Thinking big

If asked to say what polymers are used for, most of us might think of plastic cups or nylon fabric. But in biomedicine, polymer science is a rapidly developing area of research. One promising field of enquiry is based on the linkage of a drug to a soluble polymer. Such polymer conjugates may have important medical benefits in conditions such as arthritis and cancer.

"A polymer conjugate is made up of a polymer, linker and the drug; together they form a therapeutic agent," says Steve Brocchini, a chemist at the Centre for Polymer Therapeutics, University of London, who was recently awarded his second Showcase grant. "The sum is greater than the parts. This trick is that, for some medical applications, the drug is essentially biologically inert when attached by a linker to a polymer. So a drug that would otherwise cause side-effects can exist in the bloodstream as a conjugate and not harm the patient."

Large molecules such as polymers are not easily absorbed from the bloodstream into the body’s tissues. But blood vessels in diseased, inflamed tissue – such as in an arthritic joint – can be more permeable than vessels in healthy tissue. "The conjugates can be taken up preferentially at the inflamed site – it’s known as ‘passive targeting’ in the trade," says Dr Brocchini. The conjugate strategy takes advantage of the complex pathway whereby large molecules are taken up into the cell and ferried to an acidic compartment called the lysosome. There, the linker is degraded and the drug is released into the cell.

The approach has been studied for a few decades. "The most systematically studied polymer–drug conjugate – a benchmark in the field – is called PK1," says Dr Brocchini. Developed in the 1980s and 1990s, PK1 is now in phase II clinical trials in the UK for the treatment of cancer. "This conjugate has a potent and toxic cancer drug called doxorubicin attached to the polymer by a linker that does not degrade in the bloodstream. The maximum tolerated dose of the conjugate is about four or five times more than doxorubicin alone. Also, with doxorubicin alone, a patient can only have three to four doses; more than that and the heart can be severely damaged – it has a cumulative toxicity. But with PK1, the phase I trials showed that there is little cardiotoxicity."

Although PK1 is a promising cancer treatment, the polymer is not biodegradable, so there are issues as to how it is metabolised and cleared from the body. "We got the first Showcase grant to see if we could make a polymer that was soluble, biodegradable and biocompatible – harmless to the body," says Dr Brocchini. "The design criteria make the chemistry quite tricky and we had a few false starts. But then we looked at a ‘degradable element’, made a soluble polymer out of it, and found that the polymer degrades slowly at pH 7.4 – the same pH as the bloodstream – and faster in more acidic conditions like in the lysosome. This research would not have happened nearly so efficiently without the funding just to have a go."

In the second Showcase grant, Dr Brocchini and colleagues are refining the synthesis of the soluble polymers and are beginning to study their uptake into cells. "We want to study the fate of the degradable polymer in the cell as it degrades," says Dr Brocchini. "But to get a better understanding of the biology we need biocompatible polymers with defined structural features."

A soluble, biodegradable polymer has the potential to be used in many different ways – in particular for the treatment of chronic illnesses and conditions requiring repeat doses of a drug. "You can imagine many different kinds of drugs being attached to a polymer," says Dr Brocchini, "or compounds that you want to get into a cell or to a cell surface. And there are many failed drugs that never made it – we call it the ‘graveyard hypothesis’. But if we can passively target them they may become clinically useful."

If the polymer can be made easily from simple precursors, families of conjugates can be studied during preclinical development. "The polymer is only a part of the whole therapeutic agent. We do not want it esoteric if it need not be," says Dr Brocchini. "But scientific progress often comes from designing esoteric molecules and you don’t want to lose out on scientific insight. So it’s always a judgement call."

See also

• Showcase awards: Funding details
• Brainy babies: Article describing (Showcase funded research) on prenatal stimulation
• A bug’s death: Article describing (Showcase funded research) the development of a iron uptake in pathogenic bacteria
• Gas attack: Article describing (Showcase funded research) on the development of device to safeguard divers

External links

• Centre for Polymer Therapeutics: Research interests at the Department of Pharmaceutics, The School of Pharmacy

Further reading

Brocchini S (2000). Synthetic polymers in drug delivery. Pharmaventure-Drug Delivery Companies Report, 66–72.

Brocchini S, Duncan R (1999). ‘Polymer drug conjugates: drug release from pendent linkers’ in The Encyclopedia of Controlled Drug Delivery, Wiley, New York, 786–816.

Clochard M, Rankin S, Brocchini S, (2000).Synthesis of soluble polymers for medicine that degrade by intramolecular acid catalysis. Macromol. Commun., in press.

Godwin A, Hartenstein M, Müller A, Brocchini S, (2000). Synthesis of a polymeric precursor by ATRP for conversion to polymer-drug conjugates. Polymer Preprints, 41: 1002–1003.

Brocchini S, James K, Tangpasuthadol V, Kohn J (1998). Structure–property correlations in a combinatorial library of degradable biomaterials. J. Biomed. Mater. Res., 42(1): 66–75.