Local iontophoretic administration of cytotoxic therapies to solid tumors.
Local iontophoretic administration of cytotoxic therapies to solid tumors.
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DOI：
10.1126/scitranslmed.3009951
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发表时间：
2015-02-04
影响因子：
17.1
通讯作者：
DeSimone JM
中科院分区：
文献类型：
--
作者：
Byrne JD;Jajja MR;O'Neill AT;Bickford LR;Keeler AW;Hyder N;Wagner K;Deal A;Little RE;Moffitt RA;Stack C;Nelson M;Brooks CR;Lee W;Luft JC;Napier ME;Darr D;Anders CK;Stack R;Tepper JE;Wang AZ;Zamboni WC;Yeh JJ;DeSimone JM
胃肠外和口服途径一直是向癌症患者施用细胞毒性剂的传统方法。不幸的是，由于全身毒性和肿瘤灌注不良，这些细胞毒性药物的最大潜在作用受到限制。在试图提高细胞毒性剂的疗效，同时减轻其副作用，我们已经开发了局部离子电渗递送细胞毒性剂的方式。这些离子电渗设备被设计成植入肿瘤近端，并具有对功率和药物流的外部控制。评价了三种不同的原位小鼠癌症模型和一种犬模型的器械有效性和毒性。通过器械每两周接受一次吉西他滨治疗的原位患者源性胰腺癌异种移植物的肿瘤体积平均log2倍数变化为−0.8，而静脉注射（IV）吉西他滨组的肿瘤体积平均log2倍数变化为1.1，IV生理盐水组为3.0，器械生理盐水组为2.6。在两种侵袭性原位乳腺癌模型中，每周联合全身顺铂治疗和透皮装置顺铂治疗显著增加了肿瘤生长抑制作用，并使生存期增加了一倍。在这种治疗中加入放疗进一步延长了生存期。犬中吉西他滨的器械给药导致局部药物浓度差异超过7倍，全身药物水平比IV给药低25倍。总的来说，这些器械对胰腺、乳腺和其他实体瘤的治疗具有潜在的范式转变意义。
Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents. These iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow. Three distinct orthotopic mouse models of cancer and a canine model were evaluated for device efficacy and toxicity. Orthotopic patient-derived pancreatic cancer xenografts treated biweekly with gemcitabine via the device for 7 weeks experienced a mean log2 fold change in tumor volume of −0.8 compared to a mean log2 fold change in tumor volume of 1.1 for intravenous (IV) gemcitabine, 3.0 for IV saline, and 2.6 for device saline groups. The weekly coadministration of systemic cisplatin therapy and transdermal device cisplatin therapy significantly increased tumor growth inhibition and doubled the survival in two aggressive orthotopic models of breast cancer. The addition of radiotherapy to this treatment further extended survival. Device delivery of gemcitabine in dogs resulted in more than 7-fold difference in local drug concentrations and 25-fold lower systemic drug levels than the IV treatment. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors.