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

• 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
• 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

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）：利用LCP纳米技术开发用于儿科白血病的NanoFludarabine NanoFludarabine是Qualiber公司的磷酸氟达拉滨（Fludara）的纳米颗粒配方，氟达拉滨是一种广泛用于治疗白血病和其他恶性肿瘤的药物。虽然磷酸氟达拉滨对肿瘤有效，但它也有明显的毒性。通过改变磷酸氟达拉滨的生物分布，可以潜在地减少或避免许多这些副作用。此外，如果我们能够利用靶向癌细胞的纳米颗粒将药物优先输送到癌细胞中，则可以提高磷酸氟达拉滨的治疗指数。我们的创新是将磷酸氟达拉滨封装在一种名为脂质-磷酸钙（LCP）的新型纳米颗粒配方中。将磷酸氟达拉滨的新配方命名为纳米氟达拉滨。LCP的磷酸钙核会高效包裹磷酸氟达拉滨，并迅速溶解在酸性内体中，释放出磷酸氟达拉滨到细胞质中，并进一步磷酸化成三磷酸氟达拉滨，转运到细胞核抑制DNA合成。在这个I期研究中，Qualiber将为磷酸氟达拉滨（NanoFludarabine）的递送配制LCP，并对其体外活性进行表征，并确定其作为儿科白血病治疗的可行性。目的1。利用过程控制（IPC） Qualiber将目前LCP纳米颗粒中封装磷酸氟达拉滨的生产规模提高10倍，旨在测试可扩展的固体分析物包封磷酸氟达拉滨工艺的可行性