I am currently working on formulation and characterization of nanocurcumin for improved malarial and cancer therapy. Curcumin has been extensively reported to be non-toxic to normal cells and our findings also confirmed this with RAW 264.7 murine macrophage cell lines. However, after entrapment with a polymer known to be non-toxic couple with the non-toxicity observations with RAW 264.7 cell lines in our lab, the formulation (nanocurcumin) became toxic to RAW 264.7 cell lines. I wish to know whether this is possible? We have rerun the experiment (MTT assay) four times (each with 3 replicates) and we consistently observed toxicity in nanocurcumin. Although the toxicity is concentration dependent and tilted towards the highest dosages, there was no such toxicity in non-entrapped curcumin (pure curcumin). Is there anyone with similar experience? What could have made two non-toxic agents become toxic when combined? Your answers will be highly appreciated.
It is possible for two non-toxic drugs to become toxic after combination due to drug-drug interaction, because even though the agents are individually non-toxic, their combination could produce products which can trigger reactions that could have toxic effects on tissues/cells.
Drug combinations go several ways - combinations two (or more) non-toxic drugs/agents can result in (1) a toxic outcome, or (2) an amplification of the effect or (3) even neutralise each drug's effect. This depends on how and where each drug is metabolised as well as the end metabolite as well as its excretory process. A consultation with a pharmacologist may help.
@ Raphael and Ignacia, thanks so much for your shared experiences.
How hydrophobic is the nanocurcumin formulation? Is it stable under cell culture conditions? It may be that the nanocurcumin formulation is not stable, and is forming aggregates that are disrupting the cell membrane. I have experienced decreased cell viability (using the MTT assay) of RAW 264.7 cells due to unstable nanoparticle formulations aggregating and disrupting the cell membrane, causing necrosis (similar to the situation you described, I was using two known non-toxic components, in the stable formulation cell viability was compared to the control cells at all concentrations, however, the unstable formulation reduced cell viability to < 30% even at the lowest concentration tested). Depending on your formulation, and what you know about it already, it may be worth investigating if the toxicity you are observing is due to necrosis or apoptosis.
Thanks Daniel, the nanocurcumin is not hydrophobic and readily dissolved in the cell culture media.
It is possible and that is one of the current challenges in malaria vector control. one of the major problems associated with the development of mixed insecticide products for public health is the possibility that the two active ingredients could interact in ways that are not expected from the toxicology assessments of the individual products.
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