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Bespoke polymers carry cancer drugs to the clinic

Designer polymers that boost the effectiveness of their pharmaceutical cargo are poised for wider clinical use in the next few years.

Speaking at the 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology in Lisbon, Portugal, yesterday (1 April 2014), Alexander Kabanov of the University of North Carolina, Chapel Hill, highlighted a growing number of studies showing that new polymers can improve drug solubility, enhance the drug’s uptake in specific cells and even help to avoid the rise of drug resistance. “I think that in the next decade, this technology will really enter the pharmaceutical world,” Professor Kabanov told PJ Online.

Alexander Kabanov

Source: Mark Peplow

Alexander Kabanov is confident that polymer technology can be used to enhance central nervous system drugs

Attaching a drug to polyethylene glycol (PEG) — a process known as pegylation — is now a well established way to improve its solubility or extend its time in the body. At least a dozen pegylated drugs have gained regulatory approval since 1990, and together they commanded a market value of about $7bn in 2012. But PEG’s properties can be difficult to fine-tune, and about 25 per cent of patients have antibodies to PEG that can significantly reduce the impact of pegylated drugs.

So researchers are developing a range of PEG substitutes that contain alternating blocks of two or more different polymers. Incorporating different chemical groups on each type of block offers a powerful way to tailor the polymers’ properties. “The attraction is that you have control — you can build them like Lego,” Yvonne Perrie, of Aston University, Birmingham, told PJ Online.

Polymers containing both hydrophobic and hydrophilic blocks, for example, form micelles — nanoscale pom-poms that can swaddle drug molecules inside their cores. Micelles typically have a hydrophilic outer layer that makes them soluble in water, enabling them to carry insoluble, hydrophobic drugs through patients’ bodies. (Liposomes can perform a similar function, although they are built from phospholipids and typically form a bilayer shell with a hollow centre.)

In 2007, the first micelle-drug combination reached the market after winning regulatory approval in South Korea. Genexol-PM uses a block copolymer of methoxy-PEG and poly(D,L-lactide) to wrap up the highly effective but poorly soluble anticancer agent paclitaxel. When paclitaxel was first sold as Taxol, the active ingredient made up less than 1 per cent of each treatment by weight, and the excipients used to improve its solubility had unpleasant side effects that ultimately limited the dose that patients could receive. The micelles in Genexol-PM can carry a much greater load of paclitaxel into cancer cells, improving treatment outcomes.

Rebranded as Cynviloq, a phase III clinical trial using this formulation of paclitaxel to treat breast cancer patients started in the US this week.

More medicines are following it through the pipeline. Another formulation of paclitaxel called NK105, which uses a block copolymer of PEG and a modified form of polyaspartate, is recruiting patients for a phase III trial.

And Supratek Pharma of Montreal, Canada, a company that Professor Kabanov co-founded, hopes to initiate a phase III trial of SP1049C, which blends anticancer agent doxorubicin with a block copolymer of PEG and polypropylene glycol commonly known as Pluronic.

Professor Kabanov is also seeing early promise with polyoxazoline block copolymers, where each monomer bears a carbon chain hanging from its side. Longer chains tend to make the polymer less water soluble, and several different types of block can be linked to tweak the polymer’s properties. He has compared a polyoxazoline-paclitaxel formulation with Taxol, and one of its successors abraxane, which carries a 10 per cent load of paclitaxel bound to albumin and received US Food and Drug Administration approval in 2005.

Professor Kabanov found that his formulation could reach a drug loading of 45 per cent by weight. “It’s an enormously high loading capacity,” he said. “And higher concentration translates to better treatment.” In tests on mice, the formulation delivered an eight-times larger dose of paclitaxel compared with Taxol, with 100 times less excipient.

One drawback of block copolymer formulations is that they tend to be relatively expensive, Professor Perrie said. That may explain why most clinical studies have used them to heighten the impact of cancer drugs while reducing their side effects, a crucial goal that overrides many cost concerns.

But Professor Kabanov is confident that the designer polymers can be used with other drug classes — including those aimed at the central nervous system, where transport, pharmacokinetics and metabolism can be particularly difficult to control.

And Professor Perrie agrees that with at least 10 clinical trials of block copolymer micelle drug formulations now in clinical trials, they should begin to break through to the mainstream over the coming decade: “There’s a real momentum now.”

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11136859

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