Abstract 1324: Enhancing therapeutic efficacy of albumin bound paclitaxel in breast cancer liver metastasis by homing to tumor associated macrophages: In vitro, in vivo and in silico studies
Authors: Leonard Fransisca , Louis Curtis T. , Yesantharao Pooja , Tanei Tomonori , Alexander Jenolyn F. , Xuewu Liu , Mauro Ferrari , Yokoi Kenji , Frieboes Hermann B. , Godin Biana 
Published: July 2016

Abstract
This study is aimed to evaluate and enhance the albumin-bound paclitaxel (nab-PTX) in multistage vector (MSV) for liver metastasis treatment using in silico modeling based on in vitro data, and verified via in vivo study. The resulting model will help for therapy optimization in the clinical setting.
Clinically, breast cancer liver metastases can be observed as hypoattenuated in MRI and CT images caused by low penetration of drugs or contrast agents into the lesions along with a high washout rate, which correlates to poor chemotherapeutic response. Nab-PTX is clinically used for treatment of advanced breast tumors, but not for liver metastasis. We designed MSV-nab-PTX, a new nab-PTX delivery system for specifically homing to tumor associated macrophages in the liver. MSV-nab-PTX consists of nab-PTX loaded in porous silicon multistage nanovectors which were previously shown to be efficient in delivering siRNA and other therapeutics. MSV-nab-PTX was evaluated in in vitro, in vivo and in silico models of liver metastasis. Co-culture of breast cancer tumor cells (3D-spheroids) and macrophages was developed and utilized to evaluate the drug efficacy and to study the mechanism of nab-PTX transport. Addition of macrophages in the 3D model significantly increased the efficacy of MSV-nab-PTX, but not nab-PTX, revealing the major role of macrophages in the drug transport into the lesion. Primary mouse and human macrophages were shown to uptake up to 10 ng of PTX/cell in MSV-nab-PTX with no significant effects on their viability, and later release the PTX over 24h. Treatment with MSV-nab-PTX increased chemokine production by tumor cells when compared to nab-PTX, increasing macrophage migration into the tumor sphere by more than 2-fold. Based on these data, we implemented a mathematical model linking drug release and retention from macrophages to project MSV-nAb-PTX efficacy based on the presence of macrophages in tumor biopsies. Simulation of repeat treatment every 3 days showed a significant reduction of tumor size, and was verified by the in vivo data. MSV-nab-PTX as compared to nab-PTX enhanced PTX concentration in the target lesions, increased apoptosis rate and reduced cancer cells proliferation rate, ultimately reducing the tumor size and prolonging the survival of treated mice.
This showed that MSV association with macrophages can increase drug efficacy compared to bolus injection, and that it is feasible to reach sustained lesion regression with the macromolecule-bound formulation. The in silico simulations also revealed that the timing interval is crucial for the treatment strategy, and the effect depends on the size and vascularization stage of the lesion. We conclude that an integrated in vitro, in vivo, and in silico framework may be of use to assess response to albumin bound paclitaxel targeted to breast cancer liver metastasis via tumor associated macrophages.
Citation Format: Fransisca Leonard, Curtis T. Louis, Pooja Yesantharao, Tomonori Tanei, Jenolyn F. Alexander, Liu Xuewu, Ferrari Mauro, Kenji Yokoi, Hermann B. Frieboes, Biana Godin. Enhancing therapeutic efficacy of albumin bound paclitaxel in breast cancer liver metastasis by homing to tumor associated macrophages: In vitro, in vivo and in silico studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1324.