Lower, more frequent doses of nanomedicines may enhance cancer treatment
The strategy may make tumors more vulnerable to anti-cancer therapies


Date:
March 11, 2022
Source:
Massachusetts General Hospital
Summary:
Both nanomedicines and metronomic scheduling -- when medications are
given at lower, more frequent doses -- can correct abnormalities
surrounding tumors that help protect cancer cells and foster
their growth and spread. Combining nanomedicines and metronomic
scheduling may help improve cancer treatment strategies.



FULL STORY ==========================================================================
Tiny structures called nanoparticles can be used to carry substances to
certain parts of the body -- for example, to deliver a chemotherapy drug
to a tumor.

Although such "nanomedicine" offered hope for improving cancer
therapeutics, the survival benefits of clinically approved nanomedicines
are often modest when compared with conventional chemotherapy. New
research published in the Journal of Controlled Release indicates that nanomedicine may provide additional benefits if it's administered at
lower, more frequent doses - - called metronomic dosing -- rather than
the standard maximum tolerated dose of current treatments.


========================================================================== "Nanomedicine and metronomic therapy have been regarded as two different approaches to treat cancer. Our analysis suggests that these two
approaches can be viewed using the same unified framework as strategies
to enhance treatment," says co-corresponding author Rakesh K. Jain,
PhD, director of the E.L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital and the Andrew Werk Cook Professor of
Radiation Oncology at Harvard Medical School.

Jain explains that metronomic therapy seems to help normalize the
tumor microenvironment -- meaning that it helps correct some of the abnormalities that develop around tumors that protect the tumor and
foster its growth and spread. For example, while tumors can send out
signals that compromise normal blood flow and block immune cell responses
(both of which make them hard to treat), metronomic therapy appears to
improve blood vessel function and immune activation within 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
the controlled release of their payload and the long blood circulation
time, can trigger the same cascade of activities as metronomic therapy,"
says Jain.

Using a mathematical framework and experiments conducted in mice, the
team showed that both approaches can serve as "normalization strategies"
to affect the tumor microenvironment and improve cancer treatments. Also,
in mice with triple negative breast cancer or fibrosarcoma, Doxil --
a nanomedicine that is approved to treat metastatic breast cancer and
consists of doxorubicin encapsulated in a lipid sphere -- administered
through a metronomic schedule could overcome tumor resistance typically
seen when Doxil is given through a standard dosing schedule. A metronomic schedule also improved the efficacy of the combination of Doxil plus 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, understanding the mechanisms of resistance to and development of
strategies to enhance nano- immunotherapy in breast and other cancer
types is urgently needed," 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 be a basis for the planning of future clinical studies to improve
the efficacy of nano-immunotherapy regimens." The results suggest that combining nanomedicines with metronomic scheduling can lead to a powerful attack against 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.

The study's co-authors include 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; the U.S. National Cancer
Institute grants R35-CA197743, R01-CA208205, R01-CA259253, R01NS118929, U01CA224348, U01CA261842 (to R.K.J.); 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 T.S.), a Marie Sk?odowska Curie Actions Individual Fellowship Global (MSCA-IF-GF-2020-101028945) (to C.V.) and Grant R01 HL128168 (to J.W.B.).


========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Fotios Mpekris, Chrysovalantis Voutouri, Myrofora Panagi, James
W. Baish,
Rakesh K. Jain, Triantafyllos Stylianopoulos. Normalizing tumor
microenvironment with nanomedicine and metronomic therapy to
improve immunotherapy. Journal of Controlled Release, 2022; DOI:
10.1016/ j.jconrel.2022.03.008 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220311125722.htm

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