Modulating Tumor-Associated Macrophages using Cell-specific Targeted Liposomes

Dr. J. Prakash1), University Twente/The Netherlands

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1.

Dr. Jai PrakashTargeted Therapeutics, Biomaterials Science and Technology, University of Twente, Enschede/The Netherlands

Abstract

The tumor microenvironment strongly contributes in aggravating tumor growth and causing treatment failure. Tumor-associated macrophages (TAMs), M2-type macrophages, are key cells in the tumor microenvironment inducing tumor growth, invasion, and metastasis.1)2) We have recently developed TAM-targeting liposomes by introducing carboxylated phospholipids that binds to the scavenger receptors (scrb1, collec1, CD36) expressed by TAMs [former project: Design of well-defined liposomes to target tumor-associated M2 macrophages].

In this project, these TAM-targeted liposomes were applied to specifically target M2-modulating drugs that are STAT6 inhibitor AS1517499,3) Zoledronic acid, and muramyl tripeptide (MTP-PE). Targeting of these inhibitors will specifically modulate TAMs either by inhibiting or reversing them into tumor-suppressing M1-type macrophages. TAM-targeted liposomal formulations will be evaluated in vitro for their efficacy and in vivo for their biodistribution, pharmacokinetics, and therapeutic efficacy in breast tumor model in mice. Overall, this project will explore the new applications of the specialized forms of phospholipids by modulating TAMs in the tumor microenvironment for the treatment of cancer.

Benefit for the community

There is no need to justify the impact of cancer on the society as it affects every region and socioeconomic level. The World Health Organization has estimated that about 14 million new cases and 8.2 million deaths are reported each year worldwide. The predicted number of cancer-related deaths in the European Union in 2013 is 1.3 million. There are about 100 chemotherapies and 50 targeted therapies approved for cancer, but the treatment of cancer remains the most challenging in clinic. Moreover, chemotherapies are often toxic to the patients and almost always accompanied by primary or secondary resistance. Thus, the total burden on the society due to cancer is immense.

Tumor-associated macrophages contribute to tumor initiation, progression, and metastasis and are therefore an attractive therapeutic target. Several drugs are under clinical trials to gain anticancer efficacy. However, no drug is on the market that specifically inhibit TAMs. It is evident that the development of novel liposomal-based therapeutics against TAMs may benefit cancer therapy and enhance survival rate in cancer patients. A new intellectual property is expected to be developed through this project which will pave a way to bring this technology to clinic. This may eventually reduce health burden on the society. In addition, the new knowledge developed in this project will also benefit the scientific community to explore new ideas to challenge cancer more effectively.

Results/Outcome

We have designed a TAM-targeting system using liposomes. Fluorescent microscopy and flow cytometry data showed that carboxylated lipid containing Cy-liposomes had a significantly higher uptake by M2 macrophages than M1 macrophages in vitro, while normal liposomes showed the same uptake. Also, Cy-liposomes showed ca. 2.5-fold higher accumulation in tumors compared to normal liposomes, and the accumulation was co-localized with TAMs (CD206+), as shown with flow cytometry. To modulate TAMs, we encapsulated three compounds into Cy-liposomes: (i) zoledronic acid (ZA) to deplete them, (ii) AS1517499, and (iii) MTP-PE to modulate TAMs into M1 and tested them in vivo in triple negative orthotopic 4T1 mammary tumor model in female balb/c mice to examine effect on tumor growth and pre-metastatic niche formation in lungs. In vitro, ZA-containing liposomes depleted TAMs while AS1517499- or MTP-PE-containing liposomes inhibited TAMs activation or converted them into M1-like macrophages, respectively. In vivo, ZA-liposomes reduced the tumor growth by 40% and these mice also showed depletion of TAMs (YM-1, CCR2) in lungs as well as inhibition of pre-metastatic niche markers (SDF-1a, Postn, col-1a). Inhibition of STAT6 pathway using AS1517499-liposomes did not show a reduction of the tumor growth, however, interestingly, reduced pre-metastatic niche markers in lungs. Remarkably, treatment with MTP-targeted liposomes led to reduction of the tumor growth by 70% as well as it showed reduction in lung premetastatic niche markers.

In conclusion, our novel TAM-targeting liposomes provide a versatile platform technology to target and modulate TAMs to unravel the biological significance in the tumor microenvironment. By delivering specific molecules, we could either deplete, inhibit, or re-program TAMs which resulted in inhibition of the tumor growth and/or inhibition of pre-metastatic niche formation in breast tumor model in vivo

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References:
1.
Poh, AR, Ernst M, 2018
Targeting Macrophages in Cancer: From Bench to Bedside
Front Oncol. 8, 49
2.
Binnemars-Postma KA, Storm G, Prakash J, 2017
Nanomedicine strategies to target tumor-associated macrophages
Int. J. Mol. Sci. 18, E979
3.
Binnemars-Postma KA, Bansal R, Storm G, Prakash J, 2018
Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer
FASEB J. 32, 969-978