Tissue-reactive drugs enable materials-free local depots.
Tissue-reactive drugs enable materials-free local depots.
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DOI：
10.1016/j.jconrel.2022.01.023
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Brudno Y
中科院分区：
文献类型：
--
作者：
Pandit S;Palvai S;Massaro NP;Pierce JG;Brudno Y
有效疗法的局部持续药物输送有望治疗无数局部疾病，同时消除全身副作用。然而，在硬组织如促结缔组织增生性肿瘤中引入药物递送贮库如粘性水凝胶或基于聚合物的植入物是非常有限的。在这里，我们提出了一种方法，通过组织反应性肿瘤药物（TRAPs）创建无材料的肿瘤内药物仓库。TRAP扩散到组织中并局部附着以持续释放药物。在TRAPs中，强效药物被ECM反应基团修饰，然后局部注射以快速与ECM内的可接近胺反应，从而产生局部药物仓库。我们证明，局部注射的TRAPs在小鼠和人胰腺肿瘤组织深处产生分散的、稳定的瘤内储库。基于ECM反应性紫杉醇（TRAP紫杉醇）的TRAP贮库具有比游离紫杉醇更好的溶解性，并且能够在体外和体内持续释放药物。TRAP紫杉醇诱导更高的肿瘤细胞凋亡和持续更好的抗肿瘤疗效比游离药物。通过提供持续的药物进入肿瘤细胞，这种无材料的持续药物递送强效治疗剂的方法在目前可注射储库不足的各种疾病中具有潜力。
Local, sustained drug delivery of potent therapeutics holds promise for the treatment of a myriad of localized diseases while eliminating systemic side effects. However, introduction of drug delivery depots such as viscous hydrogels or polymer-based implants is highly limited in stiff tissues such as desmoplastic tumors. Here, we present a method to create materials-free intratumoral drug depots through Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs diffuse into tissue and attach locally for sustained drug release. In TRAPs, potent drugs are modified with ECM-reactive groups and then locally injected to quickly react with accessible amines within the ECM, creating local drug depots. We demonstrate that locally injected TRAPs create dispersed, stable intratumoral depots deep within mouse and human pancreatic tumor tissues. TRAPs depots based on ECM-reactive paclitaxel (TRAP paclitaxel) had better solubility than free paclitaxel and enabled sustained in vitro and in vivo drug release. TRAP paclitaxel induced higher tumoral apoptosis and sustained better antitumor efficacy than the free drug. By providing continuous drug access to tumor cells, this material-free approach to sustained drug delivery of potent therapeutics has the potential in a wide variety of diseases where current injectable depots fall short.
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