Retargeting FDA Approved Anticancer Liposomal Drugs to Cancer Stem Cells

将 FDA 批准的抗癌脂质体药物重新靶向癌症干细胞

基本信息

批准号：
8833239
负责人：
FRANCIS C. SZOKA
金额：
$ 29.89万
依托单位：
ZONEONE PHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-03 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8833239
关键词：
4T1 Animals Antineoplastic Agents Biochemical Breast Breast Cancer Model CD44 gene Cancer Center Carbohydrates Cell Surface Receptors Cell surface Cells Clinical Trials Colon Complex Cytotoxic agent Development Dose Doxorubicin Hydrochloride Liposome Drug Delivery Systems Drug Formulations Evaluation FDA approved Generic Drugs Glioblastoma Goals Head and Neck Cancer Head and Neck Neoplasms Human Hyaluronan Hyaluronic Acid Inbred BALB C Mice Lead Ligand Binding Ligands Lipids Liposomes Liquid substance Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Metastatic Lesion Methods Micelles Modeling Molecular Weight Mus Neoplasm Metastasis Particle Size Patients Pharmaceutical Preparations Pharmacy facility Physiological Polymers Population Primary Neoplasm Prostate Protocols documentation Research Risk Scientist Signal Transduction Sterility System Technology Testing Therapeutic Time Translating Treatment Failure Vial device antitumor effect arm cancer cell cancer stem cell cancer therapy cell type commercialization density experience improved malignant breast neoplasm neoplastic cell novel ovarian neoplasm overexpression pancreatic neoplasm public health relevance receptor binding research clinical testing sugar tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to develop a ligand product and facile method to use it to target FDA approved liposomal anticancer drugs to cancer stem cells that overexpress CD44. We have devised a highly efficient chemo-enzymatic synthesis of a hyaluronan-lipid (HA-lipid) ligand and have teamed with ZoneOne Pharma to develop a simple and robust micelle transfer method to insert the HA-lipid into the FDA approved liposome cytotoxic drugs (Doxil(R), LipoDox(R) and Daunoxome(R)). This will target the approved liposomal drugs to CD44, a cell surface marker that is over-expressed on many human cancers such as: breast, prostate, colon, glioblastoma, head/neck, ovarian and pancreatic cancers. Recently, CD44 was found to be expressed at high levels on cancer stem cells, which are considered essential for rapid tumor proliferation and tumor metastases. CD44 is a cell surface receptor that is part of a complex biochemical/physiological system involved in the synthesis, degradation and signaling of hyaluronan. The principle ligand for CD44 is hyaluronan itself, a high molecular weight carbohydrate polymer that consists of a two-sugar repeat. We will pursue three aims. Aim 1: At UCSF we will synthesize and characterize large quantities of the lipid-modified HA ligand of a low molecular weight and narrow polydispersity and a fluorescent-modified HA ligand. Aim 2: Scientists at ZoneOne Pharma Inc will devise and validate a micelle transfer method to introduce the ligand into commercial available FDA approved Doxil(R), LipoDox(R) and Daunoxome(R) with retention of the drug content and particle size of the starting liposomes. They will verify the ligand density required to effectivel target the liposomes to CD44 expressing cells in culture. Aim 3: At the UC cancer center the therapeutic activity of Doxil(R) will be compared to HA-modified Doxil(R) in the primary tumor and tumor metastases in the orthotopic 4T1 breast tumor model. The company will prepare the HA-targeted Doxil(R) and transfer it to the UCSF cancer center to determine the antitumor activity of the HA-modified liposomes in the 4T1 tumor in BALB/c mice. Completion of the first two aims will enable a test of the hypothesis that the insertion of a HA-lipid ligand into approved liposomal anticancer drugs can target the liposomal drug to CD44 over expressing cancer cells. Completion of aim 3 will provide a test of the hypothesis that administration of the HA-lipid modified Doxil(R) to CD44 results in a better antitumor effect in the 4T1 breast cancer in BALB/c mice both in the primary tumor and in metastatic lesions than does administration of the non-targeted Doxil(R). Successful completion of the research plan would validate the potential of targeting FDA approved liposomes to treat human cancers that express CD44. We think the evaluation of a targeting lipid HA ligand added in the pharmacy to available liposomal drugs, would experience a rapid entry into clinical trials. This is because the comparator population would be patients who receive the unmodified liposomal drug and in the targeted arm of the study, there could be a lesser risk of treatment failures hence patients would be less likely to be placed at risk than if a completely new drug was being evaluated. Finally, the path to commercialization could be shortened since ZoneOne Pharma would manufacture the ligand product not the entire formulation and provide a robust, validated protocol for inserting the lipid HA into the currently approved liquid FDA liposome formulations.

描述（由申请人提供）：本研究的目标是开发一种配体产品和简便的方法，以使用其将 FDA 批准的脂质体抗癌药物靶向过度表达 CD44 的癌症干细胞。透明质酸脂质 (HA-脂质) 配体，并与 ZoneOne Pharma 合作开发了一种简单而强大的胶束转移方法，将 HA-脂质插入 FDA 批准的脂质体细胞毒性药物（Doxil(R)、LipoDox(R) 和 Daunoxome(R)）这会将批准的脂质体药物靶向 CD44，CD44 是一种在许多人类癌症中过度表达的细胞表面标记物，例如：乳腺癌、前列腺癌、最近发现，CD44 在结肠癌、胶质母细胞瘤、头颈癌、卵巢癌和胰腺癌中高水平表达，被认为对于肿瘤的快速增殖和肿瘤至关重要。 CD44 是一种细胞表面受体，是参与透明质酸合成、降解和信号传导的复杂生化/生理系统的一部分。CD44 的主要配体是透明质酸本身，它是一种由两个分子组成的高分子量碳水化合物聚合物。我们将追求三个目标：在 UCSF，我们将合成并表征大量低分子量、窄多分散性和荧光修饰的脂质修饰 HA 配体。目标 2：ZoneOne Pharma Inc 的科学家将设计并验证一种胶束转移方法，将配体引入 FDA 批准的市售 Doxil(R)、LipoDox(R) 和 Daunoxome(R) 中，并保留药物含量和颗粒。他们将验证将脂质体有效靶向培养物中表达 CD44 的细胞所需的配体密度。 Doxil(R) 将与 HA 修饰的 Doxil(R) 在原位 4T1 乳腺肿瘤模型中的原发肿瘤和肿瘤转移中进行比较。该公司将制备 HA 靶向的 Doxil(R) 并将其转移到 UCSF 癌症中心。确定 HA 修饰的脂质体在 BALB/c 小鼠 4T1 肿瘤中的抗肿瘤活性完成前两个目标将能够检验以下假设：将 HA-脂质配体插入已批准的脂质体抗癌药物可以将脂质体药物靶向过度表达CD44的癌细胞。目标3的完成将验证以下假设：施用HA-脂质修饰的Doxil(R)至CD44会在4T1乳腺中产生更好的抗肿瘤效果。 BALB/c 小鼠的原发性肿瘤和转移性病变中的癌症比施用非靶向 Doxil(R) 的效果要好，成功完成该研究计划将验证该研究计划。 FDA 批准的靶向脂质体治疗表达 CD44 的人类癌症的潜力我们认为，对药房中现有脂质体药物中添加的靶向脂质 HA 配体的评估将快速进入临床试验，因为比较人群将是。接受未经修饰的脂质体药物且在研究目标组中的患者，治疗失败的风险可能较小，因此患者不太可能最后，由于 ZoneOne Pharma 将生产配体产品而不是制剂，并提供可靠、经过验证的脂质插入方案，因此商业化的路径可能会缩短。 HA进入目前FDA批准的液体脂质体制剂中。