Enhancing cancer therapy using functionalized

Researchers succeed in enhancing the anticancer efficacies of purple photosynthetic bacteria by tagging them with bioactive molecules and polyethylene glycol derivatives

Japan Advanced Institute of Science and Technology

image: The membranes of photosynthetic bacteria were PEGylated to improve their biocompatibility and photothermal conversion. Fluorescent markers and an anti-PD-L1 antibody were further attached to enable tumor-targeting and immunological activation. The engineered bacteria demonstrated effective tumor suppression and immunological responses in a mouse model of colon cancer. view more

Credit: Eijiro Miyako from JAIST.

Ishikawa, Japan -- Targeting malignant tumors with high precision is challenging for biomedical researchers. However, this scenario is likely to witness a paradigm shift in the near future, through the use of specially engineered bacteria, that can eliminate malignant cells efficiently.

Using bacteria to target cancer cells, or bacterial therapy, can be further enhanced through genetic engineering and nanotechnology. However, its efficacy may be hindered due to technical constraints and the potential development of antibiotic resistance. Hence, it is crucial to achieve the moderate yet effective chemical modification of bacteria for improved biocompatibility and functionality, such that their medical abilities are not compromised.

Recently, certain types of purple photosynthetic bacteria (PPSB) have come into limelight for their potential to address the challenges of bacterial therapy. Exploring this further, a study published online on 14 August, 2023 in Nano Today reports the use of chemically modified PPSB for detecting and eliminating hard-to-eradicate cancerous cells in a mouse model.

The study, led by Associate Professor Eijiro Miyako from the Japan Advanced Institute of Science and Technology (JAIST), selected Rhodopseudomonas palustris (RP) as the optimal bacterium for conducting the studies. “RP demonstrated excellent properties, such as near-infrared (NIR) fluorescence, photothermal conversion, and low cytotoxicity. It absorbs NIR light and produces free radicals—a property that can be utilized to kill cancer cells,“ explains Prof. Miyako.

In an attempt to improve the therapeutic efficacy of the isolated strain, the team sought chemical modifications to alter the bacterial membranes. First, they performed membrane PEGylation, or the attachment of polyethylene glycol derivatives to the bacterial cell walls. Prior research indicates that bacterial PEGylation helps in evading host immune response and converts light energy into heat, which can then be utilized to selectively eliminate cancerous cells.

The initial results were encouraging. For instance, coating the RP membrane surface with a “Biocompatible Anchor for Membrane (BAM)” did not adversely affect RP cell viability for at least a week. Moreover, the BAM-functionalized RPs were not eliminated via phagocytosis by macrophages—cells that play a key role in the immune system's defensive actions against bacterial invasions.

Next, the researchers attached a fluorescent “Alexa488-BSA” conjugate to the BAM-functionalized RPs, thus creating a bacterial complex with a trackable fluorescent marker. This conjugate was subsequently replaced with a “PD-L1” antibody. Prior studies have shown that cancer cells express a protein called “Programmed Cell Death Ligand 1 (PD-L1)” on their surface. PD-L1 can smoothly turn off the host defense system by binding to PD-1 receptors. This allows the cancer cells to evade immune detection and elimination. Anti-PD-L1 antibodies block this interaction, thus preventing cancer cells from bypassing immune-system-mediated destruction.

As expected, both anti-PD-L1–BAM–RP and RP, inhibited tumor growth in a murine model of colon cancer. However, anti-PD-L1–BAM–RP, BAM–RP, and RP, when excited with a laser, showed an especially dramatic anticancer effect. In fact, solid tumors vanished completely following the laser irradiation of anti-PD-L1–BAM–RP, BAM–RP, or RP that were injected into tumor-bearing mice. Further, on assessing photothermal conversion properties, both anti-PD-L1–BAM–RP and natural RP exhibited strong photothermal conversion due to the presence of light-driven bacteriochlorophyll (BChl) molecules.

Among the various bioconjugates, anti-PD-L1–BAM–RP showed the highest efficacy in the initial stage of the treatment. Moreover, it was not toxic to surrounding healthy cells or to the murine host. Subsequent experiments revealed the underlying mechanism of colon tumor annihilation in the mouse model.

“Our findings revealed that light-driven functional bacteria demonstrated effective optical and immunological functions in the murine model of colon cancer. Moreover, the NIR fluorescence of the engineered bacterial complexes was used to locate tumors, effectively paving the way for future clinical translation,” says Prof. Miyako.

He further adds, “We believe that this bacterial technology could be available for clinical trials in 10 years and have positive implications for cancer diagnosis and therapy.”

Here’s hoping that bacterial therapy helps researchers, oncologists, and patients with cancer with much needed relief.

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Reference

Title of original paper:

Cancer immunotheranostics using bioactive nanocoated photosynthetic bacterial complexes

Authors:

Sheethal Reghu, Seigo Iwata, Satoru Komatsu, Takafumi Nakajo, Eijiro Miyako*

Journal:

Nano Today

DOI:

10.1016/j.nantod.2023.101966

About Japan Advanced Institute of Science and Technology, Japan

Founded in 1990 in Ishikawa prefecture, the Japan Advanced Institute of Science and Technology (JAIST) was the first independent national graduate school in Japan. Now, after 30 years of steady progress, JAIST has become one of Japan’s top-ranking universities. JAIST counts with multiple satellite campuses and strives to foster capable leaders with a state-of-the-art education system where diversity is key; about 40% of its alumni are international students. The university has a unique style of graduate education based on a carefully designed coursework-oriented curriculum to ensure that its students have a solid foundation on which to carry out cutting-edge research. JAIST also works closely both with local and overseas communities by promoting industry–academia collaborative research.

About Associate Professor Eijiro Miyako from Japan Advanced Institute of Science and Technology, Japan

Dr. Eijiro Miyako is an Associate Professor at the Materials Chemistry Frontiers Research Area, Japan Advanced Institute of Science and Technology (JAIST). He obtained his Ph.D. in Chemical and Biochemical Engineering from Kyushu University. Dr. Miyako’s laboratory conducts research in Biochemistry, Biomaterials, Biomedical Engineering, and Nanomaterials. He has over 70 publications to his credit, including those published in Scientific Reports, Nature Communications, Angewandte Chemie International Edition, and Proceedings of the National Academy of Sciences of the United States of America. He is also the recipient of numerous research awards.

Funding information

This work was financially supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (A) (Grant number 23H00551), JSPS KAKENHI Grant-in-Aid for Challenging Research (Pioneering) (Grant number 22K18440), the Japan Science and Technology Agency for Adaptable and Seamless Technology Transfer Program through Target-driven R&D (Grant Number JPMJTR22U1), Institute for Fermentation, Osaka (IFO), and the Uehara Memorial Foundation.

Nano Today

10.1016/j.nantod.2023.101966

Cancer immunotheranostics using bioactive nanocoated photosynthetic bacterial complexes

14-Aug-2023

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