In Vivo Bioorthogonal Chemistry Enables Local Hydrogel and Systemic Pro-Drug To Treat Soft Tissue Sarcoma.
In Vivo Bioorthogonal Chemistry Enables Local Hydrogel and Systemic Pro-Drug To Treat Soft Tissue Sarcoma.
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DOI：
10.1021/acscentsci.6b00150
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发表时间：
2016-07-27
影响因子：
18.2
通讯作者：
Royzen M
中科院分区：
文献类型：
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作者：
Mejia Oneto JM;Khan I;Seebald L;Royzen M
仅在所需位置激活药物以避免全身性免疫抑制和其他剂量限制性毒性的能力是高度期望的。在这里，我们提出了一种新的方法，命名为本地药物激活，使用生物正交化学集中和激活系统的小分子在选择的位置。该方法不依赖于内源性细胞或环境标记物，并且仅取决于在所需部位附近预植入生物材料的存在（例如，肿瘤）。我们证明了这种方法在小鼠中使用阿霉素前药对一种软组织肉瘤（HT 1080）的异种移植肿瘤进行全身治疗的明显治疗益处和最小的副作用。在软组织肉瘤肿瘤附近注射四嗪改性的水凝胶，随后进行短疗程的全身性多柔比星前药，允许有效的局部药物活化，导致肿瘤缓解，副作用最小。
The ability to activate drugs only at desired locations avoiding systemic immunosuppression and other dose limiting toxicities is highly desirable. Here we present a new approach, named local drug activation, that uses bioorthogonal chemistry to concentrate and activate systemic small molecules at a location of choice. This method is independent of endogenous cellular or environmental markers and only depends on the presence of a preimplanted biomaterial near a desired site (e.g., tumor). We demonstrate the clear therapeutic benefit with minimal side effects of this approach in mice over systemic therapy using a doxorubicin pro-drug against xenograft tumors of a type of soft tissue sarcoma (HT1080). Injection of tetrazine-modified hydrogel near soft tissue sarcoma tumors, followed by a short course of systemic doxorubicin pro-drug, allows effective local drug activation leading to tumor remission with minimal side effects.