Sustained Release Curcumin Microspheres for Breast Cancer Chemoprevention

缓释姜黄素微球用于乳腺癌化学预防

基本信息

批准号：
7751485
负责人：
Jayanth Panyam
金额：
$ 7.55万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-16 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7751485
关键词：
Address Affect Applications Grants Atypical hyperplasia BRCA1 gene BRCA2 gene Biocompatible Biological Availability Biological Markers Breast Breast Cancer Model Cancer Model Cancer cell line Cell Culture Techniques Chemoprevention Chemopreventive Agent Clinical Trials Colorectal Cancer Curcuma longa Curcumin Data Development Diagnostic Procedure Dietary Formulations Dietary Polyphenol Dose Drug Formulations Drug Kinetics ERBB2 gene Encapsulated Enzymes Family Gene Mutation Goals Health High Risk Woman Human In Vitro Inflammation Intraperitoneal Injections Lead Liver Malignant Neoplasms Mammary Neoplasms Mammary gland Metabolism Microspheres Mining Modality Morbidity - disease rate Mus Mutation Neoplasm Metastasis Oral Oral Administration Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacodynamics Phase Phenols Plant Roots Plasma Polymers Premalignant Preventive Proteins Recording of previous events Research Risk Risk Factors Solutions Staging TP53 gene Testing Tissues Transgenic Mice Transgenic Model Woman Xenograft Model absorption base biodegradable polymer cancer chemoprevention carcinogenesis cyclooxygenase 2 in vivo malignant breast neoplasm mammary epithelium mortality mouse model neoplastic cell novel overexpression poly(D,L-lactide-co-glycolide)pre-clinical response subcutaneous tumor tumor initiation

项目摘要

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.

描述（由申请人提供）：姜黄素是一种天然存在的膳食多酚，在乳腺癌细胞培养模型中显示出作为化学预防剂的巨大潜力。然而，姜黄素在体内的口服生物利用度较差，导致口服给药后全身暴露不理想。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剂的潜力。这项研究的长期目标是开发一种每年一次的姜黄素等膳食多酚储库配方，可以显着降低患乳腺癌的风险，特别是对于患乳腺癌高风险的女性（特定基因突变， Her-2 扩增等）。该 R03 拨款申请的目的是开发有关聚合缓释姜黄素制剂在 ErbB2 驱动的乳腺癌转基因模型中化学预防功效的先进初步数据。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）聚合物配制的微球可以有效地封装姜黄素并在小鼠体内持续释放数周。这项研究的中心假设是，皮下注射缓释微球制剂后，姜黄素的全身利用度增加并延长，将产生有效的化学预防作用。为了检验这一假设，将解决两个具体目标。在具体目标 1 中，我们将开发一种微球制剂，可在 3 个月内释放姜黄素，并确定单次皮下注射该制剂后姜黄素的全身暴露量。此外，姜黄素的药效学将通过评估几种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乳腺癌 BALB-neuT 模型中的化学预防功效。 ErbB2 表达、乳腺上皮癌前炎症反应和肿瘤多重性将作为终点来确定姜黄素微球的化学预防功效。总的来说，这些研究将帮助我们获得有关缓释姜黄素微球化学预防功效的关键初步数据。如果所提出的方法成功，这项研究的结果将提出一种新的乳腺癌化学预防方式。