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Synthetic macromolecules proven to kill multidrug-resistant cancer cells

Synthetic macromolecules proven to kill multidrug-resistant cancer cells

A
multidisciplinary research team from the Agency of Science, Technology and Research
(A*STAR)’s Institute of Molecular and Cell Biology (IMCB), Institute of Bioengineering
and Nanotechnology (IBN), and
Genome Institute of Singapore (GIS),
together with IBM Research, has developed
synthetic macromolecules that have been proven to kill multidrug-resistant
cancer cells and cancer stem cells. The molecules also prevent metastasis (the
spread of cancer cells to a different part of the body from
where it started) and avert
the development of drug resistance.

According
to the press release, these novel macromolecules have the potential to be
developed into an anti-cancer drug to treat cancer patients and prevent cancer
relapse. 

Cancer is a
leading cause of death worldwide. The use of multiple treatments with
conventional chemotherapeutic drugs has led to the development of drug
resistance. Cancer metastasis and relapse also occur in many patients. The
US government has established the Cancer
Moonshot initiative
with the aim of accelerating cancer research and
delivering improved treatment regimens. A critical aim of this programme,
outlined in the 2016
Blue Ribbon Panel Report
, is to overcome drug resistance of cancer. There is an urgent need to develop
new therapeutics that can kill multidrug-resistant cancer cells without
inducing drug resistance development after multiple treatments. 

To tackle this complex challenge, a multidisciplinary
research team was brought together involving researchers from diverse fields
including chemistry (IBM Research), cancer biology (IMCB), bioengineering
(IBN), and genomics (GIS).

The team focused its studies heavily on the use of
macromolecules, which are large molecules or polymeric assemblies exhibiting unique
properties to attack diseases by mechanisms different from traditional
therapies. This is an emerging discipline of study, called Macromolecular
Therapeutics and is pioneered by researchers such as Dr Yi Yan Yang from
A*STAR’s IBN and Dr James Hedrick from IBM Research.

Its use in destroying cancer cells was demonstrated in
collaboration with Dr Qingfeng Chen from A*STAR’s IMCB, and Dr Paola Florez de
Sessions from A*STAR’s GIS, and was recently published in the peer-reviewed
journal, Journal of the American Chemical Society

In this study, the researchers demonstrated that a
macromolecule containing positively charged components could bind to the
negatively charged surfaces of cancer cells. They also proved that another
portion of the macromolecule assimilated into the cell membrane, poked holes in
the cancer cell and destroyed it.

Credit: A*STAR

In early tests, the macromolecule proved successful in: 1)
combating multidrug-resistant cancer cells and cancer stem cells, 2) preventing
cancer cell migration (metastasis) and 3) defying drug resistance after
multiple treatment applications. 

The new study built on a May 2016 study about the discovery
of a macromolecule to treat viruses, as well as a more recent study published
in March 2018, which showed that macromolecules may help fight superbugs such
as MRSA
(Methicillin-resistant Staphylococcus aureus) in the future.

Dr Qingfeng
Chen, Principal Investigator at A*STAR’s IMCB, said, “Our hypothesis was that
with macromolecular compounds, we could limit the growth of tumours by inducing membrane lysis [1] and
necrosis inside tumours without significant adverse effects in patients.”

“The
macromolecules were designed to self-assemble into core-shell structured
nanoparticles, which accumulate in tumour tissues. The shell prevents the
anti-cancer core from interacting with healthy cells before reaching the
tumour. Upon arrival at the tumour site, the shell will crack open to expose
the cancer-killing component that interacts with negative charges on the cancer
cell membrane to disrupt the membrane and kill the cell,” Dr Yi Yan Yang,
Group Leader at A*STAR’s IBN said.

The team collaborated with Dr Paola Florez de Sessions from
A*STAR’s GIS to perform the transcriptomic [2]
analysis. They found that the macromolecular compounds were
relatively inert compared to conventional anti-cancer drugs. 

Macromolecular therapeutics has numerous potential
applications including consumer product additives, treating systemic viral and
bacterial infections, addressing agricultural disease, and cancer treatment.
Fundamental advancements in synthetic polymer chemistry form the foundation for
these therapeutic platforms, enabling the preparation of biocompatible and
degradable macromolecules with precisely defined properties. 

 “While we are excited
about the promise of this study, we note that it is still in its early stages
of research. We are seeking pharmaceutical industry partners to help accelerate
making this macromolecular treatment available to cancer patients,” said Dr
James Hedrick, Distinguished Research Staff Member at IBM Research – Almaden,
San Jose, California.

[1] Lysis is the disintegration of a cell by rupture of the cell wall or membrane.

[2] According to Nature magazine, ‘Transcriptomics
is the study of the transcriptome—the complete set of RNA transcripts that are
produced by the genome, under specific circumstances or in a specific cell. Comparison
of transcriptomes allows the identification of genes that are differentially
expressed in distinct cell populations, or in response to different treatments.’
Expressing a gene means manufacturing its corresponding protein. DNA makes RNA
and RNA makes protein. In the first major step, the information in DNA is
transferred to a messenger RNA (mRNA) molecule through transcription.
The resulting mRNA must next be translated into a protein molecule.

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