Nanotherapy for Breast Cancer Targeting Tumor Macrophages

Institution: The Burnham Institute for Medical Research
Investigator(s): Gaurav  Sharma , Ph.D. -
Award Cycle: 2008 (Cycle 14) Grant #: 14FB-0107 Award: $90,000
Award Type: Postdoctoral Fellowship
Research Priorities
Innovative Treatments>Immune therapy: mobilizing the body's defenses



Initial Award Abstract (2008)

Macrophages are versatile, plastic cells that are a key component of the body’s immune system. They have a variety of biological roles which include antigen “presentation”, a crucial role in initiating an immune response, scavenging debris, tissue remodeling and killing target cells such as bacteria etc. Macrophages are often prominent in tumor tissues, comprising up to 80% of the cell mass in breast carcinoma. Evidence currently available suggests that these tumor associated macrophages (TAMs) are reprogrammed by cancer cells and have little cytotoxicity for tumor cells. In fact, TAMs actually promote tumor cell proliferation and metastasis by secreting a wide range of chemicals. Due to their high concentration in breast tumor tissues, TAMs provide an ideal target for anti-breast cancer therapies, but selectively delivering drugs to kill TAMs with minimal side-effects is a major hurdle.

The goal of this project is to work at the interface of nanotechnology and medicine to design “smart” nanoparticles that will selectively target and kill TAMs, thereby suppressing tumor progression and metastasis. Recent advances in nanoparticle design, when properly integrated with the evolving knowledge of tumor microenvironment biology, can provide an ideal platform to overcome the challenges associated with conventional breast cancer therapies. Recently it was shown for the first time that legumain, a member of the endopeptidase family is highly overexpressed by TAMs in murine and human breast tumor tissues and hence provides an ideal starting point for breast tumor targeting. First, we will use a novel strategy to change the shape of nanoparticles that will endow them with the “stealth” to remain in circulation for longer times by evading the body’s reticuloendothelial system. This approach should increase the ability of TAM-directed nanoparticle to “home” in on target tumor sites. Next, to validate TAM targeting, we will use well defined macrophage cell lines and TAMs isolated from mouse breast tumor tissues. The goal is to identify specific TAM molecular “biomarkers” that can be targeted. Finally, the “stealth” nanoparticles will be made functional with targeting moieties, such as antibodies to legumain or other biomarkers identified in the course of these studies.

The proposed study has two innovative elements: (1) Instead of directly targeting and killing cancer cells, an approach that has met with limited success so far because of inefficient targeting and risk of side-effects due to high toxicity of anti-cancer drugs, we seek to alter the tumor microenvironment by targeting and killing TAMs that support angiogenesis and metastasis; and (2) to make the drug carrying nanoparticles more potent for anti-cancer therapy I propose to change their morphology to endow them with the “stealth” and give them an additional level of selectivity for tumor sites.




Progress Report 1 (2009)

Tumor associated macrophages (TAMs) are a prominent tissue in breast tumors comprising up to 80% of the cell mass in breast carcinoma. TAMs have been known to promote tumor cell proliferation, angiogenesis and metastasis by secreting a wide range of growth and pro-angiogenic factors. Therefore, TAMs can be a validated therapeutic target for cancer therapy and may complement more conventional breast cancer treatment regimens.

One way to efficiently deliver drugs to TAMs is to use polymeric nanoparticles (NPs) as drug carriers. But, a major hurdle in NP based targeting of tissues, and in particular, the macrophages, is the rapid clearance of NPs from circulation by the macrophages of the body's immune system. This has the effect of drastically limiting the availability of circulating NPs and reducing their overall accumulation at target sites. Therefore for drug delivery applications where the macrophage is a therapeutic target it is imperative to engineer NPs with a goal of limiting their interaction with the macrophages of the immune system. Towards this end, I constructed a library of different shape of nanoparticles and found that NPs in the shape of “prolate ellipsoids” show lowest internalization by macrophages. This is a significant finding and shows that the interaction of NPs with cells can be manipulated just by changing the morphology of the particles without any need for complex surface modifications. I also evaluated an oligonucleotide (polyG) as a potential ligand for targeting TAMs. Cell-based studies with polyG-functionalized NPs incubated with macrophages showed significantly higher binding to macrophages compared to non-functionalized NPs.

The ultimate goal of these targeted NPs will be to kill TAMs that promote angiogeneis and tumor metastasis. Towards this end, I designed a nanoparticle agent that is highly toxic to macrophages and takes advantage of cell’s natural phagocytic ability to induce macrophage apoptosis. In in-vitro studies I demonstrated that this nanoparticle agent is not toxic to other normal cell lines while maintaining high toxicty towards macrophages.

Overall, during the first year of the fellowship I have completed the design of long-circulating NPs that can evade the macrophages of the immune system, have identified a non-immunogenic targeting agent that can be conjugated on the surface of the NPs for targeted delivery to TAMs and have developed a drug-loaded NP agent that can selectively kill macrophages. In the second year of this fellowship, I will combine these research strategies and test in-vivo, in a breast cancer model of mice, the efficacy of these functionalized drug-loaded NPs to kill TAMs and induce tumor regression.