Department of Chemistry, College of Arts and Sciences, Washington State University, Pullman, WA, USA.
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.
Nanoscale. 2024 Mar 14;16(11):5634-5652. doi: 10.1039/d3nr06520k.
Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Although early-stage treatments exhibit promising 5-year survival rates, the treatment options for advanced stage disease are constrained, with short survival benefits due to the challenges associated with effective and selective drug delivery to PCa cells. Even though targeting Prostate Specific Membrane Antigen (PSMA) has been extensively explored and is clinically employed for imaging and radio-ligand therapy, the clinical success of PSMA-based approaches for targeted delivery of chemotherapies remains elusive. In this study, we combine a generation 4 hydroxy polyamidoamine dendrimer (PD) with irreversible PSMA ligand (CTT1298) to develop a PSMA-targeted nanoplatform () for selective intracellular delivery of potent chemotherapeutics to PCa. exhibits a PSMA IC in the nanomolar range and demonstrates selective uptake in PSMA (+) PCa cells PSMA mediated internalization. When systemically administered in a prostate tumor xenograft mouse model, selectively targets PSMA (+) tumors with significantly less accumulation in PSMA (-) tumors or upon blocking of the PSMA receptors. Moreover, the dendrimer clears rapidly from the off-target organs limiting systemic side-effects. Further, the conjugation of an anti-cancer agent, cabozantinib to the PSMA-targeted dendrimer translates to a significantly enhanced anti-proliferative activity compared to the free drug. These findings highlight the potential of nanoplatform as a versatile approach for selective delivery of high payloads of potent chemotherapeutics to PCa, where dose related systemic side-effects are a major concern.
前列腺癌（PCa）是美国男性癌症相关死亡的第二大主要原因。尽管早期治疗显示出有希望的 5 年生存率，但晚期疾病的治疗选择受到限制，由于有效和选择性地将药物递送到 PCa 细胞方面的挑战，生存获益短暂。尽管针对前列腺特异性膜抗原（PSMA）的靶向治疗已经得到广泛探索，并在临床上用于成像和放射性配体治疗，但基于 PSMA 的方法在靶向递送电化疗方面的临床成功仍然难以实现。在这项研究中，我们将第四代羟聚酰胺树枝状大分子（PD）与不可逆的 PSMA 配体（CTT1298）结合，开发了一种 PSMA 靶向纳米平台（），用于将有效的化疗药物选择性地递送至 PCa 细胞内。 表现出纳摩尔范围内的 PSMA IC，并表现出对 PSMA（+）PCa 细胞的选择性摄取和 PSMA 介导的内化。当在前列腺肿瘤异种移植小鼠模型中系统给药时， 选择性地靶向 PSMA（+）肿瘤，在 PSMA（-）肿瘤或在阻断 PSMA 受体时，其积累明显减少。此外，树枝状大分子从非靶器官迅速清除，限制了全身副作用。此外，将抗癌药物卡博替尼与 PSMA 靶向树枝状大分子偶联，与游离药物相比，显著增强了抗增殖活性。这些发现强调了 纳米平台作为一种将高负载量的有效化疗药物选择性递送至 PCa 的多功能方法的潜力，其中与剂量相关的全身副作用是一个主要问题。
