How a cancer drug carrier's structure can help selectively target cancer cells

January 28, 2021

The main culprit in cancer is healthy cells that have gone rogue and acquire the ability to divide uncontrollably. These cells acquire growth advantages over normal cells and manipulate their environment by altering the cellular pathways involved in growth and metabolism. Over the past few decades, various altered pathways and proteins have been identified as targets for therapeutic interventions. However, what remains challenging is selectively targeting cancer cells and ensuring that the drug reaches the tumor in adequate amounts, without severely affecting normal cells. And in this regard, biocompatible delivery vehicles (which are non-toxic to normal cells) can be useful.

One such potential candidate is "porphyrins," a group of organic cyclic compounds that form the functional center of several proteins in the human body. Porphyrins are known for their "photosensitizing" effects, that is, their ability to release reactive oxygen species upon light stimulation. These reactive species are what gives porphyrins their anticancer activity. Porphyrins have another advantage: structurally, they are composed of four subunits called "pyrrole subunits," which give them specific electronic properties. These electronic properties, in combination with receptors on cancer cells, facilitate the selective accumulation of porphyrins in cancer cells, thereby serving as an effective drug delivery system. But how the steric position (atomic arrangement) of the functional groups bound to porphyrins favors maximum accumulation and distribution of porphyrin-conjugated drugs in cancer cells hasn't been well studied.

To answer this question, researchers at Tokyo University of Science, including Asst. Prof. Toshifumi Tojo, Mr. Koshi Nishida, Assoc. Prof. Takeshi Kondo, and Prof. Makoto Yuasa, dug deeper into how the structure of porphyrin derivatives can affect tumor accumulation. Their findings are published in the journal . Explaining their motivation, Dr. Tojo, who led the study, says, "Porphyrins are used as the basic skeleton of new drugs for cancer treatment due to their ability to accumulate in cancer cells. They possess different functional group modification positions for drug conjugation. Whether these positions confer different physical properties and membrane permeability remains unclear. Our aim was to investigate how these differences impact drug delivery."

In their study, the researchers explored the β (third) and meso (middle) position of functional groups in porphyrins. First, using a breast cancer cell line, they looked into how these functional positions affect the time-dependent accumulation in cancer cells, ranging from 2- to 24-hour time points. They found that meso-derivatives accumulated in cells at 3-fold higher amounts than β-derivatives and that derivatives with smaller functional groups allowed better aggregation than the larger ones.

Next, they investigated how these functional group positions influence the pathway by which porphyrins enter cancer calls. They found that porphyrin conjugates form complexes with plasma proteins that facilitate their transport via endocytic vesicles. Additionally, the compounds could also diffuse into the cytoplasm through the cell membrane.

Moreover, considering their electron-rich nature, porphyrins likely interact with serum proteins that transport them to the cells. The researchers, therefore, measured how different positions influence the affinity of these porphyrin conjugates with serum proteins and how increased affinity may enhance tumor accumulation. They found that while the meso-position improves intracellular accumulation of porphyrin conjugates, it did not have a major effect on the movement of small functional groups into the cell.

Concluding their findings, Dr. Tojo remarks, "Our study reveals that the functional group modification position of porphyrin greatly affects the membrane permeability and intra-cellular tumor accumulation. We are hopeful that our findings can help inform guidelines for the structural design of novel porphyrin drugs."

Overall, their study gives insight into how the structure of drug delivery systems like porphyrins must be considered to achieve maximum efficacy, hopefully paving the way for advancements in cancer drug delivery.
About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of "Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.


About Dr. Toshifumi Tojo from Tokyo University of Science

Dr. Toshifumi Tojo is an Assistant Professor at the Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science. He has completed his PhD from the Tokyo Institute of Technology. His research areas of interest include medicinal chemistry and drug delivery systems, and he has authored several peer reviewed articles in this domain.

Tokyo University of Science

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to