While antibody-drug conjugates show promise as targeted therapeutics, alternative ligands – such as synthetic carbohydrates – could show better targeting capabilities towards select tissue.
October 31, 2016 | by Sarah Hand, M.Sc.
Targeted drug delivery has become a promising new option in the treatment of multiple conditions, including liver-associated diseases and cancerous tumors of many tissue types. Because traditional methods of drug delivery – including oral formulations, and intravenous injections – result in absorption of the drug payload by multiple organs, higher doses of the drug must often be administered to increase efficacy.
The systemic nature of these types of drug delivery often results in unwanted side effects, as is the case with most conventional forms of chemotherapy. With the availability of ligands capable of targeting drugs to a specific cell type, there is potential for the development of new therapeutic agents which are more effective, and less damaging, on surrounding tissues.
Antibody-drug conjugates are perhaps the most commonly-applied form of targeted cancer therapy. These antibodies can be designed to recognize and bind to antigens displayed only on cancer cells, at which point the cytotoxic drug can be released into the cell.
While antibody-drug conjugates show promise as targeted therapeutics, alternative ligands – such as synthetic carbohydrates – could show better targeting capabilities towards select tissue. To learn more about synthetic carbohydrates and how they can be used for targeted drug delivery, I spoke with Dr. Stewart Campbell, Head of Business Development & Product Management, Carbohydrates, CordenPharma.
As an organic chemist with expertise in carbohydrate chemistry, Dr. Campbell is an authority in the large-scale production of carbohydrates, as well as drug conjugates. With over 22 years’ experience in the pharmaceutical industry, Dr. Campbell is passionate about applying carbohydrate chemistry solutions to biological problems.
To learn more about synthetic carbohydrates and targeted drug delivery, register for CordenPharma’s webinar.
Why has much of the attention of targeted drug delivery been focused on targeting liver-associated diseases?
The primary reason is twofold: one reason is that most drugs that are injected will eventually find their way to the liver anyway, so it tends to be one of the easiest organs to target. I think people are starting with the ‘low-hanging fruit,’ so to speak, where they know that their therapeutic has a good chance to get to the liver.
The other reason is that there's a very well-known receptor on hepatocytes that a carbohydrate, known as N-Acetylgalactosamine (GalNAc), is able to bind to. There's a fundamental tendency for things to go to the liver anyway, but you can actually enhance that by incorporating this well-known ligand to further improve drug delivery.
What do you think are the next most likely tissue types to be targeted using carbohydrate ligands?
I think muscle and cardiac tissue are likely targets. Again, for one of the same two reasons as liver targeting: there's a well-known receptor, the mannose-6-phosphate receptor, which is predominantly on muscle cells. So there's an opportunity there which some companies have begun to take advantage of.
What is the most significant technical hurdle preventing more widespread use of carbohydrates as targeting moieties?
I think it's the perception that carbohydrates are very difficult to produce and manufacture. Many developers are not aware that there are actually some solutions for producing these carbohydrates, which is part of what we offer to potential users. It's getting access to the carbohydrate content that seems to be the most pronounced obstacle that researchers face.
How do carbohydrates differ from other cell targeting and delivery agents? There are two things you really need to think about when trying to target drug delivery to a particular cell. The first thing you need to ask yourself is, can you get the cell selectivity that you need to get? It’s important that you go after one cell type to the exclusion of all others if possible.
The second, is that you want to make sure that the entity you are using for targeting is not going to cause an adverse event. If you look at something like an antibody, your body knows how to deal with these proteins, and so it’s well understood how antibodies should be engineered to ensure that they behave in a certain way.
Antibodies probably provide the best overall selectivity potential, but they also have significant drawbacks. You have to make sure that they're designed in such a way to ensure that the immune system handles them appropriately, and doesn't trigger an inappropriate immune response. The second issue with antibodies, is that you have limited capacity to attach something to them before you start to interfere with the activity of the antibody.
Where carbohydrates differ, is in that they’re much smaller and thus can be modular inclusions into any delivery vehicle. You can use chemistry to incorporate carbohydrates into your delivery vehicle, and you can control the spatial orientation of the conjugate.
Are there any situations in which a carbohydrate conjugate would be inappropriate?
If you synthesized a carbohydrate that had antibiotic character, or had a propensity to take things to excretion through the kidneys, this would likely be inappropriate for cell targeting. A lot of carbohydrates are excreted through the kidneys, so you want to make sure that you minimize this to enhance binding to the target cell. Some carbohydrates can also be immunogenic, so here you have to think carefully about that in the same way you would think about a therapeutic protein or peptide.
What can attendees expect to learn in your webinar?
First and foremost, we will be demonstrating that carbohydrates are actually a viable and practical means to target any payload to a particular cell type. People are very familiar with how drugs can be targeted to the liver based on all of the work done by the leading nucleic acid drug companies, but developers have not yet thought exhaustively beyond that organ. What I hope to show is that carbohydrate protein interactions in general are so ubiquitous, that there is probably an opportunity to use a carbohydrate as a targeting agent in just about every tissue type.
The second thing is that researchers and developers can actually get access to the carbohydrate content they need because there are technologies out there now - and CordenPharma is one such Contract Development & Manufacturing Organization (CDMO) which has the expertise, manufacturing processes and technology required to produce very high quality carbohydrates from small to commercial scale.
There’s a false perception that you just can't get access to carbohydrates, therefore they shouldn’t even be considered for targeted drug delivery. I want to debunk that myth.
To learn more about synthetic carbohydrates and their applications in targeted drug delivery, register for CordenPharma’s webinar.
Are you using carbohydrate conjugates in your targeted drug delivery applications? Share your thoughts in the comments section below!
Keywords: Drug Delivery, Cell Targeting, Liver Disease
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