Targeting of Curcumin-genistein nanocomplexes for Treatment of Prostate Cancer

描述(申请人提供)：这项提案的主要目标是设计前列腺癌(PCA)的新型治疗方法，利用姜黄素和染料木素纳米复合体对前列腺癌细胞进行特定靶向治疗。前列腺癌是美国男性的第三大死因。虽然雄激素剥夺被发现对雄激素依赖型前列腺癌有效，但对晚期前列腺癌无效，晚期前列腺癌是导致死亡的主要原因。近年来，天然产物姜黄素和染料木素在临床研究中显示出抗炎和抗癌的作用，但由于生物利用度低，它们在预防或治疗前列腺癌方面的潜在应用受到了严重限制。因此，增加这些产品的溶解度和生物利用度，并将这些产品定向输送到特定的癌细胞，一直被认为是这些无毒天然产品最有前途的策略。Transgenex Nanobiotech，Inc.已经开发出新型纳米颗粒，用于定向输送小分子，如姜黄素和染料木素，以增加它们的溶解度和稳定性。壳聚糖-环糊精-姜黄素(3C)络合物显著延长了姜黄素在含血清生物介质中的半衰期。这些结果导致了一种假设，即进一步与金雀异黄素(3CG)络合的多功能3C纳米颗粒可以被输送到前列腺，以抑制前列腺癌的进展和/或转移。选择姜黄素和染料木素作为抗前列腺癌药物是基于它们在生物利用度方面的互补作用，以及在调节基因表达和信号转导以及抑制癌细胞生长方面的协同作用。为了验证这一假设，我们将在体内进行3CG纳米复合体的生物利用度和前列腺特异性靶向能力研究。姜黄素和金雀异黄素将单独或一起给一组小鼠服用，要么单独给予，要么以纳米复合制剂形式给予。药物和复合体将通过腹腔或口服给药，血清中姜黄素和染料木素的生物利用度将用高效液相色谱法测定。它还计划检测3CG纳米颗粒偶联到多肽或抗前列腺干细胞抗原(PSCA)抗体的前列腺细胞特异性递送的可能性。AIM 1的结果将确定最有效的3CG-纳米复合体的输送途径，这将提供更高的生物利用度和靶向PCa肿瘤的纳米颗粒的方法。在第二个目标中，计划评估3CG纳米复合体在TRAMP小鼠体内的抗肿瘤效果。研究所需的所有方法和试剂都是可用的。成功靶向这些纳米复合体，提高天然抗肿瘤药物的生物利用度，并证明其安全记录，有望带来治疗前列腺癌和其他癌症的新疗法。公共卫生相关性：这项提案的主要目标是设计前列腺癌(PCA)的新疗法，前列腺癌是美国男性死亡的第三大原因，它使用姜黄素和金雀异黄素纳米复合体特异性靶向前列腺癌细胞。尽管姜黄素和染料木素已被证明是安全的，但它们都没有经过临床测试，因为它们的生物利用度很低。所提出的新配方有望消除生物利用度的问题，并将抗肿瘤纳米粒靶向前列腺癌细胞，从而抑制其进展和/或转移。

DESCRIPTION (provided by applicant): The main goal of this proposal is to design novel treatments for prostate cancer (PCa) that employ specific targeting of curcumin and genistein nanocomplexes to PCa cells. Prostate cancer is the third leading cause of death among men in America. While androgen deprivation has been found to be effective in treating androgen-dependent PCa, it is ineffective in treating advanced PCas which are the major cause of mortality. Recently, the natural products curcumin and genistein have demonstrated anti-inflammatory and anticancer effects in clinical studies, but their potential use for PCa prevention or treatment has been severely limited due to their poor bioavailability. Consequently, increasing solubility and bioavailability and targeted delivery of these products to specific cancer cells has been considered as the most promising strategy for these nontoxic natural products. Transgenex Nanobiotech, Inc. has developed novel nanoparticles for targeted delivery of small molecules such as curcumin and genistein that increase their solubility and stability. Chitosan-cyclodextrin-curcumin (3C) complexes significantly increase curcumin's half-life in biological media with serum. These results have led to the hypothesis that multifunctional 3C nanoparticles further complexed with genistein (3CG) can be delivered to the prostate to inhibit PCa progression and/or metastasis. The choice of curcumin and genistein as anti-PCa agents is based on their complementary effects in terms of bioavailability and synergistic actions in regulating gene expression and signaling, and inhibition of the growth of cancer cells. To test this hypothesis, we will conduct in vivo bioavailability and prostate-specific target ability studies for 3CG nanocomplexes in the first aim. Groups of mice will be given curcumin and genistein separately or together, either alone or in nanocomplxes. The drugs and complexes will be administered intraperitoneally or orally and the bioavailability of curcumin and genistein in the serum will be determined by HPLC. It is also planned to examine the potential of prostate cell specific delivery of 3CG nanoparticles coupled to peptide or antibodies against prostate stem cell antigen (PSCA). The results of Aim 1 will define the most effective route of delivery of 3CG-nanocompleses that will provide increased bioavailability and method for targeting nanoparticles to PCa tumors. In the second aim, it is planned to evaluate the antitumor efficacy of 3CG nanocomplexes delivered specifically to the prostate in TRAMP mice. All the methods and reagents needed for the study are available. Successful targeting of these nanocomplexes with improved bioavailability of the natural antitumor agents with proven safety records is expected to lead to new therapeutics for PCa and other cancers. PUBLIC HEALTH RELEVANCE: The main goal of this proposal is to design novel treatments for prostate cancer (PCa), the third leading cause of death among men in America, that employ specific targeting of curcumin and genistein nanocomplexes to PCa cells. Despite their proven safety record, neither curcumin nor genistein have been tested clinically because of their poor bioavailability. The proposed novel formulation is expected to eliminate the problem of bioavailability and to target the antitumor nanoparticles to prostate cancer cells thereby inhibiting their progression and/or metastasis.