Highly selective targeted theranostics for prostate cancers

抽象的。前列腺癌（PCa）是最常见的恶性肿瘤，也是第二大癌症原因 在美国男性死亡。虽然低风险疾病患者的手术和放射治疗出现 适当且有效的治疗，那些患有高风险局部疾病的人几乎总是变得激素难治性， 然后迅速进步。高危局限性前列腺患者迫切需要新的治疗策略 癌症，特别是考虑使用多模式方法的方法， 和系统治疗。 细胞毒性药物广泛用于治疗血液恶性肿瘤和实体瘤，并且在某些情况下， 临床条件改变了其中一些疾病的自然病程。虽然有效，但由于其 由于其内在作用模式，它们也可能导致严重的脱靶不良事件， 临床疗效，可能导致提前停药，从而增加 肿瘤复发或复发。维持化疗有效性的替代方法 药物和最小化全身毒性的方法包括将细胞毒性剂偶联到人源化抗体（也 称为抗体药物偶联物，ADC）。维布妥昔单抗报告的持久临床应答 （SGN-35：西雅图遗传学公司/武田）和曲妥珠单抗-美坦新偶联物（T-DM 1;罗氏与 ImmunoGen）最近获得监管机构批准，深刻改变了ADC的前景 癌症治疗这些方法虽然显示出强大的潜力，但成本极高， 需要采用复杂和更具成本效益的方法。 在这里，我们描述了一种新的前列腺特异性膜抗原（PSMA，一种生物标志物）配体的用途。 用于前列腺癌）靶向有效的微管抑制剂MMAE和光动力疗法（PDT）， 药物IR 700选择性地治疗前列腺癌。这种新药分子的设计利用了前药方法 并且同时选择性地将两种药物递送至前列腺癌。通过选择性递送两种药物， 由于对癌细胞的治疗机制不同，预期具有更低毒性的改善的抗肿瘤活性。的 由于预期的药物协同作用（需要较低的药物剂量）， 前药活化和药物分子的快速清除，防止脱靶递送。这种分子将 使用两种前列腺癌动物模型，小鼠异位性人前列腺癌和 伴侣犬自发性前列腺癌。MMAE和IR 700治疗均被发现刺激 我们将在免疫活性伴侣犬中初步测试这一点。 狗前列腺癌的病理和生理与人类非常相似，狗经常被用于 药物开发试验由于小鼠疗效试验不能预测人类结果，因此犬疗效研究 将极大地促进所开发药剂的临床转化。

Abstract. Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer death in men in the United States. Although surgery and radiation therapy in patients with low risk disease appear appropriate and effective, those with high-risk localized disease almost always become hormone refractory and then rapidly progress. New treatment strategy is urgently needed for patients with high-risk localized prostate cancer, particularly an approach that considers the use of a multimodal approach and that includes both local and systemic therapies. Cytotoxic drugs are broadly used to treat hematological malignancies and solid tumors and, under certain clinical conditions, have changed the natural course of some of these diseases. While effective, due to their intrinsic mode of action, they may also cause significant off-target adverse events that could preclude their full clinical efficacy, possibly resulting in early discontinuation of medication and a consequent increased risk of tumor relapse or recurrence. Alternative approaches to both maintain the effectiveness of chemotherapeutic drugs and minimize systemic toxicity include conjugation of cytotoxic agents to humanized antibodies (also known as Antibody Drug Conjugates, ADCs). The durable clinical responses reported with brentuximab vedotin (SGN-35: Seattle Genetics/Takeda) and trastuzumab emtansine (T-DM1; Roche in partnership with ImmunoGen), which have recently obtained regulatory approval, have profoundly changed the outlook for ADC cancer therapy. These approaches, although showing strong potential, are extremely expensive, and less complex and more cost-efficient methodologies are needed. Here we describe the use of a novel ligand for prostate specific membrane antigen (PSMA, a biomarker for prostate cancer) to target a potent microtubule inhibiting agent, MMAE, and a photodynamic therapy (PDT) agent, IR700, selectively to prostate cancers. The design of this new drug molecule utilizes a prodrug approach and simultaneously delivers two drugs selectively to prostate cancer. By selective delivery of two drugs with different therapeutic mechanisms to cancer cells, improved antitumor activity with less toxicity is expected. The reduction in toxicity is expected due to anticipated drug synergy (requiring lower drug doses), site specific prodrug activation, and rapid clearance of the drug molecule, preventing off target delivery. This molecule will be developed using two animal models of prostate cancer, heterotopic human prostate cancer in mice and spontaneous prostate cancer in companion dogs. Both MMAE and IR700 therapy have been noted to stimulate immune response against cancer and we will preliminarily tested this in the immunocompetent companion dogs. Dog pathology and physiology of prostate cancer is very similar to humans and dogs are often used in drug development trials. Since efficacy trials in mice are not predictive of human results, efficacy studies in dogs will substantially encourage clinical translation of the developed agent.