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了新的希望，尤其是在预防肿瘤生长和进展方面。这与预后较差的脑神经胶质瘤特别相关，在很大程度上无法通过当前的疗法无法治愈，因此需要新颖的治疗方式。我们的研究是基于天然衍生的纳米植物，poly（p-l-malic Acid）（PMLA）的新纳米级（20-30 nm）抗肿瘤药物输送系统（Polycefin）。该通用平台很容易被修改，以包括共价附上PMLA主链的新部分，例如抑制肿瘤细胞靶标的抗癌药物。当前版本的输送平台包含：可生物降解，无毒和非免疫原性PMLA；毒品释放单位；吗啡反义寡核苷酸（AON）单元，靶向两个链的血管生成瘤蛋白质蛋白层粘着蛋白411；特定组织靶向和内体摄取的抗转化蛋白受体抗体；生物聚合物保护剂聚乙烯乙二醇（PEG）；一个用于内体膜破坏的疏水释放单元；和荧光跟踪染料。开发了纳米植物以抑制与全身递送的复杂蛋白的合成。这些蛋白质（例如三聚层粘连蛋白）在肿瘤生长，侵袭和转移中起着重要作用，但以前由于常规药物而无法阻止。初步数据表明，药物直接递送到脑肿瘤部位，抑制分子胶质瘤（层粘连蛋白链）以及体内缺乏可见毒性。结果，达到10倍肿瘤大小的减少（p <0.01）的神经胶质瘤动物的存活率增加了60％（p <0.01）。这个I.V.该建议将在本提案中评估和开发系统性交付系统。该项目将着重于对我们特征的神经胶质瘤标记物层粘连蛋白411的碱性纳米偶联物平台的临床前测试，这是一种对肿瘤血管发育重要的蛋白质。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偶联物中选择铅毒剂化合物，这将为临床使用建立固定的基本原理。我们的目的包括（1）通过改变AON的数量和靶向抗体分子的数量来对多头蛋白变体进行化学优化，以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，包括稳定性研究，体内半衰期和组织积累； （3）优化最有效的肿瘤治疗的注射次数和剂量； （4）符合GLP药物学特性的研究（毒性，分布，代谢和排泄）。相关性（请参阅说明）：该项目与NIH公告RFA-CA-05-026“癌症纳米技术平台伙伴关系”（UOL）有关。我们的多学科团队创建了一个基于聚（P-L麦酸）（PMLA）的新纳米级（20-30 LUN）抗肿瘤药物输送系统。这个通用平台可能很容易修改，以包括与PMLA主链共价附着的新部分，例如抑制肿瘤细胞靶标的抗癌药物。这与预后较差的脑神经胶质瘤特别相关，在很大程度上无法通过当前的疗法无法治愈，因此需要新颖的治疗方式。开发了纳米植物形式是为了抑制几种在肿瘤生长，侵袭和转移中起重要作用的肿瘤特定靶标的合成，但以前无法通过常规药物阻止。