Developing targeted therapy with prostate cancer specific nanomedicine

描述（由申请人提供）：前列腺癌（PCa）已经超过肺癌成为美国男性的主要癌症。由于前列腺癌是一种雄激素依赖性疾病，大多数患者在最初的临床表现时已经发生了转移性病变，雄激素消融已经成为一种标准治疗方法。去势抵抗性前列腺癌（CRPC）的复发不可避免地会导致患者死亡，因为CRPC细胞对常规化疗具有耐药性。此外，由于年龄大，前列腺癌患者往往没有良好的身体条件来忍受化疗的不良副作用。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显著提高了前列腺癌患者的生存率，但前列腺癌仍然无法治愈。癌症干细胞（cancer stem cell， CSC）模型是解释癌症复发和治疗无效的可能理论之一，其中一组肿瘤细胞负责癌症的发生和进展以及癌症复发。这些CSCs与正常干细胞具有自我更新、不朽和分化为多种细胞类型的特性，包括癌细胞的异质谱系。此外，CSC可以从治疗后留下的一些细胞中重新生长，因此开发更专门针对CSC的治疗方法将是重要的。因此，靶向肿瘤干细胞成为目前癌症治疗的一个活跃研究领域，以实现最终的治愈。为了特异性靶向前列腺癌，我们正在开发一种新的可生物降解和生物相容性纳米颗粒，它可以特异性靶向前列腺癌并具有成像能力。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，可以优先杀死表达干细胞特性的PCa细胞，然后在临床前动物模型中通过分子成像监测评估PCa的治疗效果。我们希望能够实时监测药物的传递和/或癌细胞的反应。这种实验性疗法可能成为治疗CRPC的一种更好的方案，因为这种药物具有PCa特异性，预计比化疗药物毒性更小。最重要的是，这一建议是探索一种与传统治疗策略相反的量身定制治疗的新途径；我们期望这项研究的结果对CRPC治疗有直接的临床影响。

DESCRIPTION (provided by applicant): 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.