New nanosystem enhances treatment for melanoma in animal models
Novel approach doubles therapeutic effectiveness of medications

Date:
September 8, 2020
Source:
American Friends of Tel Aviv University
Summary:
Researchers have developed an innovative nanotechnological drug
delivery system that significantly enhances the effectiveness of
treatment for the aggressive skin cancer melanoma.



FULL STORY ========================================================================== Researchers at Tel Aviv University, led by Prof. Ronit Satchi-Fainaro of
TAU's Department of Physiology and Pharmacology at the Sackler School of Medicine, have developed an innovative nanotechnological drug delivery
system that significantly enhances the effectiveness of treatment for
the aggressive skin cancer melanoma.


==========================================================================
The nanocarrier is a biocompatible and biodegradable polymer, which
comprises repeating units of glutamic acids. It packages together two
drugs belonging to different families with proven efficacy for the
treatment of melanoma: BRAF inhibitors (Dabrafenib) and MEK inhibitors (Selumetinib, approved for use in children with neurofibromatosis type I).

The research group included PhD students Evgeni Pisarevsky, Dr. Rachel
Blau, and Yana Epshtein from Prof. Satchi-Fainaro's research laboratory
at the Sackler School. The paper was published on August 10, 2020,
in Advanced Therapeutics.

"One of the major obstacles of the biological treatments is that,
after a while, the cancer cells develop resistance to the drugs,"
Prof. Satchi-Fainaro says. "We assume that by precise delivery of two
or more targeted drugs that will attack the cancer cells forcefully and simultaneously from different directions, we can delay or even prevent
the acquisition of this drug resistance.

"In this project, we looked for a solution to a problem often associated
with drug cocktails," Prof. Satchi-Fainaro continues. "Most oncological treatments today are administered in the form of cocktails of several medications. But even though the drugs are administered simultaneously,
they do not reach the tumor at the same time, due to differences in basic parameters, like how long they survive in the bloodstream and the time
it takes each drug to reach the tumor tissue. Thus, in most cases, the medications do not work concurrently, which prevents them from attaining optimal synergistic activity." Responding to these challenges, the
researchers developed an innovative, efficient, and biodegradable drug
delivery system. Two drugs known to be effective for the treatment of
melanoma, Dabrafenib and Selumetinib, were chosen, with the intention
of delivering them jointly to the tumor using a nanocarrier. The drug nanocarrier chosen for the task was PGA, a polymer of glutamic acid,
one of nature's most common amino acids. Developed in Prof.

Satchi-Fainaro's lab several years ago, the nanocarrier has already been
tested successfully for treating pancreatic, breast, and ovarian cancer
in animal models.

The researchers first determined the optimal ratio between the two
medications based on levels and types of toxicity, as well as the
resistance mechanism developed by cancer cells for each medication. This
would ultimately ensure maximum effectiveness, minimal toxicity, and
optimal synergistic activity.

Another important advantage of joint delivery is reduced dosage: a
much lower dose is required compared to each drug when administered independently.

The next step was using chemical modifications to enable bonding between
the polymeric carrier and the chosen drugs. This combined system
can travel through the body with total safety, inflicting no damage
to healthy tissues. Upon reaching the cancer cells, the nanocarrier
encounters proteins of the cathepsins enzyme family, which are highly
activated in malignant tumors. The proteins degrade the polymer,
releasing the drugs which become active and join forces to attack the
tumor. "It's like several passengers riding in one cab and getting off
together at the same address," Prof. Satchi-Fainaro explains. "They all
arrive at the same destination, right at the same time." Tested on a
mouse model of melanoma, the new treatment showed promising results. The nanocarrier delivered the two drugs to the tumor and released them there simultaneously in quantities about 20 times greater than those that reach
the tumor when similar doses of the same medications are administered independently. In addition, the therapeutic effect achieved by the drugs delivered by the nanocarrier lasted twice to three times longer compared
to a control group and a group treated with free medications.

According to the researchers, this means that the new platform enables
much lower dosages -- about one-third of the dose required in regular
drug cocktails. The treatment as a whole is also both safer and more
effective. If necessary, the new approach allows for dosages that are
much higher than the maximum dosage permissible in current methods,
thereby enhancing the effectiveness of the treatment even further.

"In this project, we developed an innovative drug delivery system for
treating melanoma, delivering two proven medications and releasing them simultaneously at the tumor site," Prof. Satchi-Fainaro summarizes. "The treatment proved both safer and more effective than the same medications administered as a cocktail.

Moreover, our new platform is highly modular and can be used for
delivering a vast range of medications. We believe that its potential
for enhancing therapeutics for different diseases is practically endless."

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


========================================================================== Journal Reference:
1. Evgeni Pisarevsky, Rachel Blau, Yana Epshtein, Dikla
Ben‐Shushan,
Anat Eldar‐Boock, Galia Tiram, Shani Koshrovski‐Michael,
Anna Scomparin, Sabina Pozzi, Adva Krivitsky, Gal
Shenbach‐Koltin, Eilam Yeini, Lidar Fridrich, Richard White,
Ronit Satchi‐Fainaro.

Melanoma: Rational Design of Polyglutamic Acid Delivering an
Optimized Combination of Drugs Targeting Mutated BRAF and MEK in
Melanoma (Adv.

Therap. 8/2020). Advanced Therapeutics, 2020; 3 (8): 2070017 DOI:
10.1002/adtp.202070017 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200908131101.htm

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