Retargeting FDA Approved Anticancer Liposomal Drugs to Cancer Stem Cells

 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方法，以使用其将FDA批准的脂质体抗癌药物靶向过表达CD 44的癌症干细胞。我们设计了一种高效的化学-酶促合成透明质酸-脂质（HA-脂质）配体的方法，并与ZoneOne Pharma合作开发了一种简单而稳健的胶束转移方法，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））中。这将使批准的脂质体药物靶向CD 44，这是一种在许多人类癌症上过度表达的细胞表面标志物，例如：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CD 44在癌症干细胞上以高水平表达，这被认为是快速肿瘤增殖和肿瘤转移所必需的。CD 44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。CD 44的主要配体是透明质酸本身，它是一种高分子量的碳水化合物聚合物，由两个糖重复组成。我们将追求三个目标。目标1：在加州大学旧金山分校，我们将合成和表征大量的低分子量和窄多分散性的脂质修饰的HA配体和荧光修饰的HA配体。目标二：ZoneOne Pharma Inc的科学家将设计并验证一种胶束转移方法，将配体引入市售的FDA批准的Doxil（R）、LipoDox（R）和Daunoxome（R）中，保留起始脂质体的药物含量和粒度。他们将验证将脂质体有效靶向培养物中表达CD 44的细胞所需的配体密度。目标3：在UC癌症中心，Doxil（R）的治疗活性将与HA修饰的Doxil（R）在原位4 T1乳腺肿瘤模型中的原发性肿瘤和肿瘤转移中进行比较。该公司将制备HA靶向Doxil（R）并将其转移到UCSF癌症中心，以确定HA修饰的脂质体在BALB/c小鼠4 T1肿瘤中的抗肿瘤活性。前两个目标的完成将使得能够检验以下假设：将HA-脂质配体插入到已批准的脂质载体中。 脂质体抗癌药物可以将脂质体药物靶向过表达CD 44的癌细胞。目标3的完成将提供对以下假设的检验：在BALB/c小鼠的4 T1乳腺癌中，给予HA-脂质修饰的Doxil（R）至CD 44在原发性肿瘤和转移性病变中均比给予非靶向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CD 44的人类癌症的潜力。我们认为，在药房中将靶向脂质HA配体添加到可用的脂质体药物中的评估将快速进入临床试验。这是因为对照人群将是接受未修饰的脂质体药物的患者，并且在研究的靶向组中，治疗失败的风险可能较小，因此患者不太可能 比评估一种全新药物面临的风险要大。最后，商业化的路径可以缩短，因为ZoneOne Pharma将生产配体产品而不是整个制剂，并提供用于插入脂质的稳健的、经验证的方案 HA加入到目前批准的液体FDA脂质体制剂中。

 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.