An Initiative to Nano-Medicine Research in Sri Lanka
“Cisplatin”is a commonly used anticancer drug which is the first of such platinum based anti-cancer chemotherapeutic drugs developed. It is used to treat different types of cancers which include sarcomas & some carcinomas such as small cell lung cancer, ovarian cancer, lymphomas, bladder cancer, cervical cancer & germ cell tumors. However, cisplatin is associated with numerous side effects such as nephrotoxicity, neurotoxicity, nausea & vomiting, ototoxicity (hearing loss), electrolyte disturbances & haemolytic anemia. Most of the side effects can be either reduced or overcome if cisplatin could be encapsulated in a suitable host material & directed towards cancer cells in a targeted manner & allowed to release only in minimum sufficient dose in a uniform manner.
Mr. Shashiprabha P. Dunuweera, a final year student from Chemistry Department of University of Peradeniya has been able to introduce a novel technique to reduce the toxicity of anticancer drug cisplatin while increasing the efficiency of the drug. Here anticancer drug cisplatin is encapsulated in a drug carrier &then it is being delivered to the site of cancer in a targeted manner. The encapsulation protects other cells of the body from toxic effects of cisplatin. Synthesized hollow nanoparticles of vaterite are used as the drug carrier. This innovative approach ensures providing of constant minimum dosage of the drug only to cancer cells. For more information we arranged a discussion with Mr. Dunuweera.
Q: Here you have selected “hollow nanoparticles of vaterite” as the drug carrier. What properties make vaterite a distinctive anticancer drug carrier?
Vaterite is a form of calcium carbonate and its spherical and hollow nanoparticles of vaterite can be easily synthesized. Drugs such as cisplatin can be easily encapsulated within these nanoparticles. Calcium carbonate is soluble in acidic media but insoluble in basic media. When administered intravenously calcium carbonate is stable in pH values of blood since blood pH is 7.35-7.45. Calcium carbonate is stable at normal cells also. Since cancer cells are acidic, calcium carbonate dissolves slowly at these pH value of around 5.0 releasing the drug. Hence the drug is released only at the cancer cells. This strategy can be used to prevent the toxicity of drugs to healthy cells. Besides, since the bioavailability of the drug is high the dosage requirement is much less than when the drug is used without encapsulation.
Q: This is a nanotechnology based approach. Why nanoparticles are used in this research instead of micro or macro particles?
Microparticles are large compared to nanoparticles. Most of the components in the blood are in the nano-range and hence nanoparticles are compatible in size with those components. Nanoparticles have a very large surface area to volume ratio and porous nanoparticles and hollow ones have even higher surface area. Therefore, material requirement for drug loading is less. Nanoparticles also have size and shape dependent optical, electrical, mechanical and thermal properties which micro particles do not have.
Q: Usual sol-gel synthesis of calcium carbonate nanoparticles results in the formation of thermodynamically stable polymorph (calcite or amorphous calcium carbonate), but vaterite are thermodynamically unstable. So how to prepare vaterite nanoparticles?
As you have very correctly pointed out, hermodynamically more stable phase of calcium carbonate crystals is calcite. Here we use soft template method to synthesize calcium carbonate. I used sodium carbonate and calcium acetate solutions mixed with ethylene glycol and water mixed solvent system. At the beginning of the reaction the vaterite nanoparticles aggregate in the system slowly. As the number of nanoparticles increase they tend to aggregate with each of them form a shell like structure with the core of ethylene glycol and water in order to minimize the total surface energy. Finally hollow CCNP are formed. This approach gives well defined particle sizes; we were able to make 25 nm 35 nm and 50 nm particles of vaterite. Further, it is possible to synthesize monodispersed (single sized) nanoparticles.
Q: How to encapsulate cisplatin in the drug carrier-hollow nanoparticles of vaterite?
It’s very easy. All what we have to do is to suspend hollow vaterite nanoparticles in cisplatin injection solution or purposely prepared cisplatin solution in saline water. cisplatin molecules then get adsorbed on vaterite nanoparticles and diffuse into the interior cavities.
Q: How does cisplatin release at the site of cancer instead of releasing the drug in anywhere else?
This is pH-dependent mechanism. As explained earlier, calcium carbonate is soluble in acidic media but not in neutral or basic media. Cancer cells are acidic and blood is nearly basic to neutral. Healthy cells are neutral. Therefore, calcium carbonate particles are dissolved only in the vicinity of the cancer cells. Statistically also, there is a more blood supply to cancer cells than to normal cells. Therefore, more supply is also there for cancer cells. We can also exploit temperature as an external trigger since the temperature of the cancer cells is higher than that of healthy cells. As such, if a carrier is chosen that has a melting point between the temperatures of the healthy cells and cancerous cells then that will make sure that drugs are specifically targeted to cancer cells only.
Q: How’s the production cost of introducing such a novel technique for clinical use? Is it economical?
Indeed. Calcium carbonate is a readily available mineral in its pure form and as mixed forms such as dolomite. These sources can be used as calcium sources. The National Science Foundation has provided us with a bigger research grant to scale up lab scale discoveries and to integrate processes with local industries. In this way, calcium carbonate nanoparticles can be produced very cheaply in large scale using our own mineral resources.
Q: Are there any potential of industrializing this product?
Yes, indeed. But it is a long way away. We need to do a lot of studies before that.
Q: Have you done a trial administration of vaterite encapsulated cisplatin for cancer patients?
Human trials cannot be done straightway. Perhaps cell line and animal studies have to be done prior to this. We are in the process of collaborating with the Veterinary Teaching Hospital, University of Peradeniya in this regard.
Q: What is the clinical recognition of such a novel technique?
Very high because drugs like cisplatin are highly toxic to all cells. They destroy DNA of cells. Therefore, they can destroy any cell. This way, we prevent the encounter of cisplatin to healthy cells thus protecting them from the toxicity of cisplatin. We therefore selectively cleave DNA of cancer cells. Q: Who sponsored the project? Funding Agency: University of Peradeniya.
Research Partnerships: The Purdue University, USA.
Institutional Collaborators: Veterinary Teaching Hospital, University of Peradeniya and the Purdue University, USA.
Laboratory/Technical Facility: Department of Chemistry, University of Peradeniya.
Studentships: Final Year Chemistry Special Degree students.
This is the first time systematic study on successful preparation of hollow vaterite nanoparticles for the encapsulation of highly toxic anticancer drug cisplatin for targeted delivery & slow-release at the sites of cancers. The introduced product has a significant medicinal use as a safe anticancer drug since the cytotoxicity of cisplatin can be drastically reduced by following this novel approach. The research group is aiming to industrialize the product once the patent is approved. The study is a surprising & highly pleasing achievement by Mr. Shashiprabha Dunuweera, a young undergraduate who is just about to complete his B.Sc. Special Degree.
The outcome of the study has been presented at International Conference in Nanoscience and Nanotechnology which was held at Sabaragamuwa University of Sri Lanka in Collaboration with University of Kyushu, Japan. In addition, Mr. Dunuweera recently published his innovative work in International Journal of Science and Engineering Research. His findings have also been accepted in the International Conference of University of Peradeniya (Sri Lanka) & in the International Pharmaceutical Method Development and Validation Conference (Dubai UAE).
His research works are mentored & encouraged by Senior Professor R.M. Gamini Rajapakse from Department of Chemistry, University of Peradeniya, who is a leading scientist currently, working towards to initiate nanomedicine & nanopharmaceutic research in Sri Lanka.
We wish Shashiprabha all the very best for his future endeavors! Discussed & Prepared By, Kusala Madhushani Premaratne Next Week, Quality & Trends of Ground Water in Jaffna Peninsula
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