Systemic administration of polymeric nanoparticle-encapsulated curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer.
Systemic administration of polymeric nanoparticle-encapsulated curcumin (NanoCurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer.
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DOI：
10.1158/1535-7163.mct-10-0172
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发表时间：
2010-08
影响因子：
5.7
通讯作者：
Maitra A
中科院分区：
文献类型：
--
作者：
Bisht S;Mizuma M;Feldmann G;Ottenhof NA;Hong SM;Pramanik D;Chenna V;Karikari C;Sharma R;Goggins MG;Rudek MA;Ravi R;Maitra A;Maitra A
姜黄素或二阿魏酰甲烷是从姜黄（Curcuma longa）根茎中提取的黄色多酚。大量已发表的报告（编号为数百）已经在每种已知主要癌症类型的临床前模型中建立了姜黄素的抗癌和化学预防特性。然而，姜黄素的临床转化由于其较差的全身生物利用度而受到严重阻碍，这要求患者每天口服高达8-10克的游离药物，以便在循环中达到可检测的水平。我们已经设计了聚合物纳米颗粒包封的姜黄素制剂（NanoCurc™），其在肠胃外施用时与游离姜黄素相比在血浆和组织中显示出显著更高的全身生物利用度。在无胸腺小鼠中建立的人胰腺癌的异种移植模型中，在皮下和原位环境中，胃肠外NanoCurc™的施用显著抑制原发性肿瘤生长。与任一单一药剂相比，肠胃外NanoCurc™与吉西他滨的组合导致增强的肿瘤生长抑制，表明体内的累加治疗影响。此外，该组合完全消除原位胰腺癌异种移植物模型中的全身性转移。在用NanoCurc™和吉西他滨处理的异种移植物中，肿瘤生长抑制伴随着核因子κ B（NFκB）活化的显著降低，以及基质金属蛋白酶MMP-9和细胞周期蛋白D1表达的显著降低。NanoCurc™是一种很有前途的新制剂，能够通过改善全身生物利用度和扩展治疗功效来克服姜黄素临床转化为癌症患者的主要障碍。
Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume of published reports (numbering in several 100s) has established the anti-cancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8-10 grams of the free drug orally each day, in order for detectable levels in the circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc™), which demonstrates remarkably higher systemic bioavailability in plasma and tissues compared to free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc™ significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc™ with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor κ B (NFκB), as well as significant reduction in expression of matrix metalloproteinase MMP-9 and cyclin D1, in xenografts treated with NanoCurc™ and gemcitabine. NanoCurc™ is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy.