Targeting the plasma high density lipoprotein (SR-B1) receptor for effective anti-cancer therapeutics.

 描述（由申请人提供）：我们的目标是评估几种戊柔比星纳米颗粒，包括白蛋白结合纳米颗粒、聚合物胶束纳米颗粒、磷脂结合纳米颗粒以及磷脂+ApoA-I结合纳米颗粒。我们预计，这些纳米颗粒的全身递送后，戊柔比星将转移到内源性HDL颗粒，促进增强的选择性肿瘤摄取戊柔比星清道夫受体B1型（SR-B1）。将利用我们过去使用白蛋白结合纳米颗粒（Abraxane-2005年批准的USFDA）、聚合物胶束（Cynviloq-2006年批准的KFDA）和含apoA-I的重构HDL（rHDL）纳米颗粒（8篇出版物）的经验执行实验计划。假设：在将纳米颗粒制剂注射到体循环中时，戊柔比星将从相应的注射的纳米颗粒掺入到循环HDL颗粒中。因此，血浆重塑的HDL/瓦尔纳米颗粒将具有通过SR-B1受体选择性地将其药物有效载荷递送至癌细胞和肿瘤的能力。预期含有戊柔比星的纳米颗粒（Nano-Val）将比用常规溶剂如Cremophor EL配制的戊柔比星在治疗上更有效。具体目标1。开发和评价四类含戊柔比星的纳米颗粒的转运能力：a）白蛋白结合的，B）聚合物胶束，c）含磷脂结合的颗粒和d）含apoA-I的纳米颗粒。在纳米颗粒的表征之后，在将各个纳米颗粒与人血浆孵育后，将建立戊柔比星在包括脂蛋白的血浆级分中的分布B。具体目标2。概念异种移植物研究的证明：基于SR-B1表达，将针对选自NCI- 60组的一组肿瘤异种移植物评价在将药物有效载荷转移至内源性HDL方面最有效的药学稳定制剂的抗肿瘤活性。将所选纳米瓦尔颗粒的抗肿瘤功效与Valstar（Cremophor瓦尔制剂）的抗肿瘤功效进行比较。抗肿瘤最有效的戊柔比星纳米颗粒Nano-Val应该是药学上相容的，可用于针对广泛的实体瘤的临床开发。我们预计，戊柔比星，作为一个初始的疏水模型药物，将导致类似的发展，在使用其他疏水药物通过一个既定的药物输送平台，从而开辟了道路，生产临床有效的抗癌制剂，以及有利可图的企业为生物技术企业家。

 DESCRIPTION (provided by applicant): Our objective is to evaluate several valrubicin nanoparticles including albumin-bound, polymeric micelles, and phospholipid bound, and phospholipid+ApoA-I bound nanoparticles. We anticipate that upon systemic delivery of these nanoparticles, valrubicin will be transferred to endogenous HDL particles facilitating enhanced selective tumor uptake of valrubicin by the scavenger receptor type B1 (SR-B1). The experimental plan will be executed utilizing our past experience with albumin-bound nanoparticles (Abraxane- approved 2005 USFDA), polymeric micelles (Cynviloq- approved 2006 KFDA), and apoA-I containing reconstituted HDL (rHDL) nanoparticles (8 publications). Hypothesis: Upon injection of the nanoparticle formulation into the systemic circulation, the valrubicin will be incorporated into the circulating HDL particles from the respective injected nanoparticles. The plasma remodeled HDL/Val nanoparticle will thus have the capability to selectively deliver its drug payload to cancer cells and tumors via the SR-B1 receptor. It is expected that the valrubicin containing nanoparticle (Nano-Val) will be more effective therapeutically than the valrubicin formulated with conventional solvents such as Cremophor EL. Specific Aim 1. Development and evaluation of the transport capabilities of four classes of valrubicin containing nanoparticles: a) albumin-bound, b) polymeric micelles, c) phospholipid bound containing particles and d) apoA-I containing nanoparticles. Following characterization of the nanoparticles, the distribution of valrubicin in plasma fractions including lipoproteins will b established upon incubation of the respective nanoparticles with human plasma. Specific Aim 2. Proof of concept xenograft studies: Anti-tumor activity of the pharmaceutically stable formulation that is most effective in transferring the drug payload to endogenous HDL will be evaluated against a panel of tumor xenografts selected from the NCI- 60 panel, based on SR-B1 expression. The anti-tumor efficacy of the selected Nano Val particle will be compared to that of Valstar (Cremophor Val formulation). The most effective valrubicin nanoparticle against tumors, Nano-Val, should be pharmaceutically compatible for clinical development against a broad range of solid tumors. We expect that valrubicin, as an initial hydrophobic model drug, will lead to a similar development in the use of other hydrophobic drugs via an established drug delivery platform thus opening the way for producing clinically effective anti-cancer formulations as well as profitable ventures for biotech entrepreneurs.