Marangon Iris, Silva Amanda A K, Guilbert Thomas, Kolosnjaj-Tabi Jelena, Marchiol Carmen, Natkhunarajah Sharuja, Chamming's Foucault, Ménard-Moyon Cécilia, Bianco Alberto, Gennisson Jean-Luc, Renault Gilles, Gazeau Florence
Laboratoire Matière et Systèmes Complexes (MSC), CNRS-UMR 7057, Université Paris Diderot, Sorbonne Paris Cité, 10 rue Alice Domon et Léonie Duquet, F-75205 Paris Cedex 13, France.
Plateforme Imagerie, Institut Cochin, Inserm U1016-CNRS UMR8104-Université Paris Descartes, Sorbonne Paris Cité Paris, 22 rue Méchain, 75014 Paris France.
Theranostics. 2017 Jan 1;7(2):329-343. doi: 10.7150/thno.17574. eCollection 2017.
Tumor stiffening, stemming from aberrant production and organization of extracellular matrix (ECM), has been considered a predictive marker of tumor malignancy, non-invasively assessed by ultrasound shear wave elastography (SWE). Being more than a passive marker, tumor stiffening restricts the delivery of diagnostic and therapeutic agents to the tumor and could modulate cellular mechano-signaling, tissue inflammation and tumor progression. Current strategies to modify the tumor extracellular matrix are based on ECM-targeting chemical agents but also showed deleterious systemic effects. On-demand excitable nanomaterials have shown their ability to perturb the tumor microenvironment in a spatiotemporal-controlled manner and synergistically with chemotherapy. Here, we investigated the evolution of tumor stiffness as well as tumor integrity and progression, under the effect of mild hyperthermia and thermal ablation generated by light-exposed multi-walled carbon nanotubes (MWCNTs) in an epidermoid carcinoma mouse xenograft. SWE was used for real-time mapping of the tumor stiffness, both during the two near infrared irradiation sessions and over the days after the treatment. We observed a transient and reversible stiffening of the tumor tissue during laser irradiation, which was lowered at the second session of mild hyperthermia or photoablation. In contrast, over the days following photothermal treatment, the treated tumors exhibited a significant softening together with volume reduction, whereas non-treated growing tumors showed an increase of tumor rigidity. The organization of the collagen matrix and the distribution of CNTs revealed a spatio-temporal correlation between the presence of nanoheaters and the damages on collagen and cells. This study highlights nanohyperthermia as a promising adjuvant strategy to reverse tumor stiffening and normalize the mechanical tumor environment.
肿瘤硬化源于细胞外基质（ECM）的异常产生和组织，被认为是肿瘤恶性程度的预测标志物，可通过超声剪切波弹性成像（SWE）进行无创评估。肿瘤硬化不仅仅是一个被动标志物，它还会限制诊断和治疗药物向肿瘤的递送，并可能调节细胞机械信号传导、组织炎症和肿瘤进展。目前改变肿瘤细胞外基质的策略基于靶向ECM的化学药物，但也显示出有害的全身效应。按需激发的纳米材料已显示出能够以时空可控的方式扰乱肿瘤微环境，并与化疗协同作用。在此，我们研究了在表皮样癌小鼠异种移植模型中，光暴露的多壁碳纳米管（MWCNT）产生的轻度热疗和热消融作用下，肿瘤硬度以及肿瘤完整性和进展的演变。在两次近红外照射期间以及治疗后的几天内，SWE用于实时绘制肿瘤硬度图。我们观察到激光照射期间肿瘤组织出现短暂且可逆的硬化，在第二次轻度热疗或光消融时硬度降低。相比之下，在光热治疗后的几天里，治疗后的肿瘤表现出明显的软化以及体积减小，而未治疗的生长肿瘤则显示出肿瘤硬度增加。胶原基质的组织和碳纳米管的分布揭示了纳米加热器的存在与胶原和细胞损伤之间的时空相关性。这项研究强调了纳米热疗作为一种有前景的辅助策略，可逆转肿瘤硬化并使肿瘤机械环境正常化。
