Background: Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. This study revealed the apoptotic and anti-growth mechanism of VTD, a previously used anti-hypertensive supplement, can elevate UBXN2A, a known tumor suppressor protein in CRC, and simultaneously enhance intrinsic and extrinsic apoptosis in metastatic cancer cells. Methods and Results: An AOM/DSS mouse model of CRC showed that UBXN2A haplosufficient (UBXN2A +/−) mice treated with VTD had less tumor burden than mice with the full UBXN2A gene treated with vehicle. We have previously shown that casein-coated mesoporous silica nanoparticles (MSNs) offer an effective local delivery of drugs at tumor sites. Our findings demonstrate that the high rate of extracellular release of matrix metalloproteinases (MMPs), particularly MMP-7, by metastatic colon cancer cells, triggers the release of VTD from casein-coated mesoporous MSNs. This shows the “Zip Code” mechanism for the local enrichment of VTD at the tumor sites. After in vitro drug release verification, two independent mouse experiments, a xenograft and a splenolepatic metastatic mouse model of CRC, were used to evaluate the therapeutic efficacy of VTD-loaded and casein-coated carboxylated mesoporous silica nanoparticles, MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg). Animal experiments revealed that MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg) slows down the progress of tumors. Mass spectrometry (MS) revealed improved pharmacokinetics (PK) profile as MSN-COOH/VTD/CAS had less VTD accumulation in non-cancerous organs compared to pure VTD. We further improved nanoparticle targeting and drug release by shifting to calcium-based particles (CBPs). The engineered CBPs demonstrated higher drug-releasing performance. Without the MMPs trigger, MSNs show slow and continuous “drug leak” over longer period of time whereas CCSMPs stops leakage within an hour. Additionally, CBPs showed higher sensitivity to MMP-7 than MMP-9, enhancing the targetability of CBPs for CRC metastatic tumors with excessive extracellular MMP-7. Conclusions: This study introduces a new platform utilizing nanoparticle-based site-specific delivery of a plant-based anti-metastatic molecule, veratridine, with enhanced safety and therapeutic efficacy for the treatment of metastatic CRC.
背景：尽管过去十年间在提高结直肠癌（CRC）生存率方面取得了显著进展，但由于原发性肿瘤的快速转移扩散，治疗挑战依然存在。本研究揭示了先前用于抗高血压的补充剂藜芦定（VTD）的凋亡与抗生长机制，该机制能够上调CRC中已知的肿瘤抑制蛋白UBXN2A，并同时增强转移性癌细胞的内源性和外源性凋亡。 方法与结果：在AOM/DSS诱导的CRC小鼠模型中，UBXN2A单倍剂量不足（UBXN2A +/-）的小鼠经VTD治疗后，其肿瘤负荷低于接受载体治疗的UBXN2A基因完整小鼠。我们先前的研究表明，酪蛋白包被的介孔二氧化硅纳米颗粒（MSNs）能够在肿瘤部位实现药物的有效局部递送。本研究发现，转移性结肠癌细胞高速释放基质金属蛋白酶（MMPs），特别是MMP-7，会触发酪蛋白包被的介孔MSNs释放VTD。这揭示了VTD在肿瘤部位局部富集的"邮政编码"机制。在体外药物释放验证后，我们通过两项独立的小鼠实验——CRC异种移植模型和脾肝转移模型，评估了负载VTD的酪蛋白包被羧基化介孔二氧化硅纳米颗粒MSN-COOH/VTD/CAS（VTD剂量0.2 mg/kg）的治疗效果。动物实验表明，MSN-COOH/VTD/CAS能够延缓肿瘤进展。质谱分析显示，与纯VTD相比，MSN-COOH/VTD/CAS在非癌器官中的VTD蓄积更少，药代动力学特征得到改善。我们通过转向钙基颗粒（CBPs）进一步提高了纳米颗粒的靶向性和药物释放性能。工程化CBPs表现出更高的药物释放性能。在没有MMPs触发的情况下，MSNs在较长时间内呈现缓慢持续的"药物渗漏"，而CBPs在一小时内即可停止渗漏。此外，CBPs对MMP-7的敏感性高于MMP-9，这增强了CBPs对细胞外MMP-7过表达的CRC转移瘤的靶向能力。 结论：本研究引入了一个新平台，利用基于纳米颗粒的位点特异性递送系统，实现植物源性抗转移分子藜芦定的靶向输送，为转移性CRC治疗提供了更高的安全性和治疗效果。
肿瘤(癌症)患者之家