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

针对血浆高密度脂蛋白 (SR-B1) 受体进行有效的抗癌治疗。

基本信息

批准号：
9046478
负责人：
WALTER J MCCONATHY
金额：
$ 22.07万
依托单位：
LIPOMEDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9046478
关键词：
Abraxane Adverse effects Albumins Antineoplastic Agents Apolipoprotein A-I Binding Biotechnology Blood Circulation Caliber Clinical Cremophor Density Gradient Centrifugation Detergents Development Drug Delivery Systems Evaluation Excipients Fluorescence Formulation High Density Lipoproteins Human Injection of therapeutic agent Lead Lipids Lipoproteins Malignant Neoplasms Mediating Micelles Modeling Molecular Molecular Weight Pharmaceutical Preparations Phospholipids Plasma Publications SR-BI receptor Solid Neoplasm Solubility Solvents Toxic effect Treatment Efficacy United States Food and Drug Administration Xenograft procedure anti-cancer therapeutic base cancer cell chemotherapeutic agent cremophor EL experience fast protein liquid chromatography improved nano nanoparticle particle physical property public health relevance receptor reconstitution scavenger receptor surfactant tumor tumor xenograft uptake zeta potential

项目摘要

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.