Intralymphatic chemotherapy using a hyaluronan-cisplatin conjugate
Intralymphatic chemotherapy using a hyaluronan-cisplatin conjugate
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DOI：
10.1016/j.jss.2008.02.048
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发表时间：
2008-06-15
影响因子：
2.2
通讯作者：
Forrest, M. Laird
中科院分区：
文献类型：
--
作者：
Cai, Shuang;Xie, Yumei;Forrest, M. Laird
背景一旦乳腺癌从原发肿瘤扩散，通常会扩散到区域淋巴结，因此对腋窝淋巴结的充分评估和治疗在早期疾病中至关重要。当前疗法的一个显著问题是化疗剂单独或组合全身产生的副作用。本研究的目的是确定靶向顺铂载体是否会增加淋巴转移灶的局部剂量而无全身毒性。透明质酸（HA）是一种高度生物相容性的聚合物，可从组织间隙进行淋巴引流。我们通过非共价缀合形成HA和顺铂的复合物。将复合物注射到雌性大鼠上乳脂肪垫皮下，测定其组织分布。顺铂-HA含有高达0.25 w/w的Pt，并在盐水中以10 h的半衰期释放药物。顺铂-HA偶联物在体外具有与游离药物相似的高抗肿瘤活性：在MCF 7和MDA-MB-231人乳腺癌细胞中顺铂-HA IC 50 7 μ g/mL（游离顺铂IC 50 7 μ g/mL）。顺铂-HA偶联物在啮齿动物中耐受良好，96 h后无注射部位发病或主要器官毒性体征。顺铂-维甲酸注射后，轴淋巴结顺铂曲线下面积较顺铂对照组增加74%。这项研究证明了一种新的乳腺癌淋巴内给药方法，可以优先治疗高危区域淋巴结，避免全身毒性。进一步的体内试验与这种方法在生存、毒性和药代动力学方面的有效性有关，以支持其在人体试验中的使用。(C)2008年爱思唯尔公司All rights reserved.
Background. Breast cancers typically spread to regional lymph nodes once they disseminate from the primary tumor, thus adequate evaluation and treatment of the axillary lymph nodes is paramount in early stage disease. One significant problem with current therapy is the side effects chemotherapy agents create systemically, either alone or in combination. The purpose of this study is to determine whether lymphatically targeted cisplatin carriers will increase the localized dose in lymphatic metastases without systemic toxicities.Methods. Hyaluronan (HA) is a highly biocompatible polymer that follows lymphatic drainage from the interstitial spaces. We formed complexes of HA and cisplatin by non-covalent conjugation. Complexes were injected subcutaneously into the upper mammary fat pad of female rats, and the tissue distribution determined.Results. Cisplatin-HA contained up to 0.25 w/w of Pt and released drug with a half-life of 10 h in saline. Cisplatin-HA conjugates had high anti-tumor activity in vitro similar to the free drug: cisplatin-HA IC50 7 mu g/mL in MCF7 and MDA-MB-231 human breast cancer cells (free cisplatin IC50 7 mu g/mL). Cisplatin-HA conjugates were well tolerated in rodents with no signs of injection site morbidity or major organ toxicity after 96 h. The area-under-the-curve of cisplatin in the axially lymph nodes after injection with cisplatin-RA increased 74% compared with normal cisplatin.Conclusions. This study demonstrates a novel intra-lymphatic drug delivery method in breast cancer to preferentially treat at-risk regional lymph nodes and avoid systemic toxicities. Further in vivo testing related to efficacy of this approach with regard to survival, toxicity, and pharmacokinetics is warranted to support its use in human trials. (C) 2008 Elsevier Inc. All rights reserved.