Smart targeting nano-doxorubicin against breast cancer

智能靶向纳米阿霉素对抗乳腺癌

基本信息

批准号：
8676442
负责人：
Yuanpei Li
金额：
$ 19.38万
依托单位：
LAMNOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676442
关键词：
AIDS with Kaposi&apos s sarcoma Abraxane Acetylcysteine Address Affinity Animal Model Animals Antineoplastic Agents Avastin Blood Blood Circulation Breast Breast Cancer Model Breast Cancer Treatment Cancer Patient Canis familiaris Cardiomyopathies Cardiotoxicity Cholic Acids Chylomicrons Clinic Clinical Combination Drug Therapy Companions Cyclophosphamide Development Disulfides Dose Doxorubicin Doxorubicin Hydrochloride Liposome Drug Formulations Drug toxicity Engineering Exhibits FDA approved Future Goals Gonadotropin-Releasing Hormone Receptor High Density Lipoproteins Hour Human Integrins Lead Legal patent Libraries Ligands Lipoproteins Liposomes Low-Density Lipoproteins Lymphoma Malignant Neoplasms Malignant neoplasm of ovary Mediator of activation protein Methods Micelles Multi-Drug Resistance Mus Myelosuppression Nanotechnology Oligonucleotides Ovarian P-Glycoprotein Paclitaxel Parents Patients Penetration Peptides Permeability Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Polymers Property Prostate Reporting Research Resistance Roche brand of trastuzumab Site Small Business Innovation Research Grant Solid Neoplasm Specificity Sterically Stabilized Liposome Structure System Taxane Compound Testing Therapeutic Index Toxic effect Transgenic Mice Transgenic Organisms Treatment Efficacy Tumor Tissue Validation Very low density lipoprotein Xenograft Model anticancer research aqueous base cancer cell cancer diagnosis cancer therapy combinatorial crosslink design drug efficacy frontier improved in vivo innovation malignant breast neoplasm nano nanocarrier nanoformulation nanomedicine nanoparticle nanotherapeutic neoplastic cell novel novel strategies overexpression particle phase 2 study pre-clinical premature prevent public health relevance screening taxane tumor

项目摘要

DESCRIPTION (provided by applicant): Currently available therapy for advanced breast cancer is inadequate. Doxorubicin (DOX), one of the most effective anticancer drugs, is commonly used against breast cancer. However, its clinical use is restricted by dose-dependent toxicity (myelosuppression and cardiotoxicity), the emergence of multidrug resistance and its low specificity against cancer cells. PEGylated liposomal doxorubicin (Doxil(R)) is the first nanoformulations of DOX approved by FDA for the treatment of breast cancer. Although the encapsulation of DOX into liposome does result in decreased DOX-induced cardiomyopathy, its clinical anti-cancer efficacy is only marginally better than the parent drug. This could in part be explained by its relatively large size (ca. 130 nm), thus limiting the tumor tissue penetration and obviating the enhanced permeability retention (EPR) effect. It has been reported that smaller nanoparticles such as 30 nm micelles could penetrate poorly permeable tumors for a better anti-tumor effect. The smart DOX loaded micelles with smaller size (~20 nm) to be developed in this proposal may offer better efficacy and toxicity profile against breast cancer, therefore have great commercial potentials to lead to a marketable DOX-nanoformulation for the treatment of breast cancer patients. The overall goal of this Phase I SBIR proposal is to develop highly effective micelle formulation of DOX against breast cancer in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filin to FDA. Our hypotheses are: (i) The smaller crosslinked micelle formulation of DOX, compared to Doxil(R) or its free form are more efficacious and less toxic against breast cancer; (ii) The addition of breast cancer targeting ligand(s) to the nanotherapeutics can facilitate the intracellular delivery of the nanocarriers to the tumor cells in vivo and therefore will greatly enhance their anti- tumor efficacies; and (iii) N-acetyl cysteine, when administered to the animal 24 hrs after the initial administration of the disulfide cross-linked nanoparticle drug, will furthr improve its therapeutic index. In this proposal, these three hypotheses will be tested in transgenic mouse mammary tumor model. The project addresses a critical issue in breast cancer research to reduce drug toxicity and increase drug efficacy. The proposed project takes advantage of the optimized high-affinity breast cancer targeting peptide ligands from the combinatorial library screening method and incorporates them into our newly developed crosslinked nanocarrier system against breast cancer. State of the art design of the nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of multiple functions, fine-tunable and highly reproducible structure and properties. The use of reversibly crosslinked targeting micelles to delivery DOX against breast cancer is highly innovative. It's an excellent approach to prevent pre-mature drug release during circulation and deliver high concentrations of drug to tumor site. It is expected that this research will lead to new approach for the treatment of breast cancer. Page 1

描述（由申请人提供）：目前针对晚期乳腺癌的可用疗法不足。阿霉素（DOX）是最有效的抗癌药物之一，通常用于治疗乳腺癌。然而，其临床应用受到剂量依赖性毒性（骨髓抑制和心脏毒性）、多药耐药性的出现及其对癌细胞特异性低的限制。聚乙二醇化脂质体阿霉素 (Doxil(R)) 是 FDA 批准用于治疗乳腺癌的第一个 DOX 纳米制剂。尽管将DOX封装到脂质体中确实可以减少DOX诱发的心肌病，但其临床抗癌功效仅比母体药物稍好一些。这可能部分是其原因是其相对较大的尺寸（约 130 nm），从而限制了肿瘤组织的穿透和消除增强渗透性保留（EPR）效应。据报道，较小的纳米粒子如30纳米胶束可以穿透渗透性差的肿瘤，从而获得更好的抗肿瘤效果。本提案中将开发的具有更小尺寸（~20 nm）的智能 DOX 负载胶束可能会提供更好的抗乳腺癌功效和毒性，因此具有很大的优势。商业潜力导致可销售的 DOX 纳米制剂用于治疗乳腺癌患者。该 I 期 SBIR 提案的总体目标是在临床前动物模型中开发针对乳腺癌的高效 DOX 胶束制剂，为 II 期研究的可行性提供验证，最终将向 FDA 提交 IND 申请。我们的假设是： (i) 与 Doxil(R) 或其游离形式相比，较小的 DOX 交联胶束制剂对乳腺癌更有效且毒性更小； (ii)在纳米治疗药物中添加乳腺癌靶向配体可以促进纳米载体在体内递送至肿瘤细胞，从而大大增强其抗肿瘤功效； (iii)N-乙酰半胱氨酸，在初次给予二硫键交联纳米粒子药物24小时后给予动物，将进一步提高其治疗指数。在该提案中，这三个假设将在转基因小鼠乳腺肿瘤模型中进行测试。该项目解决了乳腺癌研究中的一个关键问题，以降低药物毒性并提高药物疗效。该项目利用组合文库筛选方法优化的高亲和力乳腺癌靶向肽配体，并将其纳入我们新开发的抗乳腺癌交联纳米载体系统中。通过工程设计具有明确结构的末端树枝状聚合物，纳米载体的最先进设计代表了纳米医学在多功能、可微调和高度可重复的结构和性能方面的前沿发展。使用可逆交联的靶向胶束来递送 DOX 来对抗乳腺癌是高度创新的。这是防止循环过程中药物过早释放并将高浓度药物输送到肿瘤部位的绝佳方法。预计这项研究将带来治疗乳腺癌的新方法。第1页