Peptide-targeted polyglutamic acid doxorubicin conjugates for the treatment of alpha(v)beta(6)-positive cancers.
Peptide-targeted polyglutamic acid doxorubicin conjugates for the treatment of alpha(v)beta(6)-positive cancers.
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DOI：
10.1021/bc800154f
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发表时间：
2008-09
影响因子：
4.7
通讯作者：
Brown KC
中科院分区：
文献类型：
--
作者：
Guan H;McGuire MJ;Li S;Brown KC
大多数化疗药物对肿瘤细胞和健康细胞都发挥作用，导致剂量限制的副作用。细胞特异性递送治疗药物可以在保持治疗效果的同时减少不良副作用，从而增加治疗的治疗窗口。我们之前已经发现了一种名为H2009.1的肽，它与整合素αvβ6结合。在这里，我们报道了一种肽靶向聚谷氨酸聚合物的合成，其中高亲和αvβ6特异性四聚体H2009.1肽通过15个氨基酸的谷氨酸聚合物的n端硫醚结合。阿霉素通过酸不稳定的腙键结合到聚合物中。每个靶向剂可达到4个阿霉素分子的有效载荷。药物在pH 4.0和5.6时释放，但偶联物在pH 7.0时稳定。通过流式细胞分析和荧光显微镜观察，该缀合物选择性内化到αvβ6阳性细胞中。细胞摄取是由H2009.1肽介导的，因为当阿霉素- pg聚合物偶联到一个混乱的序列控制肽时，没有观察到它的内化。重要的是，与不表达整合素的细胞系相比，结合物对目标细胞的细胞毒性更大。
Most chemotherapeutics exert their effects on tumor cells as well as their healthy counterparts, resulting in dose limiting side effects. Cell-specific delivery of therapeutics can increase the therapeutic window for treatment by maintaining the therapeutic efficacy while decreasing the untoward side effects. We have previously identified a peptide, named H2009.1, which binds to the integrin αvβ6. Here, we report the synthesis of a peptide targeted polyglutamic acid polymer in which the high affinity αvβ6-specific tetrameric H2009.1 peptide is incorporated via a thioether at the N-terminus of a 15 amino acid polymer of glutamic acid. Doxorubicin is incorporated into the polymer via an acid-labile hydrazone bond. Payloads of four doxorubicin molecules per targeting agent are achieved. The drug is released at pH 4.0 and 5.6 but the conjugate is stable at pH 7.0. The conjugate is selectively internalized into αvβ6 positive cells as witnessed by flow cytometric analysis and fluorescent microscopy. Cellular uptake is mediated by the H2009.1 peptide, as no internalization of the doxorubicin-PG polymer is observed when it is conjugated to a scrambled sequence control peptide. Importantly, the conjugate is more cytotoxic toward a targeted cell than a cell line that does not express the integrin.
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