Targeting NanoJacketed Doxorubicin to Tumor Sites for Improved Treatment of Breas

描述（由申请人提供）：目前大多数化疗药物是非靶向制剂，对癌组织几乎没有选择性。因此，这些药物经常对健康组织造成损害，导致不舒服，有时无法忍受的剂量限制性毒副作用。美国癌症协会估计，2008年将有超过140万患者被诊断患有癌症，其中许多人将接受化疗。这些令人震惊的统计数据使这些药物的改进成为改善患者生活质量的必要条件，也是政府，企业和医疗利益的最高目标。阿霉素，也被称为阿霉素，是一种蒽环类抗生素，被用作乳腺癌、卵巢癌、淋巴瘤、神经母细胞瘤和霍奇金病等的一线治疗。然而，阿霉素的使用受到严重的心脏毒性副作用的限制，这些副作用限制了可以给予患者的总终生剂量。纳米颗粒递送系统具有将化学治疗剂定位于肿瘤的能力，如多柔比星纳米递送系统如Doxil所证明的。然而，许多纳米颗粒，包括Doxil，遭受复杂的因素，如材料的毒性，大粒径和缺乏胶体稳定性。磷酸钙纳米夹套解决了这些缺点，因为它们由无毒的生物可吸收材料制成，小于静脉内应用的普遍接受的100 nm尺寸限制，在生理溶液中胶体稳定，并将化疗剂保持在纳米颗粒基质的内部。我们认为，这些因素的结合使NanoJackets在商业上可行，而其他纳米输送系统则不行。将含有药物的NanoJackets直接主动靶向患病组织的能力将提供增加药物疗效的机会，同时减少令人不快的，有时是无法忍受的副作用。目前正在生产非靶向多柔比星纳米夹套，并且在初步体内实验中至少等于或优于用多柔比星治疗。我们假设，主动靶向纳米夹套阿霉素肿瘤部位将提高疗效，同时减少毒副作用。为了评估这一假设，本提案重点关注以下具体目标：1）鉴定人乳腺癌细胞上的靶标，2）通过物理化学技术确认抗体片段与阿霉素纳米夹套表面的偶联，3）通过体外生物学测定确认抗体方向和功能。虽然该项目的第一阶段侧重于NanoJacket靶向的可行性，但预计第二阶段将建立向FDA提交IND申请所需的毒性、疗效和生物分布数据。虽然该提案侧重于靶向阿霉素纳米夹套，但该技术足够灵活，可以在对合成程序进行最小调整的情况下封装许多不同的治疗化合物。靶向策略的成功开发将允许创建具有不同化疗药物和表面处理的多种NanoJacket产品，医生可以从中选择个性化治疗，以获得最佳疗效，同时副作用最小。 公共卫生相关性：尽管最近在乳腺癌的治疗选择方面取得了进展，但仍然有太多的患者对传统疗法没有反应。生物学、医学、工程学和材料科学的融合导致了纳米材料的产生，这些材料有可能从根本上改善癌症治疗，并大大增加高效治疗药物的数量。纳米级构建体可以用作可定制的、靶向的药物递送载体，其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，大大减少或消除伴随许多当前癌症疗法的不期望的副作用。

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.