Statement of Purpose:
The goal of this project is to design a new class of intravenously-administered lipid-nanoparticles (sticky liposomes) loaded with DNA damaging agents (the alpha-particle generator Actinium-225, Ac-225) to enable selective targeting of Triple Negative Breast Cancer (TNBC) cells expressing low or too low antigen densities. Alpha-particle emitters typically cause DNA double-strand breaks and, in combination with receptor-mediated targeting, could result in significant radiobiological effects. The key to this unique treatment is to use drug-carrying liposomes whose surface phase-separates to form 'sticky patches' when in proximity to tumor cells.
To better understand the material properties and mechanism of action of these nanoparticles, the kinetics of receptor binding, controlled drug release as well as transport properties of our ‘sticky’ liposomes will be assessed using monolayer cell culture as well as 3-D multicellular tumor spheroid models. By optimizing our liposome properties in these 3-D spheroid systems, which mimic small avascular tumors and micrometastases, we increase the likeliness of successful in vivo efficacy.
Methods: HER2-targeting sticky liposomes were loaded with Ac-225. The sensitivity to alpha particle emitters of various TNBC cell lines (some bearing the BRCA-1 mutation) was evaluated in vitro. Dose response studies to sticky liposomes loaded with Ac-225 were conducted on TNBC cells expressing variably low levels of HER2 receptor copies and were compared to HER2-overexpressing breast cancer cells.
Passive diffusion of fluorescently labeled phase-separating lipid nanoparticles into 3-D tumor spheroids was analyzed over time. Content release of these drug carriers into tumor spheroids was also monitored via fluorescence, using calcein as a therapeutic analogue.
Results: Liposome loading efficiency with Ac-225 was greater than 80% with stable retention in the presence of cells for over 24 hours. BRCA-1 mutated cell lines showed greater sensitivity to alpha particle irradiation. Initial experiments indicate the promising killing efficacy of HER2-targeting sticky liposomes loaded with Ac-225 towards TNBC cells when compared to radiolabeled antibodies or uniformly functionalized liposomes.
Conclusions: Initial results show promise in the capability of these Ac-225 loaded sticky liposomes to selectively target and kill cancer cells that are currently not targetable by reported functionalized nanoparticles.