Nanotechnology shows great medical promise. However, Dr Timothy Pelura, chief technical officer at Kereos, explains some of the current challenges faced in the manufacture of different nanoparticles
One of the emerging hot topics in pharmaceuticals today is the use of nanotechnologies to open new frontiers in therapy and diagnosis. For example, in the US, the National Cancer Institute (NCI) has boldly fixed its eyes on the nanobiotechnology sector to help achieve the ambitious goal of ending the suffering caused by cancer by 2015. Through its Centres of Cancer Nanotechnology Excellence (CCNE) initiative, NCI has committed more than US$120m to eight centres in order to develop new methods of diagnosis and treatment for cancer using small science and big ideas.
While there are high hopes for nanotechnology and its possibilities, many of the challenges in commercialising various applications for human pharmaceutical use will revolve around drug substance or drug product manufacture. This is especially true, because many of these applications involve "nanoparticles" dramatically different to the small molecules and biologics familiar to regulatory reviewers.
The mounting attention to healthcare costs, incited in part by the growing number of biologics with annual per patient price tags upwards of US$40,000, compounds this situation. There is a growing focus on cost-of-goods to maintain reasonable pharmaceutical margins.
Another challenge is the wide range of completely unrelated structures covered under the umbrella of nanobiotechnology. Even the nanoparticle subset includes an almost unlimited number of divergent technologies, and development chemists may find little synergy between the manufacture of one nanoparticle and another.
This review of some of the manufacturing challenges will cover "ligand-targeted" nanoparticles. Functionalised particle technologies -such as those listed in table 1 - are a particularly promising subset combining targeting with the multifunctional capabilities of nanoparticles, and promise disease-specific delivery of high concentrations of active agent to the disease site, while limiting normal tissue exposure. The hope is that this approach will yield increased efficacy and reduced toxicity.
dendrimers
While it is recognised that nanotechnology may improve the diagnosis and treatment of cancer, there are many challenges facing scientists regarding nanotechnology manufacturing. Dendrimers, highly branched polymer molecules, have been credited as one of the most imaginative and promising forms of nanotechnology simply because of the nature of their construction. Self-destructing dendrimers, light-harvesting dendrimers, webbed dendrimers, and graphite-like dendrimers have already been created by researchers to facilitate drug and gene delivery to treat cancer.
However, these complex structures involve complicated syntheses with long reaction times and high dilutions resulting in high costs, escalating as more branches are built. It has been estimated that 300 milligrams of one of the better established seventh-generation polyamidoamine (PAMAM) dendrimers would cost about $600 before the derivatisation process, which adds targeting and diagnostic or therapeutic functions. This alone has limited commercialisation to date, but such approaches must also confront the complex impurity and metabolite profiles that may result from their chemical complexity.
Despite these challenges there are a few companies developing dendrimer technology for therapeutic use, including Avidimer Therapeutics (formerly NanoCure). Avidimer is developing dendrimers as delivery agents for either drugs or imaging agents.
Inorganic particulates, such as quantum dots, are not as expensive as dendrimers, but they do introduce a manufacturing challenge faced by many of the other forms of nanotechnology: a need for expertise. Many of these inorganic materials must be surface coated to be functionalised for targeting, to reduce toxicity and stabilize them in vivo.
Nanospectra, a company developing quantum dot technology in the form of an infrared laser, contends that its treatment is advantageous because of the targeting possibilities, minimal side effects and ability to treat a number of tumours.
fullerenes & nanotubes
Organic particulates such as fullerenes (also known as "buckyballs") and carbon nanotubes have also attracted a lot of attention, yet significant questions remain about their long-term bio-distribution and toxicity. Fullerenes and nanotubes use a similar carbon make-up but have different shapes: nanotubes are shaped as a hollow tube, and fullerenes as a hollow ball. By attaching targeting ligands to the surface of the structures and incorporating therapeutic molecules in their internal cavities, these nanoparticles have the ability to be an effective drug delivery modality.
Among the two, fullerenes have become the organic particulate of choice due to their relative ease of manufacturing. A more structured order of carbon atoms and their uniform properties make fullerenes preferable to nanotubes, but fullerenes still offer challenges with respect to obtaining pharmaceutical purity. Fullerenes tend to be quite stable, but because their small size enables them to penetrate into deep tissue, this stability may ultimately prove to be a toxicity liability. C Sixty is currently developing fullerenes to deliver contrast agent to specific tissues in the body based on environmental cues within the tissue.
Low-density lipoprotein (LDL) particulates, another class of drug delivery nanoparticles, actually mimic those occurring naturally in the body. By adding targeting ligands, the particulate can deliver contrast agents or chemotherapeutics directly to the tumour, facilitating more specific treatment.
A major challenge facing those trying to commercialise LDL particulates is the complexity of manufacture, especially if they incorporate protein domains. Marillion Pharmaceuticals is currently developing "conjugated lipoproteins" designed to deliver anti-cancer drugs directly to tumour cells. They believe their molecules are more effective due to the fact that they are naturally-occurring, unlike other synthetic nanotechnologies.
Gas-filled microbubbles, currently manufactured and used in ultrasound imaging, may have additional uses for drug delivery. While microbubbles are very promising for earlier tumour detection and treatment, they tend to be quite unstable and typically must be reconstituted at the time of use, with resulting quality control concerns. Reliably incorporating targeting ligands onto microbubbles can be a difficult process to undertake, particularly if they are reconstituted at the patient bedside.
ImaRx, a company already using and manufacturing microbubbles as an imaging agent with ultrasound, is now developing microbubbles filled with chemotherapeutics for specific release at tumour sites.
liposomes
Because liposomes were one of the first "nanoparticles" used as a therapeutic, their manufacturing process is now more widely accepted than newer technologies. Consisting of a simple water core surrounded by a phospholipid bilayer, the liposome is similar to a living cell, making it a more understandable nanoparticle. Further, targeting ligands can be incorporated relatively straightforwardly - though half of the ligand load in any such liposome will be effectively lost, since it will point inward.
Liposome particulates cannot be engineered as precisely as other nanoparticles (such as fullerenes) as they can be very difficult to manufacture reproducibly. Another complication is the need to adjust the pharmacokinetics of liposomes through the use of pegylated lipids, or by polymerisation of the lipids after the liposomes are formed. Hermes Biosciences is one company that may face this challenge in the future - the firm is currently developing liposomes loaded with chemotherapeutics to bind with cancer cells, in order to facilitate drug delivery.
Similarly to liposomes, emulsion droplets have been used in pharmaceutical products for decades, but the incorporation of targeting ligands is novel. Generically, these utilise hydrophobic liquid droplets stabilised with surfactants in the aqueous carrier. At Kereos we have found that liquid perfluorocarbon emulsions can be made reliably and used effectively for either imaging or treatment of cancer and other diseases - both targeting ligands and contrast or therapeutic agent are incorporated non-covalently into the phospholipid surface layer of the droplet. Once the particle is formed, this synthesis is accomplished using traditional methods, without any chemistry.
The sooner researchers understand the challenges facing them in regard to the manufacturing of various nanotechnologies, the more likely we are to reach the NCI's goal of ending the suffering and death due to cancer by 2015. The development and manufacture of these nanoparticles are essential to using nanotechnology for the fight against cancer. Unfortunately, toxicity, price and extensive training are just some of the common problems scientists are encountering when trying to produce imaging agents and therapeutics using nanotechnology.
Despite this, researchers must continually look for new, more efficient ways to manufacture more effective treatments for the market, ultimately ending the suffering endured by patients around the world.