毒性。此外,装载在GB4-BPL中的siCXCR2和pPTEN (GB4-BPL@siCXCR2/pPTEN)协同抑制肿瘤生长和转移,在Enz耐药模型中,Enz的作用提高了69.45%。此外,GB4-BPL@siCXCR2/pPTEN可显著减少MDSCs、Tregs和m2样tam的数量,分别减少55.01%、64.75%和52.53%,同时使M1巨噬细胞、NK细胞和CD8+ T细胞的比例分别增加1.65倍、1.40倍和4.60倍。此外,这种纳米系统减少了与骨骼相关的事件。结论:我们的研究证明了GB4-BPL将siCXCR2/pPTEN传递到肿瘤和骨转移部位的潜力。GB4-BPL@siCXCR2/pPTEN单独或联合Enz可为耐药BmCRPC的治疗提供新的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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