Sustained Release Curcumin Microspheres for Breast Cancer Chemoprevention

描述(由申请人提供)： 姜黄素是一种天然存在的饮食多酚，在乳腺癌细胞培养模型中显示出巨大的化学预防潜力。然而，姜黄素在体内的口服生物利用度很低，导致口服给药后全身暴露不佳。口服给药后无法达到有效的血浆和组织浓度是一个关键问题，因为这限制了姜黄素作为乳腺癌化学预防的潜力。这项研究的长期目标是开发一种每年一次的饮食多酚(如姜黄素)的仓库配方，可以显著降低患乳腺癌的风险，特别是在患乳腺癌的高危女性(特定基因突变、HER-2扩增等)。这项R03拨款申请的目的是开发关于聚合物缓释姜黄素制剂在ErbB2驱动的乳腺癌转基因模型中的化学预防效果的高级初步数据。我们有限的初步研究表明，由可生物降解的聚(D，L-丙交酯-乙交酯共聚)聚合物制成的微球可以有效地包裹姜黄素，并在小鼠体内保持数周的释放。这项研究的中心假设是，皮下注射缓释微球制剂后，增加和延长姜黄素的全身可利用度将导致有效的化学预防。为了验证这一假设，我们将提出两个具体目标。在具体目标1中，我们将开发一种微球制剂，在3个月内释放姜黄素，并测定单次皮下注射该制剂后姜黄素的全身暴露。此外，姜黄素的药效学将通过评估几个化学预防生物标志物来确定。在具体目标2中，我们将研究缓释微球在BALB-Neut乳腺癌模型中的化学预防效果。ERBB2的表达、癌前炎症反应和肿瘤的多样性将作为终点来确定姜黄素微球的化学预防效果。总的来说，这些研究将帮助我们获得有关姜黄素缓释微球化学预防效果的关键初步数据。如果建议的方法是成功的，这项研究的结果将为乳腺癌提供一种新的化学预防模式。

DESCRIPTION (provided by applicant): Curcumin, a naturally occurring dietary polyphenol, has shown significant potential as a chemopreventive in cell culture models of breast cancer. However, curcumin suffers from poor oral bioavailability in vivo, resulting in sub-optimal systemic exposure following oral administration. The inability to achieve effective plasma and tissue concentrations following oral administration is a critical problem, because this limits curcumin's potential as a chemopreventive in breast cancer. The long-term objective of this research is to develop a once-a-year depot formulation of dietary polyphenols like curcumin that could significantly lower the risk of developing breast cancer, especially in women at high risk of developing breast cancer (specific gene mutations, Her-2 amplification, etc). The objective of this R03 grant application is to develop advanced preliminary data regarding the chemopreventive efficacy of a polymeric sustained release curcumin formulation in a transgenic model of ErbB2-driven breast cancer. Our limited preliminary studies show that microspheres formulated from the biodegradable poly(D,L-lactide-co-glycolide) polymer can efficiently encapsulate curcumin and sustain its release in mouse over several weeks. The central hypothesis of this research is that increased and prolonged systemic availability of curcumin following subcutaneous administration of a sustained release microsphere formulation will result in effective chemoprevention. To test this hypothesis, two Specific Aims will be addressed. In Specific Aim 1, we will develop a microsphere formulation that releases curcumin over a 3-month period and determine the systemic exposure of curcumin following a single subcutaneous dose of the formulation. In addition, pharmacodynamics of curcumin will be determined by evaluating several chemoprevention biomarkers. In Specific Aim 2, we will investigate the chemopreventive efficacy of sustained release microspheres in the BALB-neuT model of breast cancer. ErbB2 expression, pre-malignant inflammation response in the mammary epithelium, and tumor multiplicity will be used as endpoints to establish the chemopreventive efficacy of curcumin microspheres. Collectively, these studies will help us in acquiring critical preliminary data regarding the chemopreventive efficacy of sustained release curcumin microspheres. If the proposed approach is successful, results of this research will suggest a novel chemoprevention modality for breast cancer.