School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Zhangjiang Hi-Tech Park, Pudong New District, Shanghai, 201203, People's Republic of China.
J Nanobiotechnology. 2020 May 30;18(1):83. doi: 10.1186/s12951-020-00638-x.
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.
乳腺癌肺转移发生于超过 60%的所有乳腺癌患者，而大多数受其影响的患者最终死于复发。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地预防或抑制肺转移。水飞蓟宾和丹参酮是具有抗转移作用的天然植物产物，通过不同途径调节肿瘤微环境。然而，它们的水溶性、膜通透性和口服生物利用度较差。口服给药可能有助于提高乳腺癌患者的生活质量和顺应性，尤其是在长期和/或随访治疗下。在此，我们开发了聚-N-(2-羟丙基)甲基丙烯酰胺(pHPMA)-包覆的麦胚凝集素修饰的脂质-聚合物杂化纳米粒，共载有水飞蓟宾和丹参酮(S/C-pW-LPNs)。我们评估了它们的口服生物利用度，并在 4T1 乳腺癌荷瘤裸鼠模型中评价了它们的抗转移疗效。
体外黏液扩散研究表明，pHPMA 增强了 W-LPN 对黏液的穿透性。口服给药后，pHPMA 增加了纳米粒在大鼠空肠中的分布，并显著提高了口服生物利用度。S/C-W-LPNs 显著增加了 4T1 细胞的毒性，并抑制了细胞侵袭和迁移。与单独载有水飞蓟宾或丹参酮的 LPNs 相比，S/C-pW-LPNs 显著减缓了 4T1 荷瘤裸鼠的肿瘤进展。S/C-pW-LPNs 在光滑的肺表面表现出最强的抗转移活性，并减轻了肺转移灶。它们还下调了促进转移的肿瘤微环境生物标志物，如 CD31、TGF-β1 和 MMP-9。
共载有水飞蓟宾和丹参酮的 pW-LPNs 能够有效地穿透肠道屏障，从而提高药物的口服生物利用度。这些纳米粒在乳腺癌荷瘤裸鼠中表现出良好的抗转移作用。因此，S/C-pW-LPNs 是有前途的抑制乳腺癌肺转移的口服药物纳米载体。
