Smart targeting nano-doxorubicin against breast cancer

智能靶向纳米阿霉素对抗乳腺癌

• 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
• 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' 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

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）：目前可用于晚期乳腺癌的治疗不足。多柔比星（DOX）是最有效的抗癌药物之一，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的低特异性的限制。PEG化脂质体阿霉素（Doxil（R））是FDA批准用于治疗乳腺癌的第一种DOX纳米制剂。虽然将DOX包封到脂质体中确实导致减少DOX诱导的心肌病，但其临床抗癌功效仅略优于母体药物。这可能部分是 由于其相对较大的尺寸（CA. 130 nm），从而限制肿瘤组织渗透， 避免了增强渗透率保留（EPR）效应。据报道，较小的纳米颗粒如30 nm胶束可以穿透渗透性差的肿瘤，以获得更好的抗肿瘤效果。在该提议中开发的具有较小尺寸（~20 nm）的智能DOX负载胶束可以提供针对乳腺癌的更好的功效和毒性特征，因此具有很大的应用前景。 商业潜力，导致用于治疗乳腺癌患者的可销售的DOX纳米制剂。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DOX高效胶束制剂，为II期研究的可行性提供验证，最终将导致向FDA提交IND申请。我们的假设是：（i）与Doxil或其游离形式相比，DOX的较小交联胶束制剂对乳腺癌更有效且毒性更小;（ii）向纳米治疗剂中加入乳腺癌靶向配体可促进纳米载体向体内肿瘤细胞的细胞内递送，因此将大大增强其抗肿瘤功效;和（iii）N-乙酰半胱氨酸，当在二硫化物交联的纳米颗粒药物初始给药后24小时给药于动物时，将进一步提高其治疗指数。本研究拟在转基因小鼠乳腺肿瘤模型中对这三个假说进行验证。该项目解决了乳腺癌研究中的一个关键问题，以减少药物毒性并提高药物疗效。该项目利用组合库筛选方法中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针对乳腺癌的交联纳米载体系统中。通过设计具有明确结构的末端树枝状聚合物来设计纳米载体的最新技术水平代表了纳米医学在多功能、精细可调和高度可再现的结构和性质方面的前沿发展。使用可逆交联的靶向胶束递送针对乳腺癌的DOX是高度创新的。这是一种很好的方法，以防止药物在循环过程中过早释放，并提供高浓度的药物到肿瘤部位。预计这项研究将为乳腺癌的治疗带来新的方法。第1页