Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, United States.
Mol Pharm. 2013 May 6;10(5):1683-94. doi: 10.1021/mp300505w. Epub 2013 Apr 17.
Surgery, radiation and chemotherapy remain the mainstay of current cancer therapy. However, treatment failure persists due to the inability to achieve complete local control of the tumor and curtail metastatic spread. Vascular disrupting agents (VDAs) are a class of promising systemic agents that are known to synergistically enhance radiation, chemotherapy or thermal treatments of solid tumors. Unfortunately, there is still an unmet need for VDAs with more favorable safety profiles and fewer side effects. Recent work has demonstrated that conjugating VDAs to other molecules (polyethylene glycol, CNGRCG peptide) or nanoparticles (liposomes, gold) can reduce toxicity of one prominent VDA (tumor necrosis factor alpha, TNF-α). In this report, we show the potential of a gold conjugated TNF-α nanoparticle (NP-TNF) to improve multimodal cancer therapies with VDAs. In a dorsal skin fold and hindlimb murine xenograft model of prostate cancer, we found that NP-TNF disrupts endothelial barrier function and induces a significant increase in vascular permeability within the first 1-2 h followed by a dramatic 80% drop in perfusion 2-6 h after systemic administration. We also demonstrate that the tumor response to the nanoparticle can be verified using dynamic contrast-enhanced magnetic resonance imaging (MRI), a technique in clinical use. Additionally, multimodal treatment with thermal therapies at the perfusion nadir in the sub- and supraphysiological temperature regimes increases tumor volumetric destruction by over 60% and leads to significant tumor growth delays compared to thermal therapy alone. Lastly, NP-TNF was found to enhance thermal therapy in the absence of neutrophil recruitment, suggesting that immune/inflammatory regulation is not central to its power as part of a multimodal approach. Our data demonstrate the potential of nanoparticle-conjugated VDAs to significantly improve cancer therapy by preconditioning tumor vasculature to a secondary insult in a targeted manner. We anticipate our work to direct investigations into more potent tumor vasculature specific combinations of VDAs and nanoparticles with the goal of transitioning optimal regimens into clinical trials.
手术、放疗和化疗仍然是当前癌症治疗的主要手段。然而，由于无法完全控制肿瘤并遏制转移扩散，治疗失败仍然存在。血管破坏剂（VDA）是一类有前途的系统药物，已知它们可以协同增强实体瘤的放疗、化疗或热疗。不幸的是，仍然需要具有更有利的安全性和更少副作用的 VDA。最近的工作表明，将 VDA 与其他分子（聚乙二醇、CNGRCG 肽）或纳米颗粒（脂质体、金）偶联可以降低一种突出的 VDA（肿瘤坏死因子-α，TNF-α）的毒性。在本报告中，我们展示了金偶联 TNF-α纳米颗粒（NP-TNF）在改善 VDA 的多模态癌症治疗中的潜力。在前列腺癌的背部皮肤褶皱和后肢异种移植模型中，我们发现 NP-TNF 破坏内皮屏障功能，并在系统给药后 1-2 小时内导致血管通透性显著增加，随后在 2-6 小时内灌注急剧下降 80%。我们还证明，使用临床使用的动态对比增强磁共振成像（MRI）技术可以验证肿瘤对纳米颗粒的反应。此外，在亚生理和超生理温度范围内的灌注低谷处进行热疗的多模态治疗可使肿瘤体积破坏增加超过 60%，并与单独热疗相比导致显著的肿瘤生长延迟。最后，发现 NP-TNF 增强了在没有中性粒细胞募集的情况下的热疗，这表明免疫/炎症调节不是其作为多模态方法一部分的主要作用。我们的数据表明，纳米颗粒偶联的 VDA 具有通过有针对性地预处理肿瘤血管以应对二次损伤来显著改善癌症治疗的潜力。我们期望我们的工作能够指导更有效地针对肿瘤血管的 VDA 和纳米颗粒的组合的研究，并将最佳方案转化为临床试验。
