The coating also helps solubilise the drugs in an aqueous media giving them the added potential to be taken orally rather than injected intravenously. The research was led by Dr Maria Paula Marques, Molecular Physical-Chemistry R&D Centre - Coimbra University, Portugal, along with Dr Luís Batista de Carvalho.
Could a sugar coating be the answer to delivering platinum-based anti-cancer drugs?
Cisplatin was the first platinum-based chemotherapy drug discovered in the 1960s and it’s now one of three platinum containing compounds used worldwide to treat a variety of tumours. However, although many cancer patients show a high response to the drug initially many subsequently acquire resistance to it and one of the reasons for this is a natural antioxidant, glutathione, found in our cells.
Dr Maria Paula explains, “Glutathione is an antioxidant which is needed by us, but unfortunately those drugs that contain a metal, like cisplatin and other platinum agents, bind very strongly to glutathione. This means that when administered, these drugs find glutathione in our cells and they bind to it. This is a big problem as once bound to the glutathione the drugs are not available anymore to bind to the DNA of cancer cells where they should exert their therapeutic effect.”
Cisplatin and other Pt-based drugs crosslink cellular DNA, thus causing severe damage and triggering cell death. The team have come up with novel platinum- and palladium-based compounds which have the potential to become new effective anticancer agents. However, as explained, these compounds can also undergo partial scavenging by cellular glutathione (as shown by these researchers in previous experiments at ISIS) which is the basis of an undesired acquired resistance.
In order to overcome this resistance mechanism, in their most recent experiment they have included these agents in cyclodextrins (sugar polymeric entities) and used neutrons to reveal that this sugary coating, often used as a food additive, effectively protects the drugs from glutathione binding.
“We have shown that the drugs are indeed included into the cyclodextrin packet which does not affect the therapeutic agents in any way, simply acting as a carrier”, explains Maria Paula. “Equally, we have verified there are no changes in the spectra when adding glutathione, which means that the included complex doesn´t change in the presence of the antioxidant. Hence, glutathione-drug binding does not occur. What’s exciting is that this coating is not only protecting the drug from degradation but it also renders it water soluble, which is of the utmost relevance for clinical use and patient compliance to treatment. In fact, by solubilising the drugs they have the potential to be administered orally rather than via injection.
“Making these drugs soluble may allow them to be delivered to the patient orally instead of intravenously and that’s a very big step for public health because it avoids several hours for chemotherapy treatment at a health centre. The patient would be able to take the drug at home - patient compliance would therefore be much higher and the economic burden on the government much lower.”
Following in vitro assays in human cells (both healthy and cancer), the next step will be to start in vivo tests for these cyclodextrin-included agents, starting by using chick embryos.
Maria Paula explains, “Results are promising; we have shown that one of our complexes, containing palladium, displays a high cytoxicity towards human breast cancer cells. We are presently investigating whether the cyclodextrin-included complex exerts a similar antineoplastic effect. What we need now is more funding, that would allow us to go on to clinical trials, so we are looking to pharmaceutical companies to invest.”
The team are mainly focusing on breast cancer but Maria Paula believes this packaging method could be extended to other agents, selective for different types of cancer, using. The cyclodextrin coatings could also be chemically modified, with a view to target cancer cells even more specifically.
“We have looked along the years at several types of cancers such as melanoma for instance and refractory prostate cancer, for which there is no cure. Now we mainly focus on a highly aggressive form of breast cancer which is not easily curable and is highly metastatic (mainly to the bones and brain). Our palladium complex has proved to be very effective against this type of cancer.”
Maria Paula and her team regularly take advice from oncologists at the highly reputed Oncology Institute of Coimbra, for their research to match up with what is known about the cell´s histology and the clinical experience regarding the type of cancer under study.
“Of course the overall strategy may be applied to other compounds, following the same strategy and cyclodextrin-inclusion to avoid glutathione competition, but the compound itself needs to be selective for a specific type of cancer,” explains Maria Paula. “Another important fact about cyclodextrins as drug carriers is that they are easily modified chemically, in such a way that they recognise only the cancer cells and not the healthy ones, thus targeting the drug to the diseased tissue and lowering its deleterious side effects. This means the drug goes only to the target like a missile and the healthy cells are almost untouched - it is something we are looking into in future experiments.”
The team have been regular users of ISIS over the past fifteen years; “these kinds of experiments we have been conducting here are something we could only do at ISIS. Maybe they could be carried out at other facilities, but the user support and sample environment at ISIS are exceptional and the reason that has kept us coming back for since our first experiment in 1999.”
Research date: July 2014
For further information please contact Dr Maria Paula Marques