Enhanced performance of macrophage-encapsulated nanoparticle albumin-bound-paclitaxel in hypo-perfused cancer lesions

Abstract

Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in-vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.

Towards personalized computational oncology: from spatial models of tumour spheroids, to organoids, to tissues

“…Model simulations predicted a synergistic effect of combining conventional and macrophage-based therapies; however, the efficacy of this combined treatment was the greatest when the macrophage-based therapy was administered shortly before or concurrently with chemotherapy. Leonard et al [117] proposed a mathematical model simulating how macrophages can deliver a nanodrug to metastatic lesions in the liver, combining the level-set method to represent the evolving tumour, discrete representation of the tumour vasculature and diffusion-reactions equations for drug and metabolites dynamics, integrating it with laboratory experiments. The model predicted the macrophage and the encapsulated nanodrug concentrations needed inside the lesion to achieve growth inhibition.…”

Examining the effects of macrophage populations on cancerous tumor growth.

“…The computational model builds upon recent work simulating generic tumorassociated macrophages (TAMs) in a vascularized tumor environment (Leonard, Curtis et al 2016), in which a breast cancer lesion metastasized to the liver was simulated -in an microenvironment that is known to favor the recruitment of TAMs (Bocuk, Krause et al 2015). In (Leonard, Curtis et al 2016), macrophages were utilized as a drug vector, and their performance was evaluated experimentally and via computational simulation.…”

“…In (Leonard, Curtis et al 2016), macrophages were utilized as a drug vector, and their performance was evaluated experimentally and via computational simulation. Here, we do not assume that drug is vectored by macrophages, and instead focus on the effects of various macrophage population subtypes on the tumor lesion progression.…”

“…Hypoxia-induced factors such as VEGF-A, endothelin-2, and interleukin-10 secreted in the tumor environment encourage differentiation towards the M2 phenotype (Murdoch, Giannoudis et al 2004). Within the tumor microenvironment, M2s secrete factors such as TGF-β1 which facilitates cancer cell proliferation (Leonard, Curtis et al 2016) (Italiani and Boraschi 2014), VEGF-A which promotes angiogenesis and recruits additional macrophages, and MMP-9 which facilitates angiogenesis by degrading the extracellular matrix (Chanmee, Ontong et al 2014). The proportion of M2 macrophages in the microenvironment tends to increase with tumor progression.…”

“…In (Chen, Bobko et al 2014) the role of tumor macrophage hypoxia inducible factors (HIFs) in chemotherapy effectiveness was evaluated. Recently, a model exploring the efficacy of nanoparticle albumin-boundpaclitaxel (nAb-PTX) using macrophages in a multistage vector system as a therapy for hypervascularized breast cancer metastases in the liver was developed (Leonard, Curtis et al 2016). …”