Development of NanoFludarabine for Pediatric Leukemia using LCP Nanotechnology

利用 LCP 纳米技术开发治疗小儿白血病的纳米氟达拉滨

基本信息

批准号：
8780357
负责人：
Jun Li
金额：
$ 15万
依托单位：
QUALIBER, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-17 至 2015-06-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8780357
关键词：
Adverse effects Autoimmune Process Biodistribution Bone Marrow Suppression CD44 gene Calcium Cancer Patient Cell Culture Techniques Cell Nucleus Cells Child Childhood Childhood Leukemia Clinical Research Cytoplasm DNA Synthesis Inhibition Development Diagnosis Drug Formulations Effectiveness Encapsulated Endocytosis Endosomes Ensure Fludarabine phosphate Folate Folic Acid Future Grant Hematologic Neoplasms Hyaluronan Hyaluronic Acid In Vitro Incidence Inhibitory Concentration 50 Kidney Ligands Lipid Bilayers Lipids Lung Malignant Childhood Neoplasm Malignant Neoplasms Measurement Metabolism Modeling Names Nanotechnology Neurologic Normal Cell Nucleic Acids Nucleotides Osmotic Pressure Particle Size Pharmaceutical Preparations Phase Plant Leaves Precipitation Process Production Reaction Research Reticuloendothelial System Small Business Innovation Research Grant Solid Staging Surface Testing Therapeutic Index Toxic effect Transfusion Treatment Efficacy base calcium phosphate cancer cell chemotherapy design fludarabine folate-binding protein graft vs host disease improved in vitro activity innovation leukemia leukemia/lymphoma manufacturing process nanoparticle nanosized novel particle phosphodiester pre-clinical public health relevance receptor scale up tripolyphosphate tumor uptake zeta potential

项目摘要

DESCRIPTION (provided by applicant): Development of NanoFludarabine for Pediatric Leukemia using LCP Nanotechnology NanoFludarabine is Qualiber's nanoparticle formulation of fludarabine phosphate (Fludara), a drug widely used for treating leukemia and other malignancies. While fludarabine phosphate is effective against tumors, it also has significant toxicities. Many of these side effects can potentially be minimized or avoided by modifying the biodistribution of fludarabine phosphate. Furthermore, fludarabine phosphate's therapeutic index can be improved if we can preferentially deliver the drug to cancer cells using nanoparticles which have been targeted to cancer cells. Our innovation is the encapsulation of fludarabine phosphate in a novel nanoparticle formulation, called Lipid-Calcium-Phosphate (LCP). The new formulation of fludarabine phosphate in LCP nanoparticles is named NanoFludarabine. The calcium phosphate core of LCP would encapsulate fludarabine phosphate with a high efficiency and rapidly dissolve in the acidic endosome releasing fludarabine phosphate in the cytoplasm where it is further phosphorylated to fludarabine triphosphate and transported to the nucleus for inhibition of DNA synthesis. In this Phase I, Qualiber will formulate LCP for the delivery of fludarabine phosphate (NanoFludarabine) and characterize them for in vitro activity and determine feasibility for development as pediatric leukemia treatment. Aim 1. Increase Current Production Scale of Encapsulated Fludarabine Phosphate in LCP Nanoparticles by 10 Fold with In-Process Controls (IPC) Qualiber aims to test the feasibility of scalable process to encapsulate fludarabine phosphate with solid analytical measurements. The preliminary results show that fludarabine phosphate can be encapsulated into LCP particles at lab scale with batch size of 1 mg of fludarabine phosphate encapsulated. Two challenges exist at this stage: (i) small scale of production and (ii) lack of process controls Aggregation of particles was observed partly due to a low surface zeta potential. Successful production to improve the scale of nanoparticles to 10x of current scale with batch size of >10 mg of fludarabine phosphate will be the criteria for progressing to Aim 2. Also, in-process controls such as drug encapsulation efficiency (>40%), particle size and poly-dispersity will be put in place to ensure future process designs for a scalable manufacturing process that would allow further pre-clinical development and clinical studies regulated by FDA. Aim 2. Select One Targeted Ligand and Make NanoFludarabine to Target Leukemia with Proof of Concept (POC) In Vitro Studies NanoFludarabine nanoparticles produced in the above scale-up process will be further targeted to leukemia cells. Qualiber is planning to make NanoFludarabine with at least two different ligands to target (i) CD44 receptor with Hyaluronan/Hyaluronic Acid (HA) and (ii) Folate receptor with PEGylated folic Acid (FA). Free fludarabine phosphate, NanoFludarabine without ligand, NanoFludarabine with HA or FA targeting ligands will be tested in in vitro cell culture models. The results will be used to determine the following: (a) Is NanoFludarabine more efficacious than free fludarabine phosphate and (b) Which targeting ligand provides highest cell uptake via endocytosis of the nanoparticles. One ligand will be chosen based on the targeting efficacy, availability and manufacturing feasibility to move forward. Successfully demonstrating that NanoFludarabine (with HA or FA targeting ligand) has a IC50 values at least 2-5 fold lower than free fludarabine phosphate will be a key milestone for progressing the product for further preclinical development and Phase II SBIR grant.

描述（由申请人提供）：使用LCP纳米技术纳米链甲滨开发用于儿科白血病的纳米氟甲滨开发是Qualiber的Fludarabine磷酸盐（Fludara）的纳米颗粒制剂，该制剂是一种用于治疗白血病和其他恶性肿瘤的药物。虽然氟达拉滨磷酸盐可有效抵抗肿瘤，但它也具有明显的毒性。通过修饰氟达拉滨磷酸盐的生物分布，可以避免这些副作用中的许多副作用。此外，如果我们可以使用针对癌细胞的纳米颗粒将药物递送到癌细胞中，则可以改善氟达拉滨磷酸盐的治疗指数。我们的创新是在一种新型纳米颗粒制剂中封装氟达拉滨磷酸盐，称为脂质 - 钙磷酸盐（LCP）。 LCP纳米颗粒中氟达拉滨磷酸盐的新配方称为纳米氟甲滨。 LCP的磷酸钙核心将以高效率封装氟达拉滨磷酸盐，并迅速溶解在酸性内体释放的细胞质中氟达拉滨磷酸盐的磷酸盐中，进一步将其进一步磷酸化至Fludarabine三磷酸并运输到核酸核中，以抑制DNA合法性的核酸核。在这阶段，Qualiber将制定LCP，用于递送氟达拉滨磷酸盐（纳米氟滨），并将其表征为体外活性，并确定作为儿科白血病治疗的发育可行性。 AIM 1。通过10倍在过程内控制（IPC）质量质量量增加10倍（IPC）质量器旨在测试可伸缩过程以固体分析封装氟达拉滨测量。初步结果表明，氟达拉滨磷酸盐可以按实验室尺度封装在LCP颗粒中，批次大小为1 mg氟达拉滨磷酸盐封装。在此阶段存在两个挑战：（i）少量的生产和（ii）缺乏过程控制颗粒的聚集部分是由于表面Zeta电位低。成功的生产将纳米颗粒的尺度提高到当前尺度的10倍，批量> 10 mg的氟达拉滨磷酸盐的大小将成为进步目标2的标准。此外，在进程中的控制措施（例如药物封装效率（> 40％）），粒度和多分散性将在未来的过程中进行临时设计，从而进一步进行制造过程。 AIM 2。选择一种靶向的配体，并使纳米氟甲滨在体外研究中靶向白血病（POC）在上述扩大过程中产生的纳米氟甲滨纳米颗粒，将进一步针对白血病细胞。 Qualiber计划用至少两种不同的配体制作纳米氟甲滨，用透明质酸/透明质酸（HA）和（ii）叶酸受体和（II）叶酸受体和（II）叶酸受体和（ii）叶酸受体。游离氟达拉滨磷酸盐，无配体的纳米氟甲滨，具有HA或FA靶向配体的纳米氟甲滨将在体外细胞培养模型中进行测试。结果将用于确定以下内容：（a）比游离氟达拉滨磷酸盐和（b）靶向配体通过纳米颗粒的内吞作用最高的细胞摄取。将根据靶向功效，可用性和制造可行性来选择一个配体。成功地证明纳米氟甲滨（具有HA或FA靶向配体）的IC50值至少比游离氟达拉滨磷酸盐低2-5倍将是进一步临床前开发和II期SBIR赠款的关键里程碑。