Breast cancer lung metastasis occurs in more than 60% of all patients with breast cancer, and most of those afflicted by it eventually die of recurrence. The tumor microenvironment plays vital roles in metastasis. Modulating the tumor microenvironment via multiple pathways could efficiently prevent or inhibit lung metastasis. Silibinin and cryptotanshinone are natural plant products that demonstrate anti-metastasis effects and modulate the tumor microenvironment via different pathways. However, they have poor aqueous solubility, membrane permeability, and oral bioavailability. Oral drug administration may help improve the quality of life and compliance of patients with breast cancer, primarily under long-term and/or follow-up therapy. Herein, we developed poly-N-(2-hydroxypropyl) methacrylamide (pHPMA)-coated wheat germ agglutinin-modified lipid-polymer hybrid nanoparticles, co-loaded with silibinin and cryptotanshinone (S/C-pW-LPNs). We assessed their oral bioavailability, and evaluated their anti-metastasis efficacy in a 4T1 breast cancer tumor-bearing nude mouse model. An in vitro mucus diffusion study revealed that pHPMA enhanced W-LPN mucus penetration. After oral administration, pHPMA enhanced nanoparticle distribution in rat jejunum and substantially augmented oral bioavailability. S/C-W-LPNs markedly increased 4T1 cell toxicity and inhibited cell invasion and migration. Compared to LPNs loaded with either silibinin or cryptotanshinone alone, S/C-pW-LPNs dramatically slowed tumor progression in 4T1 tumor-bearing nude mice. S/C-pW-LPNs presented with the most robust anti-metastasis activity on smooth lung surfaces and mitigated lung metastasis foci. They also downregulated tumor microenvironment biomarkers such as CD31, TGF-β1, and MMP-9 that promote metastasis. Silibinin- and cryptotanshinone-co-loaded pW-LPNs efficiently penetrate intestinal barriers, thereby enhancing the oral bioavailability of the drug loads. These nanoparticles exhibit favorable anti-metastasis effects in breast cancer-bearing nude mice. Hence, S/C-pW-LPNs are promising oral drug nanocarriers that inhibit breast cancer lung metastasis.

中文翻译：

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功能性口服纳米颗粒，可提供水飞蓟宾和隐丹参酮抗乳腺癌肺转移的作用。

乳腺癌肺癌转移发生在所有乳腺癌患者中的60％以上，大多数受乳腺癌折磨的患者最终会死于复发。肿瘤微环境在转移中起着至关重要的作用。通过多种途径调节肿瘤微环境可以有效预防或抑制肺转移。水飞蓟宾和隐丹参酮是天然植物产品，具有抗转移作用并通过不同途径调节肿瘤微环境。然而，它们具有差的水溶性，膜通透性和口服生物利用度。口服药物可能主要在长期和/或后续治疗下，有助于改善乳腺癌患者的生活质量和依从性。在这里 我们开发了聚N-（2-羟丙基）甲基丙烯酰胺（pHPMA）涂层的小麦胚芽凝集素修饰的脂质-聚合物杂化纳米颗粒，并与水飞蓟宾和隐丹参酮（S / C-pW-LPNs）共同加载。我们评估了它们的口服生物利用度，并评估了其在具有4T1乳腺癌肿瘤的裸鼠模型中的抗转移功效。一项体外黏液扩散研究表明，pHPMA增强了W-LPN黏液渗透。口服后，pHPMA增强了大鼠空肠中的纳米颗粒分布，并大大提高了口服生物利用度。S / CW-LPNs明显增加4T1细胞毒性并抑制细胞侵袭和迁移。与单独装有水飞蓟宾或隐丹参酮的LPNs相比，S / C-pW-LPNs显着减慢了携带4T1肿瘤的裸鼠的肿瘤进展。S / C-pW-LPN在光滑的肺表面和减轻的肺转移灶方面表现出最强的抗转移活性。他们还下调了促进转移的肿瘤微环境生物标志物，例如CD31，TGF-β1和MMP-9。水飞蓟宾和隐丹参酮共同负载的pW-LPN可有效穿透肠道屏障，从而提高药物负载的口服生物利用度。这些纳米颗粒在患有乳腺癌的裸鼠中表现出有利的抗转移作用。因此，S / C-pW-LPNs是有希望的抑制乳腺癌肺转移的口服药物纳米载体。水飞蓟宾和隐丹参酮共同负载的pW-LPN可有效穿透肠道屏障，从而提高药物负载的口服生物利用度。这些纳米颗粒在患有乳腺癌的裸鼠中表现出有利的抗转移作用。因此，S / C-pW-LPNs是有希望的抑制乳腺癌肺转移的口服药物纳米载体。水飞蓟宾和隐丹参酮共同负载的pW-LPN可有效穿透肠道屏障，从而提高药物负载的口服生物利用度。这些纳米颗粒在患有乳腺癌的裸鼠中表现出有利的抗转移作用。因此，S / C-pW-LPNs是有希望的抑制乳腺癌肺转移的口服药物纳米载体。