Lower, more frequent doses of nanomedicines could improve cancer treatment

Nanomedicine and metronomic therapy have been considered as two different approaches to treat cancer. Our analysis suggests that these two approaches can be considered using the same unified framework.

Rakesh K. Jain, PhD
Director, EL Steele Laboratories for Tumor Biology, Massachusetts General Hospital

BOSTON- Tiny structures called nanoparticles can be used to transport substances to certain parts of the body, for example, to deliver a chemotherapy drug to a tumor. Although such “nanomedicine” offered the hope of improving cancer therapies, the survival benefits of clinically approved nanomedicine are often modest compared to conventional chemotherapy. New search published in the Controlled Release Diary indicates that nanomedicine may provide additional benefits if given in lower, more frequent doses – called metronomic dosages – rather than the standard maximum tolerated dose of current treatments.

“Nanomedicine and metronomic therapy have been considered two different approaches to treating cancer. Our analysis suggests that these two approaches can be considered using the same unified framework as strategies to improve treatment,” says co-corresponding author Rakesh K. Jain, PhD, director of EL Steele Laboratories for Tumor Biology in Massachusetts. General Hospital and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School.

Jain explains that metronomic therapy appears to help normalize the tumor microenvironment, which means it helps correct some of the abnormalities that develop around tumors that protect the tumor and promote its growth and spread. For example, while tumors can send signals that compromise normal blood flow and block immune cell responses (making them difficult to treat), metronomic therapy appears to improve blood vessel function and immune activation in a tumor. Recent preclinical studies suggest that nanomedicines can cause similar changes in the tumor microenvironment.

“In this study, we hypothesized that nanoparticle formulations, given their controlled payload release and long blood circulation time, may trigger the same cascade of activities as metronomic therapy,” explains Jain.

Using a mathematical framework and experiments in mice, the team showed that both approaches can serve as “normalizing strategies” to affect the tumor microenvironment and improve cancer treatments. Additionally, in mice with triple-negative breast cancer or fibrosarcoma, Doxil – a nanomedicine approved to treat metastatic breast cancer and composed of doxorubicin encapsulated in a lipid sphere – administered according to a metronomic regimen could overcome tumor resistance generally observed when Doxil is administered by a standard dosage regimen. A metronomic program also improved the effectiveness of the combination of Doxil and a type of immunotherapy called an immune checkpoint inhibitor.

“Nano-immunotherapy, which combines nanomedicines with immunotherapy, has high potential to improve patient outcomes, and for this reason there is an urgent need to understand the mechanisms of resistance and to develop strategies to improve nano -immunotherapy in breast cancer and other types of cancer,” says co-corresponding author Triantafyllos Stylianopoulos, PhD, director of the Cancer Biophysics Laboratory and associate professor at the University of Cyprus. “The results of this work could serve as the basis for planning future clinical studies aimed at improving the effectiveness of nano-immunotherapy regimens.”

The results suggest that combining nanomedicines with metronomic programming can lead to a powerful attack on hard-to-treat tumors. By acting together to normalize the tumor microenvironment, these two strategies give drugs a better chance of reaching cancer cells and targeting them effectively.

Co-authors of the study are Fotios Mpekris and Myrofora Panagi (University of Cyprus), Chrysovalantis Voutouri (Massachusetts General Hospital) and James W. Baish (Bucknell University).

This work was supported by grants from the National Foundation for Cancer Research, the Ludwig Center at Harvard; the Jane’s Trust Foundation; Nile Albright Medical Research Foundation; US National Cancer Institute grants R35-CA197743, R01-CA208205, R01-CA259253, R01NS118929, U01CA224348, U01CA261842 (to RKJ); the European Research Council (ERC-2013-StG-336839, ERC-2019-CoG-863955); and the Cyprus Research and Innovation Foundation (INFRASTRUCTURE/1216/0052, POST-DOC/0718/0084) (to TS), Marie Skłodowska Curie Actions Global Individual Fellowship (MSCA-IF-GF-2020-101028945) (to CV) and Grant R01 HL128168 (to JWB).

About Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is Harvard Medical School’s first and largest teaching hospital. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and includes more than 9,500 researchers working in more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in the US News and World Report list of “America’s Best Hospitals”.

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