Retargeting FDA Approved Anticancer Liposomal Drugs to Cancer Stem Cells

 描述(申请人提供)：这项研究的目标是开发一种配体产品和简便的方法，使用它来靶向FDA批准的脂质体抗癌药物到过表达CD44的癌症干细胞。我们设计了一种高效的化学-酶法合成透明质酸-脂(HA-LID)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-Liped插入FDA批准的脂质体细胞毒药(Doxil(R)、Lipodox(R)和Daunoxome(R))。这将以CD44为靶点，CD44是一种细胞表面标记，在许多人类癌症中过度表达，如乳腺癌、前列腺癌、结肠癌、胶质母细胞瘤、头颈癌、卵巢癌和胰腺癌。最近发现，CD44在肿瘤干细胞上高水平表达，这被认为是肿瘤快速增殖和肿瘤转移所必需的。CD44是一种细胞表面受体，是参与透明质酸合成、降解和信号转导的复杂生化/生理系统的一部分。CD44的主要配体是透明质酸本身，这是一种由两个糖重复组成的高分子碳水化合物聚合物。我们将追求三个目标。目的1：在加州大学旧金山分校，我们将合成和表征大量低分子量窄多分散性的脂质修饰的HA配体和荧光修饰的HA配体。目的2：ZoneOne制药公司的科学家将设计并验证一种胶束转移方法，将该配体引入FDA批准的商用Doxil(R)、Lipodox(R)和Daunoxome(R)，同时保留起始脂质体的药物含量和颗粒大小。他们将验证将脂质体有效靶向培养中表达CD44的细胞所需的配体密度。目的：在UC癌症中心，在原位4T1乳腺肿瘤模型中，比较Doxil(R)和HA修饰的Doxil(R)在原发肿瘤和肿瘤转移中的治疗活性。该公司将制备HA靶向的Doxil(R)，并将其转移到加州大学旧金山分校的癌症中心，以确定HA修饰的脂质体在BALB/c小鼠4T1肿瘤中的抗肿瘤活性。前两个目标的完成将使对以下假设的检验成为可能：将HA-脂质配体插入已批准的 脂质体抗癌药物可以靶向CD44高表达的癌细胞。目标3的完成将检验这样一种假设，即在BALB/c小鼠的4T1乳腺癌中，给CD44注射HA-脂质修饰的Doxil(R)在原发肿瘤和转移灶中都比给药非靶向Doxil(R)产生更好的抗肿瘤效果。该研究计划的成功完成将验证靶向FDA批准的脂质体治疗表达CD44的人类癌症的潜力。我们认为，将药房中添加到现有脂质体药物中的靶向脂质HA配体的评估将迅速进入临床试验。这是因为对照人群将是接受未经修改的脂质体药物的患者，在研究的目标组中，治疗失败的风险可能较小，因此患者将不太可能 比起正在评估一种全新的药物，这种药物处于危险之中。最后，商业化的道路可能会缩短，因为ZoneOne Pharma将生产配体产品，而不是整个配方，并为插入脂质提供可靠、有效的方案 将透明质酸制成目前批准的液体FDA脂质体制剂。

 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.