PDF(Pubmed)
Abstract：
UNASSIGNED: Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles. Despite these advancements, none of the current therapeutics are curative and show some degree of toxicity. Here we present the synthesis and preclinical evaluation of a multimodal, PSMA-targeted dendrimer-drug conjugate (PT-DDC), synthesized using poly(amidoamine) (PAMAM) dendrimers. PT-DDC was designed to enable imaging of drug delivery, providing valuable insights to understand and enhance therapeutic response.
UNASSIGNED: The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2\',2\"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA+ PC3 PIP and PSMA- PC3 flu cell lines, and in mice bearing the corresponding xenografts.
UNASSIGNED: PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA+ PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA- PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity.
UNASSIGNED: In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA+ tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer.
UNASSIGNED: The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2\',2\"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA+ PC3 PIP and PSMA- PC3 flu cell lines, and in mice bearing the corresponding xenografts.
UNASSIGNED: PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA+ PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA- PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity.
UNASSIGNED: In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA+ tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer.
摘要：
■前列腺癌（PC）是男性中第二常见的癌症，也是第五常见的癌症死亡原因。前列腺特异性膜抗原（PSMA）的表达与侵袭性PC有关，在超过90％的转移性疾病患者中表达。这些特性导致其用于PC诊断和放射性药物治疗，抗体-药物缀合物，和纳米粒子。尽管取得了这些进步,目前的治疗方法都没有治愈性，并显示出一定程度的毒性。在这里，我们介绍了多模态的综合和临床前评估，PSMA靶向树枝状聚合物-药物偶联物（PT-DDC），使用聚(酰胺基胺)(PAMAM)树枝状聚合物合成。PT-DDC被设计用于给药成像,提供有价值的见解，以理解和提高治疗反应。
■PT-DDC是通过将第4代PAMAM树状聚合物与高效抗有丝分裂剂1（DM1）连续缀合而合成的，Cy5红外染料用于光学成像，2,2\'，2“-（1,4,7-三氮杂环壬烷-1,4,7-三基）三乙酸（NOTA）螯合剂，用于用铜-64和正电子发射断层扫描/计算机断层扫描（PET/CT）进行放射性标记，赖氨酸-脲-谷氨酸（KEU）PSMA靶向部分和剩余的末端伯胺用丁烷-1,2-二醇封端。在没有KEU缀合的情况下配制非靶向对照树枝状聚合物-药物缀合物(Ctrl-DDC)。PT-DDC和Ctrl-DDC使用高效液相色谱法进行表征，基质辅助激光解吸电离质谱和动态光散射。在等基因人前列腺癌PSMAPC3PIP和PSMA-PC3流感细胞系中进行了PT-DDC和Ctrl-DDC的体外和体内评估，和携带相应异种移植物的小鼠。
■PT-DDC在1×PBS和人血浆中稳定，需要谷胱甘肽才能释放DM1。光学,PET/CT和生物分布研究证实了PT-DDC的体内PSMA特异性。PT-DDC在PSMA+PC3PIP细胞中表现出剂量依赖性的积累和细胞毒性，并显示出相应肿瘤的生长抑制。PT-DDC在PSMA-PC3流感肿瘤中不积累并且不抑制它们的生长。Ctrl-DDC未显示PSMA特异性。
■在这项研究中，我们合成了一种能够将DM1和放射性核素递送至PSMA+肿瘤的多峰治疗诊断药物.这种方法有望增强图像引导治疗的侵略性，前列腺癌的转移性亚型。
■PT-DDC是通过将第4代PAMAM树状聚合物与高效抗有丝分裂剂1（DM1）连续缀合而合成的，Cy5红外染料用于光学成像，2,2\'，2“-（1,4,7-三氮杂环壬烷-1,4,7-三基）三乙酸（NOTA）螯合剂，用于用铜-64和正电子发射断层扫描/计算机断层扫描（PET/CT）进行放射性标记，赖氨酸-脲-谷氨酸（KEU）PSMA靶向部分和剩余的末端伯胺用丁烷-1,2-二醇封端。在没有KEU缀合的情况下配制非靶向对照树枝状聚合物-药物缀合物(Ctrl-DDC)。PT-DDC和Ctrl-DDC使用高效液相色谱法进行表征，基质辅助激光解吸电离质谱和动态光散射。在等基因人前列腺癌PSMAPC3PIP和PSMA-PC3流感细胞系中进行了PT-DDC和Ctrl-DDC的体外和体内评估，和携带相应异种移植物的小鼠。
■PT-DDC在1×PBS和人血浆中稳定，需要谷胱甘肽才能释放DM1。光学,PET/CT和生物分布研究证实了PT-DDC的体内PSMA特异性。PT-DDC在PSMA+PC3PIP细胞中表现出剂量依赖性的积累和细胞毒性，并显示出相应肿瘤的生长抑制。PT-DDC在PSMA-PC3流感肿瘤中不积累并且不抑制它们的生长。Ctrl-DDC未显示PSMA特异性。
■在这项研究中，我们合成了一种能够将DM1和放射性核素递送至PSMA+肿瘤的多峰治疗诊断药物.这种方法有望增强图像引导治疗的侵略性，前列腺癌的转移性亚型。
