Spacer length impacts the efficacy of targeted docetaxel conjugates in prostate-specific membrane antigen expressing prostate cancer.
Spacer length impacts the efficacy of targeted docetaxel conjugates in prostate-specific membrane antigen expressing prostate cancer.
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DOI：
10.3109/1061186x.2013.833207
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发表时间：
2013-12
影响因子：
4.5
通讯作者：
Kopeček J
中科院分区：
文献类型：
--
作者：
Peng ZH;Sima M;Salama ME;Kopečková P;Kopeček J
靶向递送和控释的结合是一种强大的癌症治疗技术。在本文中，我们描述了靶向和非靶向N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物-多西紫杉醇缀合物的设计、合成、结构验证和生物学特性。多西他赛 (DTX) 通过四肽间隔基 (–GFLG-) 与 HPMA 共聚物缀合。 3-(1,3-二羧丙基)-脲基]戊二酸 (DUPA) 被用作靶向部分来主动递送 DTX，用于治疗表达前列腺特异性膜抗原 (PSMA) 的前列腺癌。制备了短间隔基和长间隔基DUPA单体，并通过可逆加成断裂链转移（RAFT）共聚制备了四种HPMA共聚物-DTX缀合物（非靶向、两种不同分子量的短间隔基靶向和长间隔基靶向）。在确认 C4-2 细胞系上的 PSMA 表达后，测试了 DTX 缀合物针对 C4-2 肿瘤细胞的体外细胞毒性，并在皮下荷瘤裸鼠中评估了其抗癌功效。人前列腺腺癌 C4-2 异种移植物。体内结果表明，靶向部分和HPMA共聚物主链之间的间隔长度可以显着影响DTX缀合物对携带C4-2肿瘤的nu/nu小鼠的治疗效果。此外，组织学分析表明，具有较长间隔基的 DUPA 靶向 DTX 缀合物对治疗小鼠的主要器官没有毒性。
Combination of targeted delivery and controlled release is a powerful technique for cancer treatment. In this paper, we describe the design, synthesis, structure validation and biological properties of targeted and non-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel conjugates. Docetaxel (DTX) was conjugated to HPMA copolymer via a tetrapeptide spacer (–GFLG-). 3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) was used as the targeting moiety to actively deliver DTX for treatment of Prostate-Specific Membrane Antigen (PSMA) expressing prostate cancer. Short and long spacer DUPA monomers were prepared, and four HPMA copolymer – DTX conjugates (non-targeted, two targeted with short spacer of different molecular weight and targeted with long spacer) were prepared via Reversible Addition-Fragmentation Chain Transfer (RAFT) copolymerization. Following confirmation of PSMA expression on C4-2 cell line, the DTX conjugates’ in vitro cytotoxicity was tested against C4-2 tumor cells and their anticancer efficacies were assessed in nude mice bearing s.c. human prostate adenocarcinoma C4-2 xenografts. The in vivo results show that the spacer length between targeting moieties and HPMA copolymer backbone can significantly affect the treatment efficacy of DTX conjugates against C4-2 tumor bearing nu/nu mice. Moreover, histological analysis indicated that the DUPA-targeted DTX conjugate with longer spacer had no toxicity in major organs of treated mice.