Miladi Imen, Vivier Magali, Dauplat Marie-Mélanie, Chatard Morgane, Besse Sophie, Vidal Aurélien, Chassain Karine, Jean Betty, Forestier Christiane, Chezal Jean-Michel, Rédini Francoise, Degoul Francoise, Miot-Noirault Elisabeth
Centre Jean Perrin, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, 63000, Clermont-Ferrand, France.
Département d'anatomo-pathologie, Centre Jean Perrin, 63000, Clermont-Ferrand, France.
Cancer Chemother Pharmacol. 2017 Sep;80(3):517-526. doi: 10.1007/s00280-017-3377-7. Epub 2017 Jul 13.
This study was conducted during the development of innovative treatment targeting the microenvironment of chondrosarcoma. In this context, MMP inhibitors were conjugated with a quaternary ammonium (QA) function as a targeting ligand to proteoglycans of chondrosarcoma extracellular matrix. Here we report the proof of concept of this strategy applied to the MMP13 inhibitor, doxycycline (Dox).
A quaternary ammonium derivative of the MMP13 inhibitor doxycycline (QA-Dox) was synthesized, and its anticancer activity was evaluated in the Swarm rat chondrosarcoma (SRC) model compared with the parent drug doxycycline, in vitro and in vivo. In vivo, dox and QA-Dox efficiency was assessed at equimolar doses according to a q4dx4 schedule by monitoring tumour volume by MRI and PG-targeted scintigraphy. Molecular mechanism (MMP13 expression, proteoglycan level) and histology studies were performed on tumours.
The link of QA targeting function to Dox maintained the MMP13 inhibitory activity in vitro. Interestingly, the bacteriostatic activity was lost. SRC cells incubated with both drugs were blocked in S and G2 M phases. Tumour growth inhibition (confirmed by histology) was observed for both Dox and QA-Dox. Undesirable blood effects (leukocyte decrease) were reduced when Dox was targeted to tumour tissue using the QA function.
In the SRC model, the MMP13 inhibitor Dox and its QA derivative are promising as adjuvant therapies for chondrosarcoma management.
本研究在针对软骨肉瘤微环境的创新治疗方法研发过程中开展。在此背景下，基质金属蛋白酶（MMP）抑制剂与季铵（QA）功能基团偶联，作为软骨肉瘤细胞外基质蛋白聚糖的靶向配体。在此，我们报告将该策略应用于MMP13抑制剂强力霉素（Dox）的概念验证。
合成了MMP13抑制剂强力霉素的季铵衍生物（QA-Dox），并在体外和体内的斯沃姆大鼠软骨肉瘤（SRC）模型中，将其与母体药物强力霉素相比，评估其抗癌活性。在体内，按照q4dx4方案，以等摩尔剂量通过磁共振成像（MRI）监测肿瘤体积和PG靶向闪烁扫描评估强力霉素和QA-Dox的疗效。对肿瘤进行分子机制（MMP13表达、蛋白聚糖水平）和组织学研究。
QA靶向功能与强力霉素的连接在体外维持了MMP13抑制活性。有趣的是，抑菌活性丧失。用两种药物处理的SRC细胞停滞在S期和G2/M期。观察到强力霉素和QA-Dox均有肿瘤生长抑制作用（经组织学证实）。当使用QA功能将强力霉素靶向肿瘤组织时，不良血液影响（白细胞减少）减轻。
在SRC模型中，MMP13抑制剂强力霉素及其QA衍生物有望作为软骨肉瘤治疗的辅助疗法。
