?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.
Public Health Relevance Statement: Public Health Relevance: The aim of this project is to reformulate a highly hydrophobic anti-cancer agent, valrubicin, into an effective, systemically delivered chemotherapeutic agent. We anticipate that upon systemic delivery of these valrubicin containing nanoparticles, valrubicin will be transferred to endogenous high density lipoprotein (HDL) particles. The additional advantage of transferring the drugs systemically to HDL is that it leads to the selectiv targeting of HDL to malignant tumors mediated by the scavenger receptor B1 (SR-B1). It is expected that this approach will improve the solubility of hydrophobic drugs and allow targeting of malignant tumors mediated by the SR-B1 while reducing toxicity and side effects.
Project Terms: Abraxane; Adverse effects; Albumins; anti-cancer therapeutic; Antineoplastic Agents; Apolipoprotein A-I; base; Binding (Molecular Function); Blood Circulation; Caliber; cancer cell; chemotherapeutic agent; Clinical; Cremophor; cremophor EL; Density Gradient Centrifugation; Detergents; Development; Drug Delivery Systems; Evaluation; Excipients; experience; fast protein liquid chromatography; Fluorescence; Formulation; High Density Lipoproteins; Human; improved; Injection of therapeutic agent; Lead; Lipids; Lipoproteins; Malignant Neoplasms; Mediating; Micelles; Modeling; Molecular; Molecular Weight; nano; nanoparticle; particle; Pharmaceutical Preparations; Phospholipids; physical property; Plasma; public health relevance; Publications; receptor; reconstitution; scavenger receptor; Solid Neoplasm; Solubility; Solvents; SR-BI receptor; surfactant; Toxic effect; Treatment Efficacy; tumor; tumor xenograft; United States Food and Drug Administration; uptake; Xenograft procedure; zeta potential
