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Cyclooxygenase-Inhibiting Platinum(IV) Prodrugs

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Janice Aldrich-Wright discusses that while the cytotoxicity of prodrugs 1-4 was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity.

Image courtesy of interviewee. March 15, 2024

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This video video discusses the prevalence of cancer and the current state of chemotherapy treatments, primarily focusing on platinum-based drugs like cisplatin and carboplatin, which account for a significant portion of cancer therapies. While these drugs have shown effectiveness, they often come with severe side effects and issues of resistance, leading researchers to explore alternatives.

The speaker suggests investigating platinum(IV) compounds, which are believed to be more stable in biological systems compared to platinum(II) drugs. This video video stability could potentially allow for improved delivery to cancer cells and minimize side effects. The aim is to create combination therapies within a single drug, simplifying treatment regimens for patients.

Research has led to the development of novel platinum(IV) compounds that demonstrate higher potency against cancer cells than existing treatments. The speaker outlines their work with specific compounds that incorporate COX inhibitors (like aspirin), believed to enhance cancer treatment by addressing inflammation associated with tumors.

Key points discussed include:

1. The high prevalence of cancer in society, with two out of five people affected by age 85.
2. Platinum-based chemotherapies have elusive effectiveness due to side effects and resistance.
3. There is a shift towards developing platinum(IV) drugs for better stability and efficacy.
4. New compounds combined with COX inhibitors show increased cytotoxicity and efficacy compared to traditional drugs like cisplatin.
5. Direct measures of drug uptake in cells correlate with increased potency.
6. Continued research is necessary to optimize the design of these compounds and their combination with bioactive ligands.

Overall, the text emphasizes the ongoing quest to enhance cancer treatments and improve patient outcomes through innovative drug development strategies.

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X-TIMESTAMP-MAP:LOCAL=00:00:00.000,MPEGTS=900000

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I think we're all aware that cancer

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is prevalent in our society.

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The current statistics, depending on who you read,

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they recommend that there's two out of five people who be,

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will have an interaction with, with cancer

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by the time they're 85.

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So it's not something that's going away.

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And most of the chemotherapies

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that are prominent in treatments at the moment are platinum

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based, about 60% Cisplatinum, carboplatinum,

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ox oxaliplatin are involved in treatments.

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Now this has been used and they've been effective.

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However, there are some clinical side effects.

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So there's a buildup of resistance.

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Once you've been treated with a platinum drug,

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you may not be treated the second time.

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There are some severe side effects

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that in impede its, its delivery.

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And this can impact so strongly on a patient's,

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treatment that sometimes they can't tolerate it.

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Now, these really, prompted us

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to have a look at what we might be able to do

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to improve on that.

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Okay. So, there have been many researchers

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that have made many platinum two compounds over the years

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to try and overcome those problems.

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Um, but there's only a handful

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of made into clinics worldwide.

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They often, the platinum twos are often deactivated

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before they get to the cancer cells in the body.

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So, and this is inferred as to why the side effects occur.

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So if you've got a drug that works,

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but you are only getting a small amount of it

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to the cancer cell, maybe we could make something

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that would actually get to the cancer cell

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and deliver its, its payload or deliver its activity there.

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So, not only that,

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but when we deliver platinum two at the moment,

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it's given as a cocktail.

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There are a number of other drugs that are given in addition

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to the cis platinum to monitor

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and to mitigate some of the, the, the problems that

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that patients face.

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So all of these things prompted

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many researchers, not just ourselves,

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to look at going from Platinum two

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to transforming our compounds to platinum four.

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Why would we do that? Is

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that platinum four is far more stable

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in a biological system.

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So if we make a platinum four drug, it doesn't,

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isn't as quite as promis

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promiscuous in the biological system.

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It can get to a cancer cell and deliver its payload.

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Um, and so it would be resistant to to outside influences.

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Plus it has the ability to carry with it by active ligands.

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So you may be able to, to create this combination therapy

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or cocktail in one drug.

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So you, you administer one drug rather than multiple drugs

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to a patient, which could be a much

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better outcome for the patient.

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So it could simplify this combination therapy.

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Um, and it's one

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of the reasons I think why many researchers have started

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to investigate Platinum Forward.

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It's not new, but it's been around for a bit.

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But it's certainly, a focus.

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Now they're reported to be stable in a biological system,

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and as they reach the cell

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and they transfer into the cell, the cancer cell,

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which is the active bit, okay?

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And so then it can go around doing its job,

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but hopefully will get more into the cancer cell,

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therefore more should be delivering to the cancer and,

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and stopping cancer growth.

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So that's sort of the background.

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Um, we were also involved in, in making,

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a family a flattening two compounds,

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which have exceptional activity than many times more active

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than the clinical drugs that are available today.

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So we're talking sometimes a hundred times,

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sometimes 50 times, but still very potent.

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And so we were mindful that platinum two has this,

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this ability to be promiscuous.

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Ours were not necessarily like that,

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but we thought the platinum four idea of being able

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to attach other drugs was really attractive.

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Um, so we started to engage in these making platinum fours.

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Um, and so one of the,

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the paper we're talking about now is one of those instances,

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instances where we've taken our platinum four scaffolds.

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Um, in this case we've used Platinum five six semi ss,

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which is our, you know, it's, it's it's family name

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or it's abbreviated name,

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and our San Ss, as our scaffolds.

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And we've added Cox inhibitors to it,

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or actually added one Cox inhibitor.

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So we've added, ethin and we've added aspirin

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because when you're treating cancer,

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'cause of the inflammatory response in inhibitors

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or Cox inhibitors like that are thought to be, able to

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help with the cancer cells or helps with the treatment.

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Now, five six on its own is probably,

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is pretty cytotoxic.

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It is 36 nanomolar in,

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colon cancer cells.

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And the PHUs is 710 nanomolar compared

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to cisplatin, which is something like a thousand

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or more depending on which salon you work in.

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So when we looked at the, the four compounds that we made,

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so we made two platinum thin compounds, one

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with the inter medicine, one with the aspirin, one

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with the five six with the intumescent and the aspirin.

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And what we noticed that when we incorporated the,

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these compounds, the five six

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MESS, which is, its,

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its scaffold is the most active plus a plus aspirin was

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extremely potent against h t 29 cells,

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about seven non mol, which was pretty impressive as far

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as we were concerned compared to cisplatin,

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which is the clinical drug, which is 1000, sorry,

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11,300 nanomolar.

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Now, I should explain to you that when we're looking at

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IC fifties or those sorts of value to toxicity,

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the smaller the number, the better it is

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because it is a measure of how potent the drug is,

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how much you require to kill the cells.

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Anyone who's had a family member who's had cancer

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really knows not only prognosis and how it affects a family

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and the person, but also the treatment

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and how that can, you know, that has a,

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a ravaging effect on the person themselves.

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So, I mean, I lost a mother, a father,

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and a stepmother to cancer and a best friend.

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So I mean, it, it, it's certainly something

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that motivates me to, to try and see something better.

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And I've seen them treated and my mother chose not

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to have treatment because it was so horrible for her.

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So she couldn't, she wouldn't tolerate it

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or she couldn't tolerate it.

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And that's, that's a, a real big problem.

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'cause sometimes the treatment is so intense

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that the patient can't tolerate what's the treatment.

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And so they ask for less.

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Now, if you're giving person less than the optimum dose,

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that's not good because you're not gonna kill the cancer.

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When we saw the raw data, the impr, the,

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there was an improvement in the activity

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of the overall molecules and that was great,

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but then you're trying to figure out why.

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And so then you start doing a number of separate tests.

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So you look at the, the overall structure

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of the molecule, you look at the lipophilicity, so you know

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how well it's going to get into lipids.

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Is that, is that the critical factor

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that that makes a difference?

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Um, you measure uptake

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because getting the drug to the cells

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is the most important job.

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So whatever does it, we don't care,

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but we wanna get it into the cells

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because getting it into the cells looking at that uptake,

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the higher the uptake, the more potent the drug.

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So that's, that's one of the things we measure.

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Lipophilicity is, has always been, touted

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as being one of the key factors about

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getting into the cells.

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What we found, and we have found with drugs that we've made

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before that, lipophilicity is not a clear cut case.

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Yes, it's obviously influencing,

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but it's the measures that we're using are really not

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illuminating why this drug is,

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is working better than another one which has

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better lipophilicity.

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Um, so lipophilicity alone was not,

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we didn't think was, was definitely there.

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Certainly uptake correlates perfectly with,

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with cytotoxicity.

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So that's, that's the take home message.

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Um, lipophilicity, of course it influences the molecule,

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but it may be that the combination of the drug, the,

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the scaffold plus ligand, those ratios need

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to be taken into consideration in order to, to map how

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or to predict what might be a good idea.

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We did find too that the, the Cox inhibitors

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for the ethin, which is the bigger of the two, we did see,

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inhibition of Cox inhibitors, not as much

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as the ethin on its own,

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but we certainly saw about 60%

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when we looked at the aspirin.

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We're seeing virtually none like 20%.

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So the aspirin wasn't inhibiting Cox inhibitors

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as we would think it would.

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Now again, that may be partly due to the ratio of the size,

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whether the, you know, the tail is wagging the dog

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or the dog is wagging the tail, possibly

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that maybe the aspen,

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because it's smaller really hasn't got the opportunity

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to bind to the Cox inhibitor sites.

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And so we weren't seeing the activity there.

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So what the take home me message is

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that there's obviously a complex combination of,

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of influences by the overall molecule that you make.

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You can't just say, well,

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I'm gonna put a really high lipophilic, molecule

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and this is gonna make it work better.

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It's not always the case.

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So you do need to probe all of these things together.

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And I've gotta say in all honesty, we only have

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snippets of information

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or you know, like glimpses of what we think.

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It's, if we improve the

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uptake, we know it's gonna be better.

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But whether adding a really hemophilic molecule

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or a,

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a hydrophobic molecule is gonna change it dramatically.

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Also too, we don't always see the, the molecule

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that we've attached to it.

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In part it's biological activity on the overall molecule

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and that, as I said, could be due

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to the size it could be due that it's just too close

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to the plant and maybe we need to put it on a, a little bit

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of a tether in order to get it to be able to interact.

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So there're things that we're still probing.

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I mean this,

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this molecule we're quite happy with its outcome.

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When you make a molecule,

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they don't always do what you think they're gonna do.

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You. Um, that's why you do a lot of testing afterwards.

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There are some of the, the take home messages,

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and I think every researcher is in the same boat.

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You make something planning

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or thinking this is the way it's gonna work.

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And it always surprises you.

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When we take our two scaffolds that we're having,

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and they're not the only scaffolds we have,

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but they're the two that we know, we know that the five, six

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versus the, we always see at least a tenfold increase

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in with the five.

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We also see when we add active ligands, bioactive ligands

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to them, we see the same trend,

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even though they're modulated a bit.

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So those bioactive ligands do modulate activity.

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Sometimes it's for an improvement, sometimes we see nothing.

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Um, we've also gotta be mindful that

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whatever the bioactive ligate is,

12:18.885 --> 12:21.105
if its influence on the cell is very small,

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we've got a very potent drug that it's attached to.

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So it may be so small

12:26.465 --> 12:27.985
that we don't actually see its influence.

12:28.945 --> 12:31.195
Okay? So it may modulate it,

12:31.195 --> 12:33.675
but it may not evoke the same sort of responses.

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It would when it's on its own

12:34.795 --> 12:38.235
because the concentration required is much, much higher than

12:38.235 --> 12:40.275
what our compound is, is delivering.

12:41.495 --> 12:43.755
Um, they may not always,

12:43.775 --> 12:45.835
the bioactive livings may not always in,

12:45.935 --> 12:48.955
in part their their cytotoxicity,

12:48.955 --> 12:50.315
or their, their action,

12:51.445 --> 12:53.945
but if we see an improvement in, in cytotoxicity,

12:53.955 --> 12:55.585
we're reasonably pleased with that.

12:56.185 --> 12:58.625
Although then it's a matter of them discovering what

12:58.655 --> 13:00.905
that bioactive molecule is doing.

13:01.925 --> 13:04.105
Um, they can contribute

13:04.105 --> 13:05.825
to the overall uptake, which is great.

13:07.195 --> 13:08.445
Lipophilicity may

13:08.445 --> 13:11.645
or may not be a predictor of this influence on sub toxicity.

13:13.005 --> 13:16.625
Um, and as I said it, when we're adding a bioactive ligand,

13:16.765 --> 13:19.625
it may be a consequence of its size

13:20.045 --> 13:22.185
or its distance from platinum compound

13:22.185 --> 13:23.345
that we've got to modulate.

13:23.555 --> 13:26.105
We've got to change. We found that with something else.

13:26.165 --> 13:28.465
We had a, another ligand that we, we'd attach

13:28.465 --> 13:29.905
to not this molecule but another,

13:30.525 --> 13:32.825
and we found that we had to put a link up,

13:32.825 --> 13:33.905
otherwise it didn't work.

13:34.045 --> 13:37.425
So having some distance from platinum may be important.

13:38.165 --> 13:40.905
Um, you know, depending, like aspirin

13:40.905 --> 13:42.985
for instance really isn't behaving as a,

13:42.985 --> 13:44.225
as a cox two inhibitor.

13:44.885 --> 13:47.825
Um, it just may not be able to do its job

13:47.855 --> 13:50.065
because of its distance.

13:50.795 --> 13:52.825
We've also gotta consider the relative size,

13:52.925 --> 13:54.065
the bioactive ligand.

13:54.405 --> 13:57.625
Um, if it's very small, it may not be able

13:57.625 --> 13:58.945
to bind to where it's gonna bind.

13:58.945 --> 14:01.145
So we've gotta consider those things as well

14:01.525 --> 14:03.585
and what influence that has on the oval molecule.

14:04.725 --> 14:07.825
So there's some of my conclusions, other than

14:07.825 --> 14:09.385
that one, it's achievable.

14:10.525 --> 14:13.025
We can take, our active molecules

14:13.025 --> 14:17.385
and we can decorate them with bioactive molecules that have

14:18.025 --> 14:19.305
a task or have a function.

14:20.285 --> 14:23.745
In most cases, we see that activity happening.

14:24.055 --> 14:28.105
However, as I said, it depends on that level of influence

14:28.285 --> 14:31.345
and also too how far it is from the molecule,

14:31.345 --> 14:32.825
whether it needs to be some distance.

14:33.485 --> 14:36.525
So I think it's, certainly something we're still

14:37.045 --> 14:38.565
pursuing, not necessarily Cox inhibitors,

14:38.585 --> 14:41.445
but other biologically active molecules attached

14:41.505 --> 14:43.285
to these scaffolds.

14:43.945 --> 14:46.325
Um, because they're quite potent in in

14:46.325 --> 14:48.425
cells and even in animals.

14:48.435 --> 14:50.225
We've been, we've recently discovered

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how potent they're in animals curing cancer in four weeks.

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So I mean, eradicating cancer cancer cells in four weeks.

00:00 - I think we're all aware that cancer is prevalent in our society. The current statistics, depending on who you read, they recommend that there's two out of five people who be, will have an interaction with, with cancer by the time they're 85.

00:18 - So it's not something that's going away. And most of the chemotherapies that are prominent in treatments at the moment are platinum based, about 60% Cisplatinum, carboplatinum, ox oxaliplatin are involved in treatments. Now this has been used and they've been effective. However, there are some clinical side effects. So there's a buildup of resistance. Once you've been treated with a platinum drug, you may not be treated the second time.

00:48 - There are some severe side effects that in impede its, its delivery. And this can impact so strongly on a patient's, treatment that sometimes they can't tolerate it. Now, these really, prompted us to have a look at what we might be able to do to improve on that. Okay. So, there have been many researchers that have made many platinum two compounds over the years to try and overcome those problems.

01:23 - but there's only a handful of made into clinics worldwide. They often, the platinum twos are often deactivated before they get to the cancer cells in the body. So, and this is inferred as to why the side effects occur. So if you've got a drug that works, but you are only getting a small amount of it to the cancer cell, maybe we could make something that would actually get to the cancer cell and deliver its, its payload or deliver its activity there.

01:53 - So, not only that, but when we deliver platinum two at the moment, it's given as a cocktail. There are a number of other drugs that are given in addition to the cis platinum to monitor and to mitigate some of the, the, the problems that that patients face. So all of these things prompted many researchers, not just ourselves, to look at going from Platinum two

02:21 - to transforming our compounds to platinum four. Why would we do that? Is that platinum four is far more stable in a biological system. So if we make a platinum four drug, it doesn't, isn't as quite as promis promiscuous in the biological system. It can get to a cancer cell and deliver its payload. and so it would be resistant to to outside influences. Plus it has the ability to carry with it by active ligands.

02:50 - So you may be able to, to create this combination therapy or cocktail in one drug. So you, you administer one drug rather than multiple drugs to a patient, which could be a much better outcome for the patient. So it could simplify this combination therapy. and it's one of the reasons I think why many researchers have started to investigate Platinum Forward. It's not new, but it's been around for a bit.

03:15 - But it's certainly, a focus. Now they're reported to be stable in a biological system, and as they reach the cell and they transfer into the cell, the cancer cell, which is the active bit, okay? And so then it can go around doing its job, but hopefully will get more into the cancer cell, therefore more should be delivering to the cancer and, and stopping cancer growth. So that's sort of the background.

03:44 - we were also involved in, in making, a family a flattening two compounds, which have exceptional activity than many times more active than the clinical drugs that are available today. So we're talking sometimes a hundred times, sometimes 50 times, but still very potent. And so we were mindful that platinum two has this, this ability to be promiscuous. Ours were not necessarily like that, but we thought the platinum four idea of being able

04:16 - to attach other drugs was really attractive. so we started to engage in these making platinum fours. and so one of the, the paper we're talking about now is one of those instances, instances where we've taken our platinum four scaffolds. in this case we've used Platinum five six semi ss, which is our, you know, it's, it's it's family name or it's abbreviated name, and our San Ss, as our scaffolds. And we've added Cox inhibitors to it,

04:49 - or actually added one Cox inhibitor. So we've added, ethin and we've added aspirin because when you're treating cancer, 'cause of the inflammatory response in inhibitors or Cox inhibitors like that are thought to be, able to help with the cancer cells or helps with the treatment. Now, five six on its own is probably, is pretty cytotoxic. It is 36 nanomolar in, colon cancer cells.

05:25 - And the PHUs is 710 nanomolar compared to cisplatin, which is something like a thousand or more depending on which salon you work in. So when we looked at the, the four compounds that we made, so we made two platinum thin compounds, one with the inter medicine, one with the aspirin, one with the five six with the intumescent and the aspirin. And what we noticed that when we incorporated the, these compounds, the five six MESS, which is, its,

05:59 - its scaffold is the most active plus a plus aspirin was extremely potent against h t 29 cells, about seven non mol, which was pretty impressive as far as we were concerned compared to cisplatin, which is the clinical drug, which is 1000, sorry, 11,300 nanomolar. Now, I should explain to you that when we're looking at IC fifties or those sorts of value to toxicity, the smaller the number, the better it is because it is a measure of how potent the drug is,

06:33 - how much you require to kill the cells. Anyone who's had a family member who's had cancer really knows not only prognosis and how it affects a family and the person, but also the treatment and how that can, you know, that has a, a ravaging effect on the person themselves. So, I mean, I lost a mother, a father, and a stepmother to cancer and a best friend. So I mean, it, it, it's certainly something that motivates me to, to try and see something better.

07:06 - And I've seen them treated and my mother chose not to have treatment because it was so horrible for her. So she couldn't, she wouldn't tolerate it or she couldn't tolerate it. And that's, that's a, a real big problem. 'cause sometimes the treatment is so intense that the patient can't tolerate what's the treatment. And so they ask for less. Now, if you're giving person less than the optimum dose, that's not good because you're not gonna kill the cancer.

07:34 - When we saw the raw data, the impr, the, there was an improvement in the activity of the overall molecules and that was great, but then you're trying to figure out why. And so then you start doing a number of separate tests. So you look at the, the overall structure of the molecule, you look at the lipophilicity, so you know how well it's going to get into lipids. Is that, is that the critical factor that that makes a difference?

08:00 - you measure uptake because getting the drug to the cells is the most important job. So whatever does it, we don't care, but we wanna get it into the cells because getting it into the cells looking at that uptake, the higher the uptake, the more potent the drug. So that's, that's one of the things we measure. Lipophilicity is, has always been, touted as being one of the key factors about

08:26 - getting into the cells. What we found, and we have found with drugs that we've made before that, lipophilicity is not a clear cut case. Yes, it's obviously influencing, but it's the measures that we're using are really not illuminating why this drug is, is working better than another one which has better lipophilicity. so lipophilicity alone was not, we didn't think was, was definitely there.

08:56 - Certainly uptake correlates perfectly with, with cytotoxicity. So that's, that's the take home message. lipophilicity, of course it influences the molecule, but it may be that the combination of the drug, the, the scaffold plus ligand, those ratios need to be taken into consideration in order to, to map how or to predict what might be a good idea. We did find too that the, the Cox inhibitors for the ethin, which is the bigger of the two, we did see,

09:31 - inhibition of Cox inhibitors, not as much as the ethin on its own, but we certainly saw about 60% when we looked at the aspirin. We're seeing virtually none like 20%. So the aspirin wasn't inhibiting Cox inhibitors as we would think it would. Now again, that may be partly due to the ratio of the size, whether the, you know, the tail is wagging the dog or the dog is wagging the tail, possibly

09:58 - that maybe the aspen, because it's smaller really hasn't got the opportunity to bind to the Cox inhibitor sites. And so we weren't seeing the activity there. So what the take home me message is that there's obviously a complex combination of, of influences by the overall molecule that you make. You can't just say, well, I'm gonna put a really high lipophilic, molecule and this is gonna make it work better.

10:28 - It's not always the case. So you do need to probe all of these things together. And I've gotta say in all honesty, we only have snippets of information or you know, like glimpses of what we think. It's, if we improve the uptake, we know it's gonna be better. But whether adding a really hemophilic molecule or a, a hydrophobic molecule is gonna change it dramatically.

10:54 - Also too, we don't always see the, the molecule that we've attached to it. In part it's biological activity on the overall molecule and that, as I said, could be due to the size it could be due that it's just too close to the plant and maybe we need to put it on a, a little bit of a tether in order to get it to be able to interact. So there're things that we're still probing. I mean this, this molecule we're quite happy with its outcome.

11:19 - When you make a molecule, they don't always do what you think they're gonna do. You. that's why you do a lot of testing afterwards. There are some of the, the take home messages, and I think every researcher is in the same boat. You make something planning or thinking this is the way it's gonna work. And it always surprises you. When we take our two scaffolds that we're having, and they're not the only scaffolds we have,

11:40 - but they're the two that we know, we know that the five, six versus the, we always see at least a tenfold increase in with the five. We also see when we add active ligands, bioactive ligands to them, we see the same trend, even though they're modulated a bit. So those bioactive ligands do modulate activity. Sometimes it's for an improvement, sometimes we see nothing. we've also gotta be mindful that whatever the bioactive ligate is,

12:18 - if its influence on the cell is very small, we've got a very potent drug that it's attached to. So it may be so small that we don't actually see its influence. Okay? So it may modulate it, but it may not evoke the same sort of responses. It would when it's on its own because the concentration required is much, much higher than what our compound is, is delivering. they may not always,

12:43 - the bioactive livings may not always in, in part their their cytotoxicity, or their, their action, but if we see an improvement in, in cytotoxicity, we're reasonably pleased with that. Although then it's a matter of them discovering what that bioactive molecule is doing. they can contribute to the overall uptake, which is great. Lipophilicity may

13:08 - or may not be a predictor of this influence on sub toxicity. and as I said it, when we're adding a bioactive ligand, it may be a consequence of its size or its distance from platinum compound that we've got to modulate. We've got to change. We found that with something else. We had a, another ligand that we, we'd attach to not this molecule but another, and we found that we had to put a link up, otherwise it didn't work.

13:34 - So having some distance from platinum may be important. you know, depending, like aspirin for instance really isn't behaving as a, as a cox two inhibitor. it just may not be able to do its job because of its distance. We've also gotta consider the relative size, the bioactive ligand. if it's very small, it may not be able to bind to where it's gonna bind.

13:58 - So we've gotta consider those things as well and what influence that has on the oval molecule. So there's some of my conclusions, other than that one, it's achievable. We can take, our active molecules and we can decorate them with bioactive molecules that have a task or have a function. In most cases, we see that activity happening. However, as I said, it depends on that level of influence and also too how far it is from the molecule,

14:31 - whether it needs to be some distance. So I think it's, certainly something we're still pursuing, not necessarily Cox inhibitors, but other biologically active molecules attached to these scaffolds. because they're quite potent in in cells and even in animals. We've been, we've recently discovered how potent they're in animals curing cancer in four weeks. So I mean, eradicating cancer cancer cells in four weeks.

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