Abstract 2453: Overcoming transport barriers in liver metastasis with multi-stage nanovectors (MSV)

Liver metastasis occur in 30-70% of patients dying of various malignancies. In the case of metastatic breast cancer, 50% of the patients develop liver metastasis with median survival rate of only a few months and very rare 5-year survival. We hypothesized that the inefficiency in treatment of liver metastasis of breast tumors can be related to biophysical barriers in the tumor microenvironment preventing delivery of therapeutics to tumor loci. Our research focused on physical factors involved in the progression of liver metastasis and design of systems for targeted delivery of therapeutics. Multi-stage vectors (MSV) were previously reported to overcome sequential biophysical barriers and to efficiently carry therapeutic payload to the tumor microenvironment. The first stage porous silicon particles target tumor-associated endothelium or macrophages releasing second stage therapeutic nanoparticles in the close proximity to the tumor. The objectives of this work were to investigate: (1) in vivo barriers associated with drug delivery in breast tumor liver metastasis; (2) in vitro/in vivo interaction of MSV with macrophages; and (3) to perform initial therapeutic efficiency study with MSV loaded with Abraxane (albumin bound paclitaxel). Liver metastases were produced by intra-splenic injected of 4T1 breast cancer cells to balb/C mice. A small incision in the abdomen of the animals was made to expose the liver and the kinetics of distribution of tracers/MSV was recorded. Intravital microscopy was used to observe the distribution of tracers (MW 4 and 30KDa dextrans) and MSV particles. Macrophages and RBC were pre-labeled 4-48 hours prior to the experiment. For therapy experiment, 10-14 days following tumor inoculation mice were randomly divided in three groups: untreated, MSV-Abraxane treated and Abraxane treated. The mice were sacrificed on day 7 following the treatment and the number of metastasis and liver weight were recorded. From the intravital microscopy studies, it appears that liver metastasis of 4T1 tumors have insufficient functional vascularization, which can be the reason for inability to efficiently treat metastatic loci. Dextran −4KDs with nominal diameter of 2-3nm (similar to unbound chemotherapeutics) penetrate into the tumor but washed out within minutes, while dextran ∼30KdA (d=12nm) retain longer, but penetrate less due to the limited vascular permeability. MSV were efficiently Internalized by murine and human macrophages in vitro and by liver macrophages in vivo in the metastatic liver. MSV encapsulated Abraxane enabled an almost complete elimination of the metastatic loci, while Abraxane was not efficient. The initial therapy data suggest that MSV targeted macrophages in breast cancer liver metastasis enabling high concentrations of chemotherapeutic agents to accumulate in the tumor loci. This can be an efficient strategy for overcoming physical barriers in breast cancer liver metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2453. doi:1538-7445.AM2012-2453