Nanoconjugate based on polymalic acid for brain tumor treatment

基于聚苹果酸的纳米缀合物用于脑肿瘤治疗

• 批准号: 8322866
• 负责人: JULIA Y LJUBIMOVA
• 金额: $ 15.72万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-25 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322866
• 关键词: Acids; Acute; Acute Toxicity Tests; Adverse effects; Animal Model; Animals; Antibodies; Antineoplastic Agents; Antisense Oligonucleotides; Apoptosis; Area; Biochemical; Biocompatible; Biological Assay; Biological Markers; Biopolymers; Brain; Brain Neoplasms; Callithrix; Cell Culture Techniques; Cell Survival; Cells; Chemicals; Chicago; Clinical; Collaborations; Data; Development; Development Plans; Dose; Drug Compounding; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Dyes; Endotoxins; Equipment; Excretory function; Glioma; Goals; Half-Life; Human; Illinois; Image; Immunology; In Vitro; Injection of therapeutic agent; Instruction; Label; Laboratories; Laboratory Chemicals; Laboratory Research; Laminin; Lead; Malignant Neoplasms; Measures; Membrane; Metabolism; Methods; Modality; Molecular Target; Mus; Mutagenesis; Nanoconjugate; Nanotechnology; Neoplasm Metastasis; Organ; Pharmaceutical Preparations; Pharmacology; Physarum polycephalum; Plasma; Play; Polyethylene Glycols; Polymers; Preclinical Testing; Prevention; Principal Investigator; Property; Proteins; Publishing; Radiolabeled; Research; Research Personnel; Role; Safety; Services; Site; Solid; System; Testing; Time; TimeLine; Tissues; Toxic effect; Toxicity Tests; Toxicology; Transferrin Receptor; Treatment Efficacy; United States National Institutes of Health; Universities; Variant; Vertebral column; Western Blotting; Work; absorption; antitumor drug; base; cancer therapy; cytotoxicity; dosage; drug distribution; experience; immunogenicity; in vitro testing; in vivo; meetings; multidisciplinary; nanoscale; neoplastic cell; neurotoxicity; nonhuman primate; novel; outcome forecast; preclinical evaluation; prevent; protein complex; radiotracer; research study; success; targeted delivery; tumor; tumor growth; tumor progression; uptake

DESCRIPTION (provided by applicant): Recent advances in nanotechnology may offer a new hope for a significant improvement and success of cancer treatment, especially in preventing tumor growth and progression. This is particularly relevant to brain gliomas that have very poor prognosis, are largely incurable by current therapy, and therefore, need novel treatment modalities. Our research is dealing with a new nanoscale (20-30 nm) anti-tumor drug delivery system (Polycefin) based on naturally derived nanoplatform, poly(p-L-malic acid) (PMLA) fi-om a slime mold, Physarum polycephalum. This universal platform may be easily modified to include new moieties covalently attached to PMLA backbone, such as anti-cancer drugs inhibiting tumor cell targets. The current version of the delivery platform contains: biodegradable, non-toxic, and non-immunogenic PMLA; a drug releasing unit; Morpholino antisense oligonucleotide (AON) unit targeting two chains of angiogenic glioma-increased protein laminin 411; anti-transferrin receptor antibody for specific tissue targeting and endosomal uptake; biopolymer protector polyethylene glycol (PEG); a hydrophobic release unit for endosomal membrane disruption; and a fluorescent tracking dye. The nanoplatform was developed to inhibit the synthesis of complex proteins with systemic delivery. These proteins, such as trimeric laminins play a significant role in tumor growth, invasion and metastasis, but previously could not be blocked because by conventional drugs. Preliminary data demonstrated drug delivery directly to the brain tumor site, inhibition of glioma molecular targets (laminin chains), and lack of visible toxicity in vivo. As a result, a 60% increase in survival of glioma bearing animals (p<0.01) with 10-fold tumor size reduction (p<0.01) was achieved. This I.V. systemic delivery system will be evaluated and developed in this proposal. The project will focus on the preclinical testing of basic nanoconjugate platform containing AON against our characterized glioma marker, laminin 411, a protein important for tumor vessel development. The ultimate goal is to select a lead vehicle-drug compound from several polymer-based conjugates by detailed chemical, chemical-physical and preclinical evaluation, which would establish a solid rationale for clinical usage. Our Aims include (1) chemical optimization of Polycefin variants for the most efficient blocking of laminin 411 by varying the number of AON and targeting antibody molecules; (2) chemical, physical and pharmacokinetic characterization of the platform including studies of stability, in vivo half-life and tissue accumulation; (3) optimization of the number of injections and dosage for the most effective tumor treatment; and (4) GLP-compliant study of drug pharmacological properties (toxicity, distribution, metabolism and excretion). RELEVANCE (See instructions): This project is relevant to the NIH announcement RFA-CA-05-026 "Cancer Nanotechnology Platform Partnerships" (UOl). Our multidisciplinary team created a new nanoscale (20-30 lun) anti-tumor drug delivery system based on poly(P-L-malic acid) (PMLA). This universal platform may IK easily modified to include new moieties covalently attached to PMLA backbone, such as anti-cancer drugs inhibiting tumor cell targets. This is particularly relevant to brain gliomas that have very poor prognosis, are largely incurable by current therapy, and therefore, need novel treatment modalities. The nanoplatform was developed to inhibit the synthesis of several tumor specific targets that play a significant role in tumor growth, invasion and metastasis, but previously could not be blocked by conventional drugs.

描述（由申请人提供）：纳米技术的最新进展可能为癌症治疗的显着改善和成功提供新的希望，特别是在预防肿瘤生长和进展方面。这与预后非常差的脑胶质瘤尤其相关，目前的治疗在很大程度上无法治愈，因此需要新的治疗方式。我们的研究正在研究一种新的纳米级（20-30 nm）抗肿瘤药物输送系统（Polycefin），该系统基于天然衍生的纳米平台，来自粘菌多头绒泡菌的聚（p-L-苹果酸）（PMLA）。这个通用平台可以很容易地进行修改，以包含共价连接到 PMLA 主链的新部分，例如抑制肿瘤细胞靶标的抗癌药物。当前版本的递送平台包含：可生物降解、无毒、无免疫原性的PMLA；药物释放单元；吗啉代反义寡核苷酸 (AON) 单元靶向血管生成神经胶质瘤增加的蛋白层粘连蛋白 411 的两条链；用于特定组织靶向和内体摄取的抗转铁蛋白受体抗体；生物聚合物保护剂聚乙二醇（PEG）；用于破坏内体膜的疏水释放单元；和荧光示踪染料。该纳米平台的开发目的是通过全身递送抑制复杂蛋白质的合成。这些蛋白质，如三聚层粘连蛋白，在肿瘤生长、侵袭和转移中发挥着重要作用，但以前由于常规药物无法阻断。初步数据表明，药物直接输送到脑肿瘤部位，抑制神经胶质瘤分子靶点（层粘连蛋白链），并且在体内没有可见的毒性。结果，携带神经胶质瘤的动物的存活率提高了 60% (p<0.01)，肿瘤尺寸缩小了 10 倍 (p<0.01)。这个静脉注射。本提案将评估和开发系统性输送系统。该项目将重点针对含有 AON 的基本纳米缀合物平台针对我们表征的神经胶质瘤标记物层粘连蛋白 411 进行临床前测试，层粘连蛋白 411 是一种对肿瘤血管发育很重要的蛋白质。最终目标是通过详细的化学、化学物理和临床前评估，从几种基于聚合物的缀合物中选择一种先导载体药物化合物，这将为临床使用奠定坚实的基础。我们的目标包括 (1) 对 Polycefin 变体进行化学优化，通过改变 AON 的数量和靶向抗体分子来最有效地阻断层粘连蛋白 411； (2) 平台的化学、物理和药代动力学表征，包括稳定性、体内半衰期和组织积累的研究； (3)优化注射次数和剂量以实现最有效的肿瘤治疗； (4) 符合GLP标准的药物药理特性研究（毒性、分布、代谢和排泄）。相关性（参见说明）：该项目与 NIH 公告 RFA-CA-05-026“癌症纳米技术平台合作伙伴关系”（UOl）相关。我们的多学科团队创建了一种基于聚（P-L-苹果酸）（PMLA）的新型纳米级（20-30 Lun）抗肿瘤药物输送系统。这个通用平台可以很容易地进行修改，以包含共价连接到 PMLA 主链的新部分，例如抑制肿瘤细胞靶标的抗癌药物。这与预后非常差的脑胶质瘤尤其相关，目前的治疗在很大程度上无法治愈，因此需要新的治疗方式。该纳米平台的开发目的是抑制几种肿瘤特异性靶点的合成，这些靶点在肿瘤生长、侵袭和转移中发挥重要作用，但以前无法被常规药物阻断。