Targeting of Curcumin-genistein nanocomplexes for Treatment of Prostate Cancer

姜黄素-染料木黄酮纳米复合物靶向治疗前列腺癌

• 批准号: 7746691
• 负责人: SUBHRA MOHAPATRA
• 金额: $ 15.88万
• 依托单位: TRANSGENEX NANOBIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-11 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746691
• 关键词: Abbreviations; Actins; Adenocarcinoma; Adenocarcinoma Cell; Adverse effects; Age; Americas; Androgen Receptor; Androgens; Animal Model; Anterior; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antioxidants; Antiviral Agents; Aspirin; Atrial Natriuretic Factor; Atrial Natriuretic Factor Receptors; Atrophic; Biological; Biological Availability; Biological Factors; Biological Markers; Breast; C57BL/6 Mouse; Cause of Death; Cell Surface Proteins; Cells; Chitosan; Chronic; Clinic; Clinical; Clinical Research; Complex; Coupled; Cream; Curcuma longa; Curcumin; Cyclodextrins; Cytoskeleton; Data; Dendritic Cells; Detection; Development; Diagnosis; Disease; Dorsal; Dose; Drug Formulations; Eating; Effectiveness; Ensure; Epidemiology; Gene Expression; Gene Expression Regulation; Genetic; Genistein; Genitourinary system; Glucuronides; Glycosylphosphatidylinositols; Goals; Half-Life; High Pressure Liquid Chromatography; Histocytochemistry; Histopathology; Human; Human Development; Image; Immunohistochemistry; Incidence; Inflammation; Inflammatory; Inhibition of Cancer Cell Growth; Inorganic Sulfates; Interleukin-6; Intestines; Isoflavones; Label; Laboratories; Large T Antigen; Lateral; Lead; Liver; Lung; Lung Inflammation; Malignant Neoplasms; Malignant neoplasm of prostate; Matrix Metalloproteinases; Metabolism; Methods; Microfilaments; Modality; Molecular; Mus; NF-kappa B; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; PTGS2 gene; Parents; Pathogenesis; Peptides; Pharmaceutical Preparations; Phosphotransferases; Plants; Play; Polynucleotides; Preventive Intervention; Prostate; Prostate Adenocarcinoma; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Protein Tyrosine Kinase; Reagent; Records; Reporting; Risk; Role; Route; Safety; Serum; Signal Transduction; Simian virus 40; Small Interfering RNA; Solubility; Soybeans; Spices; Stanolone; Stat3 protein; System; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Translating; Tumeric; Tumor Burden; Unspecified or Sulfate Ion Sulfates; absorption; antitumor agent; atrial natriuretic factor receptor A; base; cancer cell; cancer initiation; cancer prevention; deprivation; design; effective therapy; experience; improved; in vivo; inhibitor/antagonist; male; men; mortality; mouse model; nanoparticle; neoplastic cell; nonhuman primate; novel; novel therapeutics; overexpression; particle; prevent; probasin; prostate cancer prevention; prostate stem cell antigen; public health relevance; scale up; small molecule; soy; targeted delivery; tumor; tumor progression; tumorigenesis; water solubility

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.

描述（由申请人提供）：该提案的主要目标是设计新的前列腺癌（PCa）治疗方法，将姜黄素和金雀异黄素纳米复合物特异性靶向前列腺癌（PCa）细胞。前列腺癌是美国男性第三大死因。虽然雄激素剥夺已被发现可有效治疗雄激素依赖性前列腺癌，但对治疗晚期前列腺癌无效，而晚期前列腺癌是死亡的主要原因。最近，天然产物姜黄素和金雀异黄素在临床研究中显示出抗炎和抗癌作用，但由于其生物利用度差，它们在前列腺癌预防或治疗中的潜在用途受到严重限制。因此，增加溶解度和生物利用度以及将这些产品靶向递送至特定癌细胞被认为是这些无毒天然产品最有前途的策略。 Transgenex Nanobiotech, Inc. 开发了新型纳米颗粒，用于靶向递送小分子，例如姜黄素和染料木黄酮，从而提高其溶解度和稳定性。壳聚糖-环糊精-姜黄素 (3C) 复合物可显着延长姜黄素在含血清的生物介质中的半衰期。这些结果引发了这样的假设：进一步与金雀异黄素 (3CG) 复合的多功能 3C 纳米粒子可以被递送到前列腺以抑制 PCa 进展和/或转移。选择姜黄素和金雀异黄素作为抗 PCa 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传导以及抑制癌细胞生长方面的协同作用。为了检验这一假设，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服用姜黄素和金雀异黄素，无论是单独服用还是以纳米复合物形式服用。药物和复合物将腹膜内或口服给药，血清中姜黄素和染料木黄酮的生物利用度将通过 HPLC 测定。还计划检查与前列腺干细胞抗原 (PSCA) 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 的结果将确定 3CG 纳米复合物最有效的递送途径，从而提供更高的生物利用度以及将纳米颗粒靶向 PCa 肿瘤的方法。第二个目标是评估专门递送至 TRAMP 小鼠前列腺的 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。成功靶向这些纳米复合物，提高天然抗肿瘤药物的生物利用度，并具有经过验证的安全记录，预计将带来治疗前列腺癌和其他癌症的新疗法。公共健康相关性：该提案的主要目标是设计针对前列腺癌 (PCa) 的新型疗法，该疗法是美国男性第三大死因，采用姜黄素和金雀异黄素纳米复合物特异性靶向 PCa 细胞。尽管姜黄素和金雀异黄素的安全记录已得到证实，但由于其生物利用度较差，因此尚未经过临床测试。所提出的新制剂有望消除生物利用度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。

项目成果

Dual-purpose magnetic micelles for MRI and gene delivery.

用于 MRI 和基因传递的双用途磁性胶束。

• DOI: 10.1016/j.jconrel.2012.04.030
• 发表时间: 2012-10-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Wang C;Ravi S;Martinez GV;Chinnasamy V;Raulji P;Howell M;Davis Y;Mallela J;Seehra MS;Mohapatra S
• 通讯作者: Mohapatra S

Natriuretic peptide receptor a as a novel target for prostate cancer.

利尿钠肽受体a作为前列腺癌的新靶点。

• 发表时间: 2011
• 影响因子: 37.3
• 作者: Wang, Xiaoqin;Raulji, Payal;Mohapatra, Shyam S;Patel, Ronil;Hellermann, Gary;Kong, Xiaoyuan;Vera, Pedro L;Meyer;Coppola, Domenico;Mohapatra, Subhra
• 通讯作者: Mohapatra, Subhra

Manganese-loaded lipid-micellar theranostics for simultaneous drug and gene delivery to lungs.

负载锰的脂质胶束治疗诊断剂，用于同时将药物和基因递送至肺部。

• DOI: 10.1016/j.jconrel.2013.01.029
• 发表时间: 2013-04-28
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Howell M;Mallela J;Wang C;Ravi S;Dixit S;Garapati U;Mohapatra S
• 通讯作者: Mohapatra S

A chitosan-modified graphene nanogel for noninvasive controlled drug release.

壳聚糖修饰的石墨烯纳米凝胶，用于无创控制药物释放。

• DOI: 10.1016/j.nano.2013.01.003
• 发表时间: 2013-10
• 期刊: Nanomedicine : nanotechnology, biology, and medicine
• 影响因子: 5.4
• 作者: Wang, Chunyan;Mallela, Jaya;Garapati, Ujjwala Sree;Ravi, Sowndharya;Chinnasamy, Vignesh;Girard, Yvonne;Howell, Mark;Mohapatra, Subhra
• 通讯作者: Mohapatra, Subhra