Doxorubicin Conjugate of Poly( Ethylene Glycol)- Block Polyphosphoester for Cancer Therapy
Doxorubicin Conjugate of Poly( Ethylene Glycol)- Block Polyphosphoester for Cancer Therapy
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DOI：
10.1002/adhm.201300091
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发表时间：
2014-02-01
影响因子：
10
通讯作者：
Wang, Jun
中科院分区：
文献类型：
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作者：
Sun, Chun-Yang;Dou, Shuang;Wang, Jun
具有重复磷酸键的多磷酸酯易于功能化，具有生物可降解性和潜在的生物相容性，可能是药物偶联物聚合物载体的潜在候选者。本文首次对多聚磷酸酯药物偶联物作为体内抗癌剂的疗效进行了评价。在可控的合成条件下，阿霉素通过不稳定的腙键与聚乙二醇嵌段聚磷酸酯（PPEH-DOX）偶联，在水溶液中形成平均直径约为60纳米的球形纳米颗粒。这些纳米颗粒被MDA-MB-231乳腺癌细胞有效内化，并根据胞内核内体和溶酶体的pH值释放偶联的阿霉素，从而在癌细胞中产生显著的抗增殖活性。与游离阿霉素注射剂相比，PPEH-DOX注射剂在小鼠血浆中的循环时间更长，并导致药物在肿瘤细胞中的积累增强。在MDA-MB-231异种移植小鼠模型中，与游离阿霉素注射相比，全身递送PPEH-DOX纳米颗粒对肿瘤生长的抑制作用更为明显，这表明多磷酸酯作为药物偶联物载体在癌症治疗中的潜力。
Polyphosphoesters with repeating phosphoester linkages in the backbone can be easily functionalized, are biodegradable and potentially biocompatible, and may be potential candidates as polymer carriers of drug conjugates. Here, the efficacy of a polyphosphoester drug conjugate as an anticancer agent in vivo is assessed for the first time. With controlled synthesis, doxorubicin conjugated to poly(ethylene glycol)-block-polyphosphoester (PPEH-DOX) via labile hydrazone bonds form spherical nanoparticles in aqueous solution with an average diameter of approximate to 60 nm. These nanoparticles are effectively internalized by MDA-MB-231 breast cancer cells and release the conjugated doxorubicin in response to the intracellular pH of endosomes and lysosomes, resulting in significant antiproliferative activity in cancer cells. Compared with free doxorubicin injection, PPEH-DOX injection exhibits much longer circulation behavior in the plasma of mice and leads to enhanced drug accumulation in tumor cells. In an MDA-MB-231 xenograft murine model, inhibition of tumor growth with systemic delivery of PPEH-DOX nanoparticles is more pronounced compared with free doxorubicin injection, suggesting the potential of polyphosphoesters as carriers of drug conjugates in cancer therapy.