A low molecular weight multifunctional theranostic molecule for the treatment of prostate cancer.
A low molecular weight multifunctional theranostic molecule for the treatment of prostate cancer.
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DOI：
10.7150/thno.68715
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Basilion JP
中科院分区：
文献类型：
--
作者：
Wang X;Sun R;Wang J;Li J;Walker E;Shirke A;Ramamurthy G;Shan L;Luo D;Carmon L;Basilion JP
基本原理：虽然手术和放射治疗在低风险前列腺癌患者中似乎是适当和有效的，但那些具有高风险局部疾病的患者几乎总是成为激素难治性的，然后迅速进展。对于高危局限性前列腺癌患者，迫切需要一种新的治疗策略，特别是将两种具有不同机制的药物结合起来的方法。光动力疗法（PDT）和化疗的组合在临床试验中显示出协同效应，但受到脱靶毒性的限制。前列腺特异性膜抗原（PSMA）是前列腺癌的公认生物标志物。在这里，我们描述了使用PSMA配体选择性地同时递送有效的微管抑制剂单甲基澳瑞他汀E（MMAE）和PDT剂IR 700至前列腺癌。方法：利用PSMA的双功能配体PSMA-1-Cys-C6-Lys，设计合成了一个新的治疗诊断分子PSMA-1-MMAE-IR 700。在体外和体内测试该分子的选择性和抗肿瘤活性研究。结果如下：PSMA-1-MMAE-IR 700在体外和体内均在PSMA阳性的PC 3 pip细胞中显示出选择性和特异性摄取，但在PSMA阴性的PC 3flu细胞中不显示出选择性和特异性摄取。在体外细胞毒性研究中，当暴露于690 nm光时，与有光照射的PSMA-1-IR 700或无光照射的PSMA-1-MMAE-IR 700相比，PSMA-1-MMAE-IR 700表现出协同效应，导致对PC 3 pip细胞的更大细胞毒性。体内抗肿瘤活性研究进一步显示，与接受等摩尔量的PSMA-1-IR 700和光照射或PSMA-1-IR 700-MMAE而不接受光照射的小鼠相比，PSMA-1-MMAE-IR 700和光照射显著抑制PC 3 pip肿瘤生长并延长存活时间。结论：我们已经合成了一种新的多功能治疗诊断分子，它结合了成像，化疗和PDT，用于治疗表达PSMA的癌症组织。这项工作可能为晚期前列腺癌提供新的治疗选择。
Rationale: Although surgery and radiation therapy in patients with low risk prostate cancer appear appropriate and effective, those with high-risk localized disease almost always become hormone refractory and then rapidly progress. A new treatment strategy is urgently needed for patients with high-risk localized prostate cancer, particularly an approach that combines two drugs with different mechanisms. Combinations of photodynamic therapy (PDT) and chemotherapy have shown synergistic effects in clinical trials, but are limited by off-target toxicity. Prostate specific membrane antigen (PSMA) is a well-established biomarker for prostate cancer. Here we describe the use of a PSMA ligand to selectively and simultaneously deliver a potent microtubule inhibiting agent, monomethyl auristatin E (MMAE), and a PDT agent, IR700, to prostate cancers. Methods: Using a bifunctional PSMA ligand PSMA-1-Cys-C6-Lys, we created a novel theranostic molecule PSMA-1-MMAE-IR700. The molecule was tested in vitro and in vivo for selectivity and antitumor activity studies. Results: PSMA-1-MMAE-IR700 showed selective and specific uptake in PSMA-positive PC3pip cells, but not in PSMA-negative PC3flu cells both in vitro and in vivo. In in vitro cytotoxicity studies, when exposed to 690 nm light, PSMA-1-MMAE-IR700 demonstrated a synergistic effect leading to greater cytotoxicity for PC3pip cells when compared to PSMA-1-IR700 with light irradiation or PSMA-1-MMAE-IR700 without light irradiation. In vivo antitumor activity studies further showed that PSMA-1-MMAE-IR700 with light irradiation significantly inhibited PC3pip tumor growth and prolonged survival time as compared to mice receiving an equimolar amount of PSMA-1-IR700 with light irradiation or PSMA-1-IR700-MMAE without light irradiation. Conclusion: We have synthesized a new multifunctional theranostic molecule that combines imaging, chemotherapy, and PDT for therapy against PSMA-expressing cancer tissues. This work may provide a new treatment option for advanced prostate cancer.
影响因子：
1.4
作者：
Marciscano AE;Hardee ME;Sanfilippo N
通讯作者：
Sanfilippo N