Nanoconjugate based on polymalic acid for brain tumor treatment

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著改善和成功提供新的希望，特别是在防止肿瘤生长和进展方面。这尤其与预后非常差的脑胶质瘤有关，目前的治疗方法在很大程度上无法治愈，因此需要新的治疗方式。我们的研究涉及一种新的纳米级（20-30纳米）抗肿瘤药物递送系统（Polycefin），该系统基于天然衍生的纳米平台，聚（p- l -苹果酸）(PMLA) -来自粘液霉菌，多绒泡菌。这个通用平台可以很容易地修改，以包括新的共价连接到PMLA主链，如抗癌药物抑制肿瘤细胞靶点。当前版本的递送平台包含：可生物降解，无毒，非免疫原性PMLA；药物释放装置；靶向血管生成性胶质瘤两条链的反义寡核苷酸（AON）单元-层粘连蛋白411特异性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；用于破坏内体膜的疏水释放单元；还有荧光追踪染料该纳米平台的开发是为了抑制复杂蛋白质的合成和全身递送。这些蛋白，如三聚体层粘连蛋白，在肿瘤的生长、侵袭和转移中起着重要的作用，但以前由于常规药物的原因无法阻断。初步数据显示药物直接递送到脑肿瘤部位，抑制胶质瘤分子靶点（层粘连蛋白链），并且在体内没有明显的毒性。结果，胶质瘤动物的存活率提高了60% (p<0.01)，肿瘤大小缩小了10倍（p<0.01）。本提案将评估和发展这种静脉注射系统。该项目将专注于含有AON的基本纳米偶联平台的临床前测试，以对抗我们表征的胶质瘤标志物层粘连蛋白411（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偶联物中选择一种先导载体药物化合物，这将为临床应用建立坚实的基础。我们的目标包括：(1)通过改变AON的数量和靶向抗体分子，对Polycefin变体进行化学优化，以最有效地阻断层粘连蛋白411；(2)该平台的化学、物理和药代动力学特性，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，使肿瘤得到最有效的治疗；(4) glp依从性药物药理学特性（毒性、分布、代谢和排泄）研究。相关性（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。我们的多学科团队基于聚p - l -苹果酸（PMLA）创建了一种新的纳米级（20-30个lun）抗肿瘤药物递送系统。这个通用平台可以很容易地修改，以包括新的共价连接到PMLA主链的部分，如抗癌药物抑制肿瘤细胞靶点。这尤其与预后非常差的脑胶质瘤有关，目前的治疗方法在很大程度上无法治愈，因此需要新的治疗方式。该纳米平台的开发是为了抑制几种肿瘤特异性靶点的合成，这些靶点在肿瘤生长、侵袭和转移中起着重要作用，但以前无法被常规药物阻断。

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.