Design of well-defined liposomes to target tumor-associated M2 macrophages
Dr. J. Prakash1), University of Twente/The Netherlands
People involved
Karin A. Binnemars-Postma (PhD fellow sponsored by the PRC) – University of Twente/The Netherlands
Abstract
The tumor microenvironment contains a variety of nonmalignant cell types along with malignant tumors cells. Most of the nonmalignant cells include stromal cells such as tumor-associated macrophages (TAMs), fibroblasts, and tumor vasculature cells. TAMs promote key processes in tumor progression, like angiogenesis, immunosuppression, invasion, and metastasis.1) In tumors, M2 macrophages are the activated form of macrophages, that compose most of the TAMs, promote angiogenesis, suppress immune system, and enhance chemoresistance, thus limiting efficacy of chemotherapy.2) Therefore, specific inhibition of pro-tumoral activities of M2 macrophages within the tumor microenvironment represents a promising strategy contributing to the fight against cancer.
Liposomes are the most commonly used drug carrier to deliver drugs to tumors. Many liposomal formulations, such as Myocet® (non-PEGylated formulation of doxorubicin), Doxil® (PEGylated liposomal formulation of doxorubicin), DaunoXome® (PEGylated liposomal formulation of daunorubicin) and Marqibo® (liposomal formulation of vincristine sulfate), have been used clinically for the treatment of different cancer types. Liposome-enabled tumor targeting is mainly based on the principal of passive targeting that relies on the phenomenon so-called Enhanced Permeability and Retention (EPR) effect.
Macrophages express different phagocytosis receptors such as pattern-recognizing receptors (e.g. mannose receptor), opsonic receptors, and apoptosis corpse receptors (e.g. CD36).3) To target some of these receptors, many approaches such as surface modifications with mannose sugar, targeting peptides or monoclonal antibodies have been proposed to induce macrophagic uptake of nanoparticles.4) It has been reported that the apoptosis corpse receptors CD36 is overexpressed by M2 macrophages compared to M1. Specific targeting to CD36 receptor might give an opportunity to target M2 macrophages.
Oxidized phospholipids have been shown to interact with macrophages through CD36 receptor.5) This study showed that oxidized phosphatidylcholine (OxPC) present in the oxidized lipids can bind to the CD36 receptor. However, non-oxidized form of PC did not show binding to the CD36 receptor. These oxidized lipids are well-defined lipid molecules and can therefore be applied for the development of clinical products.
The aim of the project is to design M2 macrophage-targeted liposomes using oxidized phosphatidylcholine in their lipid composition, which could be potentially used for drug delivery purposes.
Benefit for the community
Tumor-associated macrophages (TAMs) contribute to tumor initiation, progression and mortality and are therefore an attractive therapeutic target. However, there are currently no drugs on the market that specifically aim to inhibit macrophage activities. Currently used systemic and targeted chemotherapy is often toxic to the patients and almost always accompanied by primary or secondary resistance. There is no need to justify the impact of cancer on the society as it affects every region and socio-economic level. The World Health Organization (WHO) has estimated that about 84 million people will die from cancer between 2005 and 2015 worldwide. The predicted number for cancer deaths in the European Union in 2013 is 1.3 million. Thus, the total burden on the society due to cancer is immense. It is evident that the development of novel therapeutics against TAMs, as proposed in this project, may improve the survival, promote the cure of the cancer patients and concomitantly decrease the toxic side effects associated with current chemotherapy, which will benefit not only cancer patients but also the society in general by reducing healthcare costs.
Results/Outcome
In conclusion, we have successfully prepared different OxPC containing liposomes and demonstrated that OxPC-containing liposomes at specific ratio show specific interaction with M2 macrophages. The in vivo distribution studies confirmed the specific targeting to tumor-associated macrophages in breast tumor model in mice. This novel M2 targeting technology holds promises for generating new intellectual property by targeting specific M2 inhibitor, which will be considered to apply in further studies. Altogether, our novel M2-taregted liposomes can be promising nanocarrier for drug targeting to tumor-associated macrophages for developing anticancer therapies.
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