Hepatitis C, a blood borne virus that infects the liver to cause diseases like cancer and liver cirrhosis, infects more than 130 people worldwide. While existing antivirals cure 90% of infected patients, there is currently no vaccine and more than 5 lakh people die each year due to chronic hepatitis C virus (HCV) infection. A major problem in the treatment of this disease is the growing drug resistance of the virus and the side effects of the antiviral therapy that limit the dosage that can be safely used. In a breakthrough for nano-drug delivery systems, scientists from the Indian Institute of Science, Bangalore have engineered a nanovector that can specifically home in on liver cells and destroy viral RNA.
The study recently published in the journal ‘Nanoscale’ demonstrates the functionality of a special class of drug delivery molecules called poly (propyl ether imine) or PETIM dendrimers. Named for their extensive branching, dendrimers are hyper-branched polymer molecules that can be used to carry other molecules like drugs or nucleic acids. “The major hurdle that we face (in drug therapy) is the targeted delivery of any drug” says Dr. Saumitra Das, corresponding author of the study. “Having a specific delivery system allows us to reduce the dosage of the drug and make it more effective”. In this proof-of-concept study, the scientists have modified PETIM to specifically deliver anti-hepatitis C siRNA (molecules that degrade a specific RNA of HCV) to liver cells.
One of the unique and most important features of PETIM when compared to other dendrimer molecules developed is its monodispersity. Polymers in solution tend to clump or aggregate, a phenomenon called ‘polydispersity’. Polydispersity leads to aggregation of the molecules and subsequently toxicity to the nearby cells. “PETIM, till today is the most non-toxic dendrimer that has been developed” explains Abirami, who is the first author of the study.
The researchers were able to demonstrate that PETIM produces a 77% reduction in HCV RNA levels and specifically travels to the liver of mice injected with the dendrimer. While anti-viral siRNA therapy is plagued with problems of siRNA stability, PETIM conjugated siRNA were shown to be completely stable and were taken up by the cells in a process called endocytosis. The targeting of PETIM to liver cells was achieved by the addition of galactose molecules to the dendrimer, which binds to receptors found only on liver cells. In principle however, PETIM can be modified to target other cells of the body. “Today we have targeted HCV in the liver, but tomorrow anywhere else, functionalized at your will” says Dr. Das.
The unique structural features of PETIM allow researchers to encapsulate or conjugate a variety of molecules for targeted delivery. “Here we have used PETIM to deliver siRNA, further down the line, even (encapsulation of) drugs are possible” says Abirami. The study also highlights the inter-disciplinary nature of research involved in the development and characterization of PETIM, with scientists across three departments in collaboration. “This is a unique effort where biologists, organic chemists, physicists and computational biologists have come together to solve problems in healthcare” explains Dr. Das.
Specific and efficacious drug delivery is an urgent requirement in all forms of healthcare from the treatment of cancer to anti-bacterial and anti-viral therapies. A vehicle that can carry any type of molecule preferentially to any part of the body makes PETIM an important player in the future of medicine and therapy.
About the authors
Dr. Saumitra Das is a Professor at the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore.
Abirami Lakshminarayanan is a joint PhD student at the Department of Organic Chemistry and the Department of Microbiology and Cell Biology.
About the paper
The paper titled “A galactose-functionalized dendritic siRNA-nanovector to potentiate hepatitis C inhibition in liver cells” was published in the journal ‘Nanoscale’ in August, 2015.