Evaluation of intraductal delivery of poly(ethylene glycol)-doxorubicin conjugate nanocarriers for the treatment of ductal carcinoma in situ (DCIS)-like lesions in rats.
Evaluation of intraductal delivery of poly(ethylene glycol)-doxorubicin conjugate nanocarriers for the treatment of ductal carcinoma in situ (DCIS)-like lesions in rats.
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DOI：
10.1002/jin2.51
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Sinko PJ
中科院分区：
文献类型：
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作者：
Gu Z;Al-Zubaydi F;Adler D;Li S;Johnson S;Prasad P;Holloway J;Szekely Z;Love S;Gao D;Sinko PJ
导管原位癌是最常见的早期乳腺癌。在原位导管癌样大鼠模型中，研究了导管内递送聚乙二醇-阿霉素（PEG - DOX）纳米载体（由一种或多种DOX偶联各种PEG聚合物组成）的疗效。采用MTT法对13762个matb III细胞进行体外细胞毒性评价。将癌细胞接种于雌性Fischer 344退休繁殖大鼠乳腺导管中，建立原位模型。在体外实验的基础上，研究了六种纳米载体中的两种（5kda PEG - DOX和40kda PEG - (DOX)4）的导管保留和体内抗肿瘤功效。DOX和PEG - DOX纳米载体的乳腺保留使用体内成像进行量化。还研究了DOX和PEG - DOX纳米载体对乳腺导管结构的组织病理学影响。小的线性PEG - DOX纳米载体（5和10 kDa）的细胞毒性与DOX没有区别，而较大的PEG - DOX纳米载体的效力降低。在正常和荷瘤大鼠中，乳腺保留的顺序为40 kDa PEG‐（DOX）4 > 5 kDa PEG‐DOX >> DOX。导管内给药PEG - DOX纳米载体和DOX在降低肿瘤发生率和提高生存率方面有效，三个治疗组之间没有显著差异。然而，同样剂量的纳米载体静脉注射无效，并且静脉注射游离DOX引起严重的局部毒性。导管内给药PEG - DOX纳米载体比游离DOX和静脉给药DOX/PEG - DOX有效且毒性更小。此外，PEG - DOX纳米载体显示出延长DOX导管保留的额外好处，这将需要更少的给药频率。
Ductal carcinoma in situ is the most commonly diagnosed early stage breast cancer. The efficacy of intraductally delivered poly(ethylene glycol)‐doxorubicin (PEG‐DOX) nanocarriers, composed of one or more DOX conjugated to various PEG polymers, was investigated in an orthotopic ductal carcinoma in situ‐like rat model. In vitro cytotoxicity was evaluated against 13762 Mat B III cells using MTT assay. The orthotopic model was developed by inoculating cancer cells into mammary ducts of female Fischer 344 retired breeder rats. The ductal retention and in vivo antitumour efficacy of two of the six nanocarriers (5 kDa PEG‐DOX and 40 kDa PEG‐(DOX)4) were investigated based on in vitro results. Mammary retention of DOX and PEG‐DOX nanocarriers was quantified using in vivo imaging. Histopathologic effects of DOX and PEG‐DOX nanocarriers on mammary ductal structure were also investigated. Cytotoxicities of small linear PEG‐DOX nanocarriers (5 and 10 kDa) were not different from DOX whereas larger PEG‐DOX nanocarriers showed reduced potency. The order of mammary retention was 40 kDa PEG‐(DOX)4 > 5 kDa PEG‐DOX >> DOX, in normal and tumour‐bearing rats. Intraductally administered PEG‐DOX nanocarriers and DOX were effective in reducing tumour incidence and increasing survival rate, with no significant differences found among the three treatment groups. However, nanocarriers administered intravenously at the same doses were not effective, and intraductally administered free DOX caused severe local toxicity. Intraductal administration of PEG‐DOX nanocarriers is effective and less toxic than that of free DOX, as well as IV DOX/PEG‐DOX. Furthermore, PEG‐DOX nanocarriers demonstrate the added benefit of prolonging DOX ductal retention, which would necessitate less frequent dosing.