Targeting of Curcumin-genistein nanocomplexes for Treatment of Prostate Cancer

描述（由申请人提供）：该提案的主要目标是设计用于前列腺癌（PCa）的新型治疗方法，其采用姜黄素和染料木黄酮纳米复合物对PCa细胞的特异性靶向。前列腺癌是美国男性死亡的第三大原因。虽然雄激素剥夺已被发现在治疗雄激素依赖性前列腺癌中是有效的，但它在治疗晚期前列腺癌中是无效的，晚期前列腺癌是死亡的主要原因。近年来，天然产物姜黄素和染料木黄酮在临床研究中表现出抗炎和抗癌作用，但由于生物利用度低，其在前列腺癌预防和治疗中的应用受到严重限制。因此，增加这些产品的溶解度和生物利用度以及将这些产品靶向递送至特定的癌细胞被认为是这些无毒天然产品的最有前途的策略。Transgenex Nanobiotech，Inc.已经开发了新型纳米颗粒，用于靶向递送小分子，如姜黄素和染料木黄酮，增加其溶解度和稳定性。壳聚糖-环糊精-姜黄素（3C）复合物显著增加姜黄素在含血清的生物介质中的半衰期。这些结果导致了这样的假设，即进一步与染料木素（3CG）复合的多功能3C纳米颗粒可以被递送至前列腺以抑制PCa进展和/或转移。选择姜黄素和染料木黄酮作为抗PCa剂是基于它们在生物利用度方面的互补效应和在调节基因表达和信号传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，我们将在第一个目标中对3CG纳米复合物进行体内生物利用度和前列腺特异性靶向能力研究。各组小鼠将单独或一起给予姜黄素和染料木黄酮，单独或以纳米复合物形式给予。将通过腹膜内或口服施用药物和复合物，并通过HPLC测定血清中姜黄素和染料木黄酮的生物利用度。还计划检查与针对前列腺干细胞抗原（PSCA）的肽或抗体偶联的3CG纳米颗粒的前列腺细胞特异性递送的潜力。目标1的结果将定义3CG-纳米复合物的最有效递送途径，其将提供增加的生物利用度和将纳米颗粒靶向PCa肿瘤的方法。在第二个目的中，计划评估特异性递送至TRAMP小鼠中前列腺的3CG纳米复合物的抗肿瘤功效。研究所需的所有方法和试剂均可用。这些纳米复合物的成功靶向与天然抗肿瘤剂的生物利用度提高，具有已证实的安全性记录，预计将导致新的治疗前列腺癌和其他癌症。公共卫生相关性：该提案的主要目标是设计前列腺癌（PCa）的新疗法，这是美国男性死亡的第三大原因，该疗法采用姜黄素和染料木黄酮纳米复合物对PCa细胞的特异性靶向作用。尽管姜黄素和染料木黄酮的安全性已得到证实，但由于它们的生物利用度差，因此尚未进行临床试验。所提出的新制剂预期消除生物利用度的问题，并将抗肿瘤纳米颗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.