Targeting NanoJacketed Doxorubicin to Tumor Sites for Improved Treatment of Breas

将纳米夹克阿霉素靶向肿瘤部位以改善乳腺癌的治疗

• 批准号: 7745580
• 负责人: Mylisa Parette
• 金额: $ 10万
• 依托单位: KEYSTONE NANO, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2010-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745580
• 关键词: Address; Adenocarcinoma Cell; Adriamycin PFS; Adverse effects; American Cancer Society; Anthracycline Antibiotics; Antibodies; Biocompatible Materials; Biodistribution; Biological; Biological Assay; Biology; Breast Adenocarcinoma; Breast Cancer Treatment; Businesses; Caliber; Cancerous; Cardiotoxicity; Cell Line; Cells; Chemicals; Coupled; Custom; Data; Development; Diagnosis; Dose; Dose-Limiting; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Delivery Systems; Drug Formulations; Engineering; Europe; Evaluation; FDA approved; Goals; Government; Hodgkin Disease; Human; Immunoglobulin Fragments; In Vitro; Infusion procedures; Intravenous; Lead; Libraries; Life; Liposomes; Lymphoma; Malignant Neoplasms; Malignant neoplasm of ovary; Marketing; Medical; Medicine; Membrane Proteins; Modeling; Myelosuppression; Neuroblastoma; Particle Size; Patients; Pharmaceutical Preparations; Phase; Physicians; Physiological; Procedures; Reaction; Science; Site; Solutions; Surface; System; Techniques; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; calcium phosphate; cancer cell; cancer therapy; cancer type; chemotherapeutic agent; conventional therapy; drug efficacy; flexibility; improved; in vivo; interest; malignant breast neoplasm; nano; nanoparticle; nanoparticulate; nanoscale; neoplastic cell; novel; particle; protein expression; public health relevance; research study; response; statistics; therapeutic gene; treatment program; tumor; uptake

DESCRIPTION (provided by applicant): Most current chemotherapeutics are untargeted formulations that have little to no selectivity for cancerous tissue. As a result, these drugs often cause damage to healthy tissues which leads to uncomfortable and at times intolerable dose-limiting toxic side effects. The American Cancer Society estimates that over 1.4 million patients will be diagnosed with cancer in 2008 and many of those will be treated with chemotherapeutics. These startling statistics make the improvement of these drugs a necessity for improving the quality of patient's lives and an utmost goal for government, business and medical interests. Doxorubicin, also known as Adriamycin, is an anthracycline antibiotic that is used as a front-line treatment for breast cancer, ovarian cancer, lymphoma, neuroblastoma and Hodgkin's disease among others. However, the use of Doxorubicin has been limited by severe cardiotoxic side effects that limit the total lifetime dose that can be given to a patient. Nanoparticle delivery systems have the ability to localize chemotherapeutics to tumors as evidenced by Doxorubicin nano-delivery systems such as Doxil. However, many nanoparticulates, including Doxil, suffer from complicating factors such as toxicity of materials, large particle size and lack of colloidal stability. Calcium phosphate NanoJackets address those shortcomings as they are made of non-toxic, bioresorbable material, smaller than the commonly accepted 100nm size limit for intravenous applications, colloidally stable in physiological solutions and maintain the chemotherapeutic on the inside of the nanoparticle matrix. We believe that this combination of factors allow NanoJackets to be commercially viable where other nano-delivery systems are not. The ability to actively target the drug-containing NanoJackets directly to diseased tissue would provide the opportunity to increase the drug's efficacy while reducing unpleasant and sometimes intolerable side effects. Untargeted Doxorubicin NanoJackets are currently being produced and are at least equal to or better than treatment with Doxorubicin in preliminary in vivo experiments. We hypothesize that actively targeting NanoJacketed Doxorubicin to tumor sites will enhance efficacy while decreasing toxic side effects. To assess this hypothesis, this proposal focuses on the following specific aims: 1) identification of targets on human breast adenocarcinoma cells, 2) conjugation of antibody fragments to the surface of Doxorubicin NanoJackets with confirmation by physicochemical techniques and 3) the confirmation of antibody orientation and function by in vitro biological assays. Though Phase I of this project focuses on the feasibility of NanoJacket targeting, it is anticipated that Phase II will establish the toxicity, efficacy and biodistribution data necessary for an IND application to the FDA. While this proposal focuses on targeting Doxorubicin NanoJackets, this technology is flexible enough to allow encapsulation of many different therapeutic compounds with minimal adjustments to the synthesis procedure. The successful development of targeting strategies would permit the creation of numerous NanoJacket products with different chemotherapeutics and surface treatments from which a physician could select from to individualize treatment for optimal efficacy with minimal side effects. PUBLIC HEALTH RELEVANCE: Despite recent advances in the treatment options for breast cancer, there are still far too many patients who do not respond to conventional therapies. The convergence of biology, medicine, engineering and material sciences has led to the creation of nanoscale materials that have the potential to radically improve change cancer therapies and dramatically increase the number of highly effective therapeutic agents. Nanoscale constructs can serve as customizable, targeted, drug delivery vehicles capable of ferrying large doses of chemotherapeutic agents or therapeutic genes into malignant cells while sparing healthy cells, greatly reducing or eliminating the undesirable side effects that accompany many current cancer therapies.

描述（由申请人提供）：大多数当前的化学治疗剂是无靶的制剂，对癌组织几乎没有选择性。结果，这些药物通常会对健康组织造成损害，从而导致不舒服，有时无法忍受的剂量限制毒性副作用。美国癌症协会估计，2008年将被诊断出超过140万名癌症，其中许多将接受化学治疗治疗。这些令人震惊的统计数据使这些药物的改善是改善患者生活质量的必要条件，也是政府，商业和医疗利益的最大目标。阿霉素，也称为阿霉素，是一种蒽环类抗生素，用作乳腺癌，卵巢癌，淋巴瘤，神经母细胞瘤和霍奇金氏病的前线治疗。但是，阿霉素的使用受到严重的心毒性副作用的限制，这些副作用限制了可以给予患者的总终生剂量。纳米粒子递送系统具有将化学疗法定位在肿瘤中的能力，阿霉素纳米转换系统（如多克西尔）证明了这一点。然而，许多纳米关节（包括多克西尔）患有复杂因素，例如材料的毒性，巨大的粒度和缺乏胶体稳定性。磷酸钙纳米夹克解决了这些缺点，因为它们是由无毒的，可生物可吸收的材料制成的，该材料比静脉内应用的普遍接受的100nm尺寸限制小，在生理溶液中胶体稳定并保持纳米粒子基质内部的化学疗法。我们认为，这种因素的组合使纳米夹具在其他纳米递送系统不可行的情况下可以在商业上可行。将直接靶向含药物的纳米夹克靶向患病组织的能力将提供增加药物功效的机会，同时减少不愉快的副作用，有时甚至无法忍受。目前正在生产未靶向的阿霉素纳米夹克，并且至少等于或比在体内实验中用阿霉素治疗的治疗。我们假设将纳米夹克的阿霉素靶向肿瘤部位将增强功效，同时降低毒性副作用。为了评估这一假设，该提案的重点是以下具体目的：1）鉴定人类乳腺腺癌细胞的靶标，2）将抗体碎片结合到阿霉素纳米夹具表面的抗体片段与实物化学技术的确认以及3）确认抗体通过抗体的抗体抗体和功能性鉴定。尽管该项目的第一阶段侧重于纳米夹克靶向的可行性，但预计II期将确定IND应用于FDA所需的毒性，功效和生物分布数据。尽管该建议着重于靶向阿霉素纳米夹克，但该技术足够灵活，可以允许对许多不同的治疗化合物封装，并且对合成过程的调整很少。目标策略的成功开发将允许创建具有不同化学治疗和表面处理的众多纳米夹克产品，医生可以从中从中选择个性化治疗，以获得最佳疗效，并具有最小的副作用。 公共卫生相关性：尽管乳腺癌治疗方案的最新进展，但仍有太多患者对常规疗法反应。生物学，医学，工程和材料科学的融合导致了纳米级材料的创造，这些材料有可能从根本上改善变化癌症疗法并大大增加高效治疗剂的数量。纳米级构建体可以用作可定制的，有针对性的药物输送车辆，能够将大剂量的化学治疗剂或治疗基因运送到恶性细胞中，同时保留健康细胞，从而大大降低或消除伴随许多当前许多当前癌症疗法的不良副作用。