Liposomal Doxorubicin and Pluronic Combination for Cancer Therapy

聚乙二醇脂质体多柔比星（Doxil， PLD）在临床上用于治疗卵巢癌（OC）和乳腺癌（BC）；然而，PLD治疗这两种疾病的有效率有待提高。基于强有力的初步数据，我们提出了一种新的简单策略，通过促进活性成分（阿霉素，（Dox））从脂质体颗粒直接在肿瘤基质内释放，同时使肿瘤对药物敏感，从而提高PLD治疗的疗效。在该策略中，两亲性Pluronic嵌段共聚物（聚（环氧乙烷）-嵌段聚（环氧乙烷）-嵌段聚（环氧乙烷），PEO-PPO-PEO）在PLD治疗后，当肿瘤内脂质体药物浓度达到最大值时静脉（IV）给药。我们假设，共聚物随后进入肿瘤，结合到PLD颗粒中，并促进被封装的药物释放，从而提高药物的生物利用度，改善肿瘤反应。此外，肿瘤内产生的Dox和Pluronic的组合在消除多药耐药（MDR）和肿瘤启动细胞（TIC）方面非常有效，可以进一步改善癌症的治疗效果。我们的目标是：确定PLD后给予Pluronic增加抗肿瘤活性的机制；使用OC和BC的基因工程小鼠模型（GEMMs）提供原理证明，这些模型密切代表了患者实体瘤的生物学和微环境；并选择Pluronic组合物和治疗方案，以最大化转化和临床结果。目的：1)测定多替尼在PLD中的体外释放动力学和Pluronic的体内药代动力学（PK），选择最佳的多替尼成分、剂量和方案；2)评估PLD单独或与选定的Pluronic(s)联合的PK，以确定血浆中脂质体释放的Dox量和肿瘤中的药物暴露；3)评价治疗方案的抗肿瘤活性和安全性；4)确定PLD后给予Pluronic是否会导致TIC的消耗，并降低癌细胞的致瘤性和侵袭性。该联合疗法如果成功，将有很大的潜力转化为临床研究，因为它简单，可以提高临床可用的PD（如Doxil）的疗效，并且可能是安全的，因为Pluronics在非脂质体Dox/Pluronic配方SP1049C的临床试验中被证明是安全的。

DESCRIPTION: PEGylated liposomal doxorubicin (Doxil, PLD) is used clinically to treat ovarian cancer (OC) and breast cancer (BC); however, the response rates of PLD treatment in both diseases need to be improved. Based on strong preliminary data, we propose a novel simple strategy to increase the efficacy of PLD treatment by promoting the release of the active ingredient (doxorubicin, (Dox)) from the liposomal particles directly within the tumor matrix, whil concurrently sensitizing this tumor to the drug. In this strategy, amphiphilic Pluronic block copolymers (poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide), PEO-PPO-PEO) are intravenously (IV) administered after the PLD treatment, when the concentration of the liposomal drug within the tumor reaches its maximum. We posit, the copolymer then depots into tumors, incorporates into the PLD particles, and promotes the encapsulated drug release, thus increasing drug bioavailability and improving the tumor response. Moreover, a combination of Dox and Pluronic generated within tumors is highly potent in eliminating multidrug resistant (MDR) and tumor-initiating cells (TIC) that can further improve the therapeutic outcomes in cancer. Our objectives are: to determine mechanism by which administration of Pluronic after the PLD increases the anti-tumor activity; provide proof of principle using genetically engineered mouse models (GEMMs) of OC and BC that closely represent biology and microenvironment of solid tumors in patients; and select Pluronic compositions and treatment regimen to maximize the translational and clinical outcomes. The aims will: 1) determine in vitro release kinetics of Dox from PLD and in vivo pharmacokinetics (PK) of Pluronic to select the best Pluroinic composition, doses and schedule; 2) evaluate PK of PLD alone and in combination with the selected Pluronic(s) to determine the amount of Dox released from liposomes in plasma and drug exposure in tumor; 3) evaluate the anti-tumor activity and safety of the proposed treatments; and 4) determine whether administration of Pluronic after PLD results in depletion of TIC, and decreases tumorigenicity and aggressiveness of cancer cells. The proposed combination therapy if successful has high potential for translation to clinical studies, since it is simple, can improve efficacy of clinically available PD (such as Doxil(r)), and is likely to be safe, since Pluronics were shown to be safe in clinical trils of non-liposomal Dox/Pluronic formulation, SP1049C.