Precisely targeted liposomes inhibit the metastasis of triple-negative breast cancer in mice


Researchers at the Boston Children's Hospital teamed up with bioengineers at the City College of New York (CCNY), found in a mouse model of triple-negative breast cancer, dual targets with existing chemotherapy drugs targeted the nanoparticles to the antibody significantly increased tumor targeting, reduced tumor, and metastatic growth, and obviously improved survival. There were no obvious side effects. The study was published in the journal of Science Advances.

Breast cancer has become a common tumor that threatens women's physical and mental health. Triple-negative breast cancer (TNBC) accounts for approximately 20% of all breast cancers. It refers to a special type of breast cancer, negative for estrogen receptor, progesterone receptor and type 2 human epidermal growth factor receptor. Because such breast cancers lack targets for endocrine and anti-HER2 therapy, there is currently no targeted standard treatment. It has a poor prognosis and limited treatment options, so finding treatments that distinguish cancer cells from normal cells is especially challenging.

The researchers first carefully screened African-American and Caucasian triple-negative breast cancer cell lines to see if they carried any of the 68 common cancer antigens. Among the 16 shared potential targets identified, they chose two surface receptors called ICAM1 and EGFR, which are abundant on cancer cells but rare in non-cancer cells.

Next, the researchers determined that the ratio of ICAM1 to EGFR receptor in cancer cell lines ranged from 1.5:1 to 4.2:1. Based on these ratios, the team designed customized liposomes using complementary targeting techniques in which antibodies target ICAM1 and EGFR in corresponding proportions.

The researchers realized that if they wanted to selectively deliver drugs into a tumor, the synergy between the two targets was significantly better than using a single target. Therefore, understanding the molecular proportions and structure of the two targets is the key to successfully achieving the dual goals.

So they designed double-complementing liposomes (DCLs) containing two fatty lipid molecules, DOPC and DSPE-PEG-COOH, and loaded with the FDA-approved breast cancer drug doxorubicin. By microscopic, they observed that liposomes were specifically localized to breast cancer cells and bound to target cells.

In the mouse model, they found that more chemotherapeutic drugs were specifically delivered to tumor cells. This achieved a reduction in the total amount of drug needed to treat a tumor and can decline adverse reactions in patients with triple-negative breast cancer caused by chemotherapy. By treating free doxorubicin (unpackaged in liposomes), DCL inhibited the growth of triple-negative breast tumors by approximately 40 percent. And the inhibition results were also better than liposomes directed only to ICAM or EGFR.

Importantly, none of the mice treated with dual-targeted liposomes developed lung metastases, whereas mice treated with liposomes targeting ICAM1 or EGFR alone and mice treated with free doxorubicin and untreated control mice had lung metastasis. Lung metastasis is the leading cause of death in triple-negative breast cancer. In addition, mice treated with DCL had the longest survival time and no disease progression.

The researchers also measured the "off-target" toxicity of different doses of DCL by examining the organ and blood chemistry of the animals. Even at the highest dose, they did not show signs of liver or kidney toxicity.

Researchers have applied for their technology patents, which can serve as a platform to create customized treatments for other cancers and diseases. And they wanted to shift the strategy to clinical development.
 
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