Developing targeted therapy with prostate cancer specific nanomedicine

项目摘要 前列腺癌(PCA)已超过肺癌成为美国男性的头号癌症。 大多数患者在最初的临床表现时就已经形成了转移性病变 由于前列腺癌是一种雄激素依赖型(AD)，雄激素消融已成为一种标准治疗方法。 疾病。抗去势PCa的复发将不可避免地导致患者的死亡。 因为CRPC细胞对常规化疗具有耐药性。此外，由于年龄较高，PCA 患者往往没有良好的身体条件来容忍 化疗。因此，开发一种新的安全有效的治疗方法成为当务之急。 尽管新开发的治疗方案使PCA患者的存活率显著提高 病情好转后，前列腺癌仍无法治愈。有一种可能的理论可以解释这种反复出现的现象 癌症治疗的无效是癌症干细胞(CSC)模型，在该模型中，肿瘤的一个子集 细胞负责癌症的发生和发展以及癌症的复发。这些CSC 与正常干细胞一样，具有自我更新、不朽和分化为各种 细胞类型包括癌细胞的异质性谱系。此外，CSC可以从几个细胞重新生长 在治疗后留下的，开发更有针对性的治疗方法将是重要的 对CSC的指控。因此，靶向肿瘤干细胞成为目前癌症研究的一个活跃领域。 治疗以达到终极治愈。为了特别针对PCA，我们正在开发一种新的 可生物降解和生物兼容的纳米颗粒，可以靶向具有成像能力的PCA。 利用这种独特的传递系统，我们建议设计一种独特的基因毒素，它可以优先 杀伤表达干细胞特性的PCA细胞，然后评估监测的PCA的治疗效果 通过在临床前动物模型中进行分子成像。我们希望能够监测药物的输送情况 和/或癌细胞的实时响应。这种实验性疗法可能会成为一种 更好的治疗CRPC的方案，因为这种药物具有PCA特异性，预计 毒性比化疗药物小。最重要的是，这项建议是为了探索一条新的途径 与传统治疗策略不同的量身定制治疗；我们预计这一治疗的结果 这项研究应该会对CRPC治疗产生直接的临床影响。

Project Summary Prostate cancer (PCa) has surpassed lung cancer as the leading cancer among American men. The majority of patients have already developed metastatic lesions at initial clinical presentation and androgen ablation has become a standard therapy because PCa is an androgen-dependent (AD) disease. Inevitably, the recurrence of castration resistant PCa (CRPC) will result in mortality of patients since CRPC cells are resistant to conventional chemotherapy. Moreover, because of high age, PCa patients often do not have favorable physical conditions to tolerate undesirable side effects of chemotherapy. Thus, developing a new, safe and effective therapy becomes a high priority. Although PCa patient survival with newly developed therapeutic regimens has been significantly improved, PCa remains incurable. One of the possible theories to explain the recurrence and ineffectiveness of cancer treatment is the cancer stem cell (CSC) model in which a subset of tumor cells is responsible for cancer initiation and progression as well as cancer recurrence. These CSCs share with normal stem cells the properties of self-renewal, immortal and differentiation into a variety of cell types including heterogeneous lineages of cancer cells. Also, CSC can re-grow from a few cells left behind after therapy, it will be important to develop therapies that are more specifically directed against CSCs. Thus, targeting cancer stem cell is now becomes an active research area of cancer therapy to achieve the ultimate cure. In order to target PCa specifically, we are developing a new biodegradable and biocompatible nanoparticle that can target PCa specifically with imaging capabilities. Using this unique delivery system, we propose to engineer a unique genotoxin that can preferentially kill PCa cells expressing stem cell properties then evaluate the therapeutic efficacy of PCa monitored by molecular imaging in pre-clinical animal models. We expect be able to monitor the drug delivery and/or response of cancer cells in a real-time manner. This experimental therapy could become a better regimen for treating CRPC because this agent has a PCa specificity, which is expected to be less toxic than chemotherapeutic agents. Most importantly, this proposal is to explore a new avenue of tailored therapy in contrast to conventional therapeutic strategy; we expect that the outcome of this study should have an immediate clinical impact on CRPC therapy.