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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