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Nanomedical research in Australia and New Zealand Although Australia and New Zealand have a combined population of less than 30 million, they have an active and interlinked community of nanomedical researchers. This report provides a synopsis and update on this network with a view to identifying the main topics of interest and their likely future trajectories. In addition, our report may also serve to alert others to opportunities for joint projects. Australian and New Zealand researchers are engaged in most of the possible nanomedical topics, but the majority of interest is focused on drug and nucleic acid delivery using nanoparticles or nanoporous constructs. There are, however, smaller programs directed at hyperthermal therapy and radiotherapy, various kinds of diagnostic tests and regenerative technologies. KEYWORDS: Australia n biosensor n dendrimer n macrophage n New Zealand n polymer therapeutics n regenerative medicine
Australia and New Zealand are relatively prosperous nations with well-developed market economies. They are closely linked, both culturally and economically, with considerable mobility of researchers and capital between the two. In Australia, funding of nanomedical research is generally through a combination of competitive granting schemes and bodies, such as the Australian Research Council (ARC), and the National Health and Medical Research Council, parastatals, such as the Commonwealth Scientific and Industrial Research Organisation (CSIRO), collaborations with commercial entities, or by the commercial entities themselves. In New Zealand, the Marsden Fund and the Ministry of Business, Innovation and Employment Science Investment Scheme are potential sources of funding for fundamental and applied projects, respectively. Some funding in both countries is potentially available from charities, such as the Ian Potter Foundation or Cancer Society. There are 47 universities of various sizes and it appears that approximately half of the universities have some activities in the nanomedical area. Several of these universities have created entities – whether standalone, virtual or partnered – to support their research efforts in nanomedicine. Examples include the Australian Centre for Nanomedicine and the Children’s Cancer Institute Australia (both at the University of New South Wales [UNSW], Sydney, Australia), the Australian Institute for Bioengineering and Nanotechnology (AIBN; at the University of Queensland, Brisbane, Australia) and the Centre for Bioengineering and Nanomedicine (Otago
University, North Dunedin, New Zealand). Other university-oriented groupings, such as the Australian Regenerative Medicine Institute and Monash Institute of Pharmaceutical Sciences (Monash University, Melbourne, Australia), Australian Centre of Excellence for Electromaterials Science (several universities in Australia), the Bosch Institute (University of Sydney, Australia), the Australian Technology Network of Universities, and the MacDiarmid Institute (Kelburn, New Zealand) also include a strong nanomedical component within their research portfolios. Nanomedical research is also conducted in-house by nonuniversity entities such as the CSIRO, the Garvan Institute of Medical Research (Sydney, Australia) or the Burnet Institute (Melbourne, Australia). Commercially oriented research is conducted by companies such as Starpharma (Melbourne, Australia), Ceramisphere (Gladesville, Australia), pSivida (North Perth, Australia) and IZON (Christchurch, New Zealand), some of which are listed on the stock exchange. Nanomedical research in Australia and New Zealand also takes place within many smaller and unaffiliated research groups. Owing to the relatively small populations of these two countries, there is considerable interest in developing research collaborations with colleagues in the northern hemisphere. In addition, the small size of the local markets generally means that early commercialization in overseas markets may be needed to ensure viability. Given the broad scope of ‘nanomedicine’ as a field, we have chosen to limit the technical discussion in this report to research in which an
10.2217/NNM.13.179 © 2013 Future Medicine Ltd
Nanomedicine (2013) 8(12), 1999–2006
Michael B Cortie*1, Eman H Nafea2, Hui Chen1,3,4, Stella M Valenzuela1,3,4, SR Simon Ting4, Fabio Sonvico1,2 & Bruce Milthorpe1,4 Institute for Nanoscale Technology, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Sydney, Australia 2 Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Sydney, Australia 3 School of Medical & Molecular Biosciences, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Sydney, Australia 4 Centre for Health Technologies, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Sydney, Australia *Author for correspondence: Tel.: +61 2 9514 2208 [email protected] 1
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artificial, nanoscale, solid-phase structure, typically an artificial nanoparticle or nanoporous scaffold, is deployed in a biomedical context. We exclude research that is principally involved with developing liquid-phase compounds or macromolecules for pharmaceutical applications, such as antibody–drug conjugates, and technologies that do not depend critically on having some dimension in at least the 1–200 nm range. Nanobiotechnology and nanomedicine in Australia was partially surveyed in Nanomedicine 6 years ago [1] and, in late 2012, these topics were very briefly discussed within a report on nanotechnology in Australia in general [2]. Both publications highlighted the particular local interests in the bio–nano interface, diagnostics and drug delivery. Here we will provide a brief snapshot that investigates these interests in more detail. We do not claim this survey to be exhaustive (although it is hopefully broadly representative), but it will provide a sense of what research is topical at the time of writing.
Diagnostic nanomedical technologies There is widespread interest in both countries in sensors based on electrochemical (capacitive or faradaic) or optical (refractometric, photonic, fluorescence, surface-enhanced Raman or surface plasmon polariton) modalities. In many cases the analyte is of medical relevance. Almost all current projects target the in vitro environment. The work is widely distributed across research groups, and we have space only to highlight some of the themes. Electrochemical biosensors of various kinds have received much attention, especially from the group of Gooding at UNSW. Older publications by Gooding and colleagues on the use of carbon nanotubes for biosensing have been highly cited [3]. As one recent example of the ongoing interest, an electrochemical displacement immunosensor was described by the same author [4]. There is also continued interest elsewhere in Australia in electrochemical sensors based on tethered lipid bilayer membrane technology – an innovation that arose at the CSIRO in the mid-1990s [5]. Commercially this interest is now driven by the company Surgical Diagnostics (Sydney, Australia). In two recent examples, the technique was used to characterize the behavior of ion channel proteins and antimicrobial peptides inserted into tethered lipid membranes [6,7]. The topic of contrast enhancement for micro scopy and MRI continues to receive attention. 2000
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There is also a closely related interest in probing the cellular environment using nanoparticles coupled to some type of optical transduction. A group at Macquarie University (Sydney, Australia) recently demonstrated a quantum dot-based fluorescent SRIF probe that exploits endocytosis to target somatostatin receptors [8]. Analogously, a University of South Australia group has developed a gold nanoparticle lymphotropic contrast agent, which binds to lymphoid cells overexpressing the CD45 antigen [9]. A labelfree fluorescence-sensing system with a detection limit of 240 fM for oligonucleotides was demonstrated by a group at the University of Auckland (New Zealand) [10], while a group at the University of Melbourne (Australia) has examined the fluorescence of the nitrogen vacancy defect in nanodiamonds as means of probing the chemical state of ion channels [11]. There has also been widespread interest in developing nanoparticles to enhance contrast in the MRI [12–14]. Refractometric sensors are less specific in their capabilities; however, biosensors based on the optical properties of porous silicon are being pursued by three or four groups, for example [15]. Finally, in New Zealand, the company IZON manufactures a useful electrophoretic instrument for measuring the size of individual particles (or organisms) in the 50 nm to 10 µm range while a biosensor, the ‘Biochip’, has been developed by a group at University of Canterbury (Christchurch, New Zealand). The latter can detect forces exerted by microscopic organisms as they move [16].
Drug delivery Polymer-based pharmaceutical technologies attract a large amount of interest, as they do elsewhere. For example, individuals at the Australian Centre for Nanomedicine are exploiting their considerable in-house chemical expertise to develop a variety of polymer platforms for drug delivery. In much of their work, reversible addition-fragmentation chain-transfer polymerization is used to construct customdesigned polymers. Recently, the group used in vitro experiments with neuroblastoma cells to demonstrate enhanced anti-tumor activity through the targeting of polymer nanoparticles to deliver a combination of nitric oxide and cisplatin [17]. The group also developed hydrophobic biodegradable acetalated dextran as a targeting delivery system for therapeutic molecules such as doxorubicin [18] and stable multifunctional soft core–shell nanoparticles via the self-assembly of predesigned diblock copolymers [19]. An future science group
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objective of this work is to demonstrate controlled release in response to biologically relevant chemical environments. The listed company Starpharma is focused on exploiting dendrimers. It has developed a range of lysine- and hydrogel-based drug delivery technologies and has a product (VivaGel®; designed to combat bacterial vaginosis and sexually transmitted viral infections) at an advanced stage of clinical testing. An anticancer product containing docetaxel is reported to be imminently approaching the clinical trial phase. Dendrimers are also a theme at the Monash Institute of Pharmaceutical Sciences where a group is evaluating novel doxorubicin-conjugated PEGylated polylysine dendrimers [20,21]. There is also research into polymer nano particles at the University of Western Australia. For example, one group demonstrated improved intracellular delivery of paclitaxel to colon cancer cells after conjugation of loaded poly(d,l-lacticco-glycolic acid) nanoparticles with wheat germ agglutinin as a tumor-targeting ligand [22]. In other work, paclitaxel-loaded nanoparticles were synthesized with an amphiphilic aminocalixarene carrier [23]. A detailed correlative microscopy study from the same university of the endocytotic pathways followed by polymer nanoparticles into neural cells is also of interest [24]. A therapeutic substance can of course be encapsulated inside another particle; for example, Caruso and colleagues at the University of Melbourne have developed a means to immobilize a pH-cleavable doxorubicin–polymer conjugate in a polydopamine capsule [25]. Researchers at the School of Pharmacy, Curtin University (Perth, Australia) are interested in polymeric nanoparticles as a potential means to deliver peptides to the brain. Both chitosan and poly(d,l-lactic-co-glycolic acid) nanoparticles have been studied for the delivery of dalargin, a model hydrophilic hexapeptide, to the CNS [26,27]. High entrapment efficiency and peptide stability, together with sustained drug release were achieved with both formulations. Inorganic nanoparticles of various types are also topical. The company pSivida is commercializing drug delivery systems based on nanoporous silicon scaffolds and has several products targeting the ophthalmology market, with some already US FDA approved. There is also interest in drug delivery from composites of porous silicon and polymers at the University of South Australia [28]. A recent research collaboration between University of Queensland and University of Wollongong in Australia has developed future science group
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mesoporous silica nanoparticles modified with hyaluronic acid for targeting doxorubicin delivery to CD44-overexpressing cancer cells [29]. These nanoparticles demonstrated improved cellular uptake and superior antiproliferative action on human colon cancer cells over free doxorubicin or nonmodified encapsulated silica nanoparticles. Researchers at the Ian Wark Research Institute of the University of South Australia have been working on hybrid silica/lipid nanoparticles with a view to enhancing encapsulation, protection and controlled release of insulin, proteins and peptides [30]. Recently, they demonstrated enhanced chemical stability of all trans-retinol, a model water-sensitive molecule, after coating submicron oil-in-water emulsions with silica nanoparticles in solid state [31]. Previously, silicacoated oil-in-water emulsion showed potential for topical targeting, resulting in improved dermal delivery of lipophilic drugs [32]. Layered double-hydroxide nanoparticles of magnesium and aluminium provide a flexible platform for the intercalation of various payloads. For example, an antirestenotic compound, low-molecular-weight heparin, intercalated into such particles has been targeted to injured arteries with the aid of antibodies by individuals at the AIBN [33]. Researchers at AIBN have also proposed a novel nanocomposite film for sustained release of anionic drugs: layered doublehydroxide nanoparticles containing ketorolac were dispersed into a hydrogel matrix to produce drug-loaded contact lenses [34]. On a somewhat different note, there is the intriguing suggestion that a modified form of lactoferrin, a milk protein, could be exploited as an anticancer nutraceutical when delivered to tumors using a calcium phosphate nanoparticle vector [35]. Finally, there have been several investigations across Australia on the functionalization and biological interactions of gold nanoparticles. One aspect that has garnered attention is the response of the immunological system to such nanoparticles. Minchin’s group at University of Queensland has investigated interfacial reactions in serum and confirmed that cytokine release is usually triggered, although interesting exceptions occur; for example, particles that are positively charged or coated with human plasma proteins are inert [36]. An intriguing but different phenomenon was recently uncovered by three of the current authors (Chen, Valenzuela and Cortie) in which it was found that citrate-stabilized gold nano particles could exert a significant downregulation of cytokine production within the adipose tissue www.futuremedicine.com
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of mice [37]. This was associated with a decrease in body fat but not appetite. Similarly, Brown et al. found that macrophage activity in arthritic rats was advantageously suppressed under some circumstances [38]. The mechanism of these curious phenomena appears to involve targeting, but not destruction, of the macrophages by the gold nanoparticles. Other types of nanoparticle are also being investigated; for example, the prospect of the nanoparticle itself being made substantially of the active ingredient has been considered. A group at CSIRO has developed a novel oral nanochemotherapeutic with sustained release properties and target-selective activation. Researchers have produced self-assembled nanostructured nanoparticles consisting of 5-fluorouracil lipid prodrugs [39]. These lipid prodrug nanoparticles inhibit the growth of a highly aggressive mouse breast tumor while avoiding systemic toxicity. The Advanced Drug Delivery group (University of Sydney) is currently focusing on tailoring drug nanoparticle architecture to enhance aerosol performance. The group succeeded in producing micron-sized aggregates of proteins (‘nanomatrix’ particles) with controlled surface roughness by spray-drying nanosuspensions [40]. The same group also developed improved lipo somal nanoparticles to overcome rapid clearance of antibiotics, such as ciprofloxacin from the lungs, with obvious applications in the treatment of respiratory infections [41]. Pulmonary delivery of nanosized particles produced in supercritical fluids is being pursued by a UNSW start up, Bioparticle Technologies (Sydney, Australia). A multifunctional hybrid nanoparticle, built on a rhodamine B/polyglycidol methacrylate core containing Fe3O4 nanocrystals, has recently been used as a vector to deliver an ion channeltargeting peptide by a group at the University of Western Australia [42]. This group has also published a detailed study on the uptake of polyethylenimine (PEI)-decorated nanoparticles by neural cells [24], with a spin-out company, Eridan Technology (Perth, Australia), established to pursue the technology. A generic method to coat nanoparticles or nanocapsules of various compositions has recently been published by Caruso’s group at University of Melbourne. In this approach a coordination complex of natural polyphenols and iron ions is induced to self-assemble on an existing substrate or particle. The advantage is that the method is rapid and versatile and the coatings are generally biocompatible. Caruso and his group are already well-known 2002
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internationally for their ongoing development of the ‘layer-by-layer’ method for producing hollow nanoparticles, for example [43]. Nanoparticle delivery systems have been used to enhance cell-mediated immune responses against purified antigens, indicating their potential for use in intranasal immunization. Researchers at the School of Pharmacy, Curtin University have developed a biodegradable nano particulate system based on chitosan–dextran sulfate nanoparticles for this role [44]. Finally, capsules suitable for drug delivery can also be manufactured by bacteria. For example, drug delivery using bacterially expressed vesicles (‘caveolae’) formed by the polymerization of the prokaryotic protein caveolin has recently been investigated by Parton’s group at the University of Queensland [45]. This vehicle offers intriguing flexibility in so far as its production is genetically encoded, allowing for ready manipulation of the surface properties or morphology. On a related note, although slightly out of the scope of this review, bacterially derived ‘minicells’ have been considered for encapsulating drugs by the Sydney-based company EnGeneIC Ltd (Australia) [46].
Nucleic acid delivery Nonviral vectors for transfection and gene therapy are being investigated by several laboratories. For example, delivery of DNA and RNA from porous silica nanospheres is being pursued by Ceramisphere, a company with its origins at the Australian Nuclear Science and Technology Organisation. RNAi has potential in the treatment of various diseases via targeted gene silencing. However, systemic delivery of naked siRNAs is ineffective owing to their susceptibility to nuclease degradation and net negative charge under physiological conditions. Therefore, development of biocompatible, synthetic nanoparticle-based RNAi vehicles would provide protection of encapsulated sensitive molecules and promote their cellular uptake [47]. Delivery of siRNA using a biodegradable star polymer has been investigated by Boyer et al. at the Australian Centre for Nanomedicine at UNSW [48], while Davis and coworkers, at the same center, developed novel PEG-coated iron oxide nanoparticles for the efficient delivery of siRNA [49]. The PEG layer provided charge shielding and hence limited protein adsorption onto nanoparticles without compromising their siRNA transfection efficiency or their magnetic properties. Davis has now relocated to the Monash Institute of Pharmaceutical Sciences, future science group
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to join the rapidly growing nanomedicine activities there. There is also research at the ARC Centre of Excellence for Functional Nanomaterials and the AIBN focused on the synthesis of layered double-hydroxide nanoparticles for siRNA delivery. Owing to the size and positive surface charge of nanoparticles, they were able to bind nucleic acids and facilitate uptake into mammalian cells via endocytosis. Moreover, researchers designed functionalized mesoporous silica nanoparticles with large pores and a cubic mesostructure as a new carrier material for delivery of model oligo-DNA [47,50]. In the same ARC Centre of Excellence, but based in UNSW, Arsianti et al. functionalized PEI onto magnetic iron oxide nanoparticles to transfect pDNA. Their study has shown that it is necessary to protect pDNA with PEI cationic polymers. In addition, uptake of nanoparticles was aided by gravitational and magnetic sedimentation onto adherent cells [51]. Monteiro and coworkers at the AIBN and the Queensland University of Technology have achieved an influenza virus-inspired polymer system for the controlled release of siRNA, allowing potential for multiple repeat doses and long-term treatment of diseases [52]. An ingenious method to engineer the release of siRNA therapeutics was described by Cass et al. at the CSIRO. siRNA was electrostatically bonded to a cationic block copolymer that also contained disulfide bridges. Upon uptake into the reductive environment of an endosome, chain scission at the disulfide bridges occurred, weakening the polyplexes and releasing nucleic acid payload [53]. Finally, at Griffith University in Queensland, the use of liposomes was employed by McCaskill and coworkers to knockdown targeted genes in a proposed treatment for lung epithelium diseases [54]. Clearly, the delivery of nucleic acid using nonviral vectors is a rapidly developing field in Australia, as it is elsewhere.
Regenerative medicine & emerging applications An important objective of regenerative techno logies is to accelerate tissue repair. For example, patient recovery after insertion of orthopedic implants can be facilitated by careful attention to the bio–nano interface. In this context, the use of porous materials derived from coral and other marine exoskeletons has been pursued for some years at the University of Technology, Sydney, Australia. As an example, a recent report describes how such material can be used to deliver simvastatin [55]. Modification of the surfaces of future science group
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cardiovascular and other implants has been a theme at the nearby University of Sydney, with treatment by a high-voltage gas plasma being a favored route [56], while at the UNSW, there has been research into the general effects of surface nanostructure on cell–material interactions for some years [57,58]. Artificial materials for transduction or transmission of neural signals have also been a recurring research theme, probably inspired by the success of the ‘bionic ear’. Part of this research is conducted by, or with, Cochlear ® (Sydney, Australia), the manufacturer of the successful cochlear ear implant, or by the Bionics Institute in Melbourne (Australia). Research into the use of conductive polymers in this arena has been ongoing at the University of Wollongong, and forms a program within the multi-institutional Australian Centre of Excellence for Electromaterials Science. A recent paper on coating electrodes with nanoscale layers of various conducting polymers is an example [59]. The exploitation of localized heat generation in nanoparticles (generated by plasmonic heating in gold nanoparticles or fluctuating magnetic fields iron oxide nanoparticles) has also caught the attention of a number of researchers. Gold nanospheres or nanorods, for example, have been investigated for potential therapeutic applications at the University of Technology Sydney. In vitro studies have shown how the particles can be selectively targeted to murine macrophages or to the infectious protozoan Toxoplasmosis gondii, either of which can then be destroyed using relatively low-power laser irradiation [60,61]. The convenient localization of radiotherapy dose enhancement using heavy element nano particles such as gold or bismuth oxide is being pursued by a group at RMIT University (Melbourne, Australia) [62]. The mechanism of this phenomenon seems to be the radiation-induced generation of free radicals on the surface of the nanoparticle – a phenomenon known since the 1950s – but the use of gold nanoparticles for this purpose may represent a new approach. Another interesting line of research has been the possible use of cerium oxide nanoparticles as scavengers for intracellular reactive oxygen species. It has been shown that the particles are taken up by monocyte cells (but not endothelial cells), for example, and a reduction in reactive oxygen species is possible [63].
Conclusion The ‘nanomedicine’ community in Australia and New Zealand is small but active, reflecting www.futuremedicine.com
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the fact that it is based in a relatively prosperous market of less than 30 million people. There are particularly well-developed research strengths for polymer therapeutics and biosensors, and other interesting activities in many other areas of nanomedicine. Some of this research has already led to commercial developments, such as the companies Starpharma (polymer therapeutic products) or pSivida (porous silicon). Although there are several larger research groupings, such as the Australian Centre for Nanomedicine, the nanomedicine research community more generally operates on a dispersed and laissez-faire basis. Australia has not benefited from targeted national support for nanomedicine research within a multi-institutional grouping; however, if this were to occur, it would no doubt be strongly beneficial in terms of activity and output. The funding model does not discourage fundamental research, and most of the current projects underway are still several years away from preclinical consideration. Another attribute of nanomedical research in the antipodes is that many of the groups are closely linked to collaborators in the northern hemisphere, distance apparently not presenting an obstacle to activity.
Future perspective The larger part of the nanomedicine community in Australia and New Zealand is focused
on developing a range of drug delivery strategies. Some of these initiatives have led to spinoff companies and commercial products; however, the local market is very small. This has the inevitable consequence that most products must eventually be pitched to northern hemisphere markets and investors. The community also has internationally competitive research strengths in respect of fundamental surface chemistry and polymer science. Links with other groups around the world are sought after and welcomed. The future trajectory of the local research community in nanomedicine will probably be strongly influenced by the success or otherwise of the pioneering commercial ventures mentioned above. If they are successful, this will no doubt inspire further spinoffs, a factor that, in turn, encourages more government investment and a new generation of nanomedical researchers and products. Financial & competing interests disclosure SRS Ting acknowledges a National Health and Medical Research Council Early Career Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Executive summary Australia and New Zealand have a small but active nanomedicine community. There is considerable interest in various strategies for targeted delivery of drugs and nucleic acids. There is a strong focus on polymer-based pharmaceutical technologies. Some nanomedical products are already on the market and several others are in trials. The local market is small and, therefore, an international perspective is necessary.
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versatile vectors for targeted drug or si/shRNA cancer therapy. Curr. Opin. Biotechnol. 22, 909–916 (2011). 47 Chen M, Cooper HM, Zhou JZ, Bartlett PF,
Xu ZP. Reduction in the size of layered double hydroxide nanoparticles enhances the efficiency of siRNA delivery. J. Colloid Interface Sci. 390, 275–281 (2013). 48 Boyer C, Teo J, Phillips P et al. Effective
delivery of siRNA into cancer cells and tumors using well-defined biodegradable cationic star polymers. Mol. Pharm. 10(6), 2435–2444 (2013). 49 Boyer C, Priyanto P, Davis TP et al.
Anti‑fouling magnetic nanoparticles for siRNA delivery. J. Mat.Chem. 20(2), 255–265 (2010). 50 Hartono SB, Gu WY, Kleitz F et al.
Poly-l-lysine functionalized large pore cubic mesostructured silica nanoparticles as biocompatible carriers for gene delivery. ACS Nano 6(3), 2104–2117 (2012). 51 Arsianti M, Lim M, Marquis C et al.
Assembly of polyethylenimine-based magnetic iron oxide vectors: insights into gene delivery. Langmuir 26(10), 7314–7326 (2010).
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adhesion and activation by chitosan through plasma and extracellular matrix proteins. Biomaterials 32(28), 6655–6662 (2011). 59 Harris AR, Morgan SJ, Chen J, Kapsa RM,
53 Cass P, Knower W, Hinton T et al. Synthesis
and evaluation of degradable polyurea block copolymers as siRNA delivery agents. Acta Biomater. 9, 8299–8307 (2013).
Wallace GG, Paolini AG. Conducting polymer coated neural recording electrodes. J. Neural Eng. 10(1), 016004 (2013). 60 Pissuwan D, Valenzuela S, Miller CM, Cortie
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Efficient biodistribution and gene silencing in the lung epithelium via intravenous liposomal delivery of siRNA. Mol. Ther. Nucleic Acids 2, e96 (2013). 55 Chou J, Ito T, Bishop D, Otsuka M,
Ben‑Nissan B, Milthorpe B. Controlled release of simvastatin from biomimetic b-TCP drug delivery system. PLoS One 8(1), e54676 (2013). 56 Wise SG, Waterhouse A, Kondyurin A, Bilek
MM, Weiss AS. Plasma-based biofunctionalization of vascular implants. Nanomedicine 7(12), 1907–1916 (2012). 57 Lord M, Cousins B, Doherty P et al. The effect
of silica nanoparticulate coatings on serum protein adsorption and cellular response. Biomaterials 27(28), 4856–4862 (2006). 58 Lord MS, Cheng B, McCarthy SJ, Jung M,
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Enhancement of radiation effects by gold nanoparticles for superficial radiation therapy. Nanomedicine 5(2), 136–142 (2009). 63 Ting SR, Whitelock JM, Tomic R et al.
Cellular uptake and activity of heparin functionalised cerium oxide nanoparticles in monocytes. Biomaterials 34(17), 4377–4386 (2013).
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Nanomedical research in Australia and New Zealand Although Australia and New Zealand have a combined population of less than 30 million, they have an active and interlinked community of nanomedical researchers. This report provides a synopsis and update on this network with a view to identifying the main topics of interest and their likely future trajectories. In addition, our report may also serve to alert others to opportunities for joint projects. Australian and New Zealand researchers are engaged in most of the possible nanomedical topics, but the majority of interest is focused on drug and nucleic acid delivery using nanoparticles or nanoporous constructs. There are, however, smaller programs directed at hyperthermal therapy and radiotherapy, various kinds of diagnostic tests and regenerative technologies. KEYWORDS: Australia n biosensor n dendrimer n macrophage n New Zealand n polymer therapeutics n regenerative medicine
Australia and New Zealand are relatively prosperous nations with well-developed market economies. They are closely linked, both culturally and economically, with considerable mobility of researchers and capital between the two. In Australia, funding of nanomedical research is generally through a combination of competitive granting schemes and bodies, such as the Australian Research Council (ARC), and the National Health and Medical Research Council, parastatals, such as the Commonwealth Scientific and Industrial Research Organisation (CSIRO), collaborations with commercial entities, or by the commercial entities themselves. In New Zealand, the Marsden Fund and the Ministry of Business, Innovation and Employment Science Investment Scheme are potential sources of funding for fundamental and applied projects, respectively. Some funding in both countries is potentially available from charities, such as the Ian Potter Foundation or Cancer Society. There are 47 universities of various sizes and it appears that approximately half of the universities have some activities in the nanomedical area. Several of these universities have created entities – whether standalone, virtual or partnered – to support their research efforts in nanomedicine. Examples include the Australian Centre for Nanomedicine and the Children’s Cancer Institute Australia (both at the University of New South Wales [UNSW], Sydney, Australia), the Australian Institute for Bioengineering and Nanotechnology (AIBN; at the University of Queensland, Brisbane, Australia) and the Centre for Bioengineering and Nanomedicine (Otago
University, North Dunedin, New Zealand). Other university-oriented groupings, such as the Australian Regenerative Medicine Institute and Monash Institute of Pharmaceutical Sciences (Monash University, Melbourne, Australia), Australian Centre of Excellence for Electromaterials Science (several universities in Australia), the Bosch Institute (University of Sydney, Australia), the Australian Technology Network of Universities, and the MacDiarmid Institute (Kelburn, New Zealand) also include a strong nanomedical component within their research portfolios. Nanomedical research is also conducted in-house by nonuniversity entities such as the CSIRO, the Garvan Institute of Medical Research (Sydney, Australia) or the Burnet Institute (Melbourne, Australia). Commercially oriented research is conducted by companies such as Starpharma (Melbourne, Australia), Ceramisphere (Gladesville, Australia), pSivida (North Perth, Australia) and IZON (Christchurch, New Zealand), some of which are listed on the stock exchange. Nanomedical research in Australia and New Zealand also takes place within many smaller and unaffiliated research groups. Owing to the relatively small populations of these two countries, there is considerable interest in developing research collaborations with colleagues in the northern hemisphere. In addition, the small size of the local markets generally means that early commercialization in overseas markets may be needed to ensure viability. Given the broad scope of ‘nanomedicine’ as a field, we have chosen to limit the technical discussion in this report to research in which an
10.2217/NNM.13.179 © 2013 Future Medicine Ltd
Nanomedicine (2013) 8(12), 1999–2006
Michael B Cortie*1, Eman H Nafea2, Hui Chen1,3,4, Stella M Valenzuela1,3,4, SR Simon Ting4, Fabio Sonvico1,2 & Bruce Milthorpe1,4 Institute for Nanoscale Technology, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Sydney, Australia 2 Graduate School of Health, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Sydney, Australia 3 School of Medical & Molecular Biosciences, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Sydney, Australia 4 Centre for Health Technologies, University of Technology Sydney, PO Box 123, Broadway, NSW 2007, Sydney, Australia *Author for correspondence: Tel.: +61 2 9514 2208 [email protected] 1
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artificial, nanoscale, solid-phase structure, typically an artificial nanoparticle or nanoporous scaffold, is deployed in a biomedical context. We exclude research that is principally involved with developing liquid-phase compounds or macromolecules for pharmaceutical applications, such as antibody–drug conjugates, and technologies that do not depend critically on having some dimension in at least the 1–200 nm range. Nanobiotechnology and nanomedicine in Australia was partially surveyed in Nanomedicine 6 years ago [1] and, in late 2012, these topics were very briefly discussed within a report on nanotechnology in Australia in general [2]. Both publications highlighted the particular local interests in the bio–nano interface, diagnostics and drug delivery. Here we will provide a brief snapshot that investigates these interests in more detail. We do not claim this survey to be exhaustive (although it is hopefully broadly representative), but it will provide a sense of what research is topical at the time of writing.
Diagnostic nanomedical technologies There is widespread interest in both countries in sensors based on electrochemical (capacitive or faradaic) or optical (refractometric, photonic, fluorescence, surface-enhanced Raman or surface plasmon polariton) modalities. In many cases the analyte is of medical relevance. Almost all current projects target the in vitro environment. The work is widely distributed across research groups, and we have space only to highlight some of the themes. Electrochemical biosensors of various kinds have received much attention, especially from the group of Gooding at UNSW. Older publications by Gooding and colleagues on the use of carbon nanotubes for biosensing have been highly cited [3]. As one recent example of the ongoing interest, an electrochemical displacement immunosensor was described by the same author [4]. There is also continued interest elsewhere in Australia in electrochemical sensors based on tethered lipid bilayer membrane technology – an innovation that arose at the CSIRO in the mid-1990s [5]. Commercially this interest is now driven by the company Surgical Diagnostics (Sydney, Australia). In two recent examples, the technique was used to characterize the behavior of ion channel proteins and antimicrobial peptides inserted into tethered lipid membranes [6,7]. The topic of contrast enhancement for micro scopy and MRI continues to receive attention. 2000
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There is also a closely related interest in probing the cellular environment using nanoparticles coupled to some type of optical transduction. A group at Macquarie University (Sydney, Australia) recently demonstrated a quantum dot-based fluorescent SRIF probe that exploits endocytosis to target somatostatin receptors [8]. Analogously, a University of South Australia group has developed a gold nanoparticle lymphotropic contrast agent, which binds to lymphoid cells overexpressing the CD45 antigen [9]. A labelfree fluorescence-sensing system with a detection limit of 240 fM for oligonucleotides was demonstrated by a group at the University of Auckland (New Zealand) [10], while a group at the University of Melbourne (Australia) has examined the fluorescence of the nitrogen vacancy defect in nanodiamonds as means of probing the chemical state of ion channels [11]. There has also been widespread interest in developing nanoparticles to enhance contrast in the MRI [12–14]. Refractometric sensors are less specific in their capabilities; however, biosensors based on the optical properties of porous silicon are being pursued by three or four groups, for example [15]. Finally, in New Zealand, the company IZON manufactures a useful electrophoretic instrument for measuring the size of individual particles (or organisms) in the 50 nm to 10 µm range while a biosensor, the ‘Biochip’, has been developed by a group at University of Canterbury (Christchurch, New Zealand). The latter can detect forces exerted by microscopic organisms as they move [16].
Drug delivery Polymer-based pharmaceutical technologies attract a large amount of interest, as they do elsewhere. For example, individuals at the Australian Centre for Nanomedicine are exploiting their considerable in-house chemical expertise to develop a variety of polymer platforms for drug delivery. In much of their work, reversible addition-fragmentation chain-transfer polymerization is used to construct customdesigned polymers. Recently, the group used in vitro experiments with neuroblastoma cells to demonstrate enhanced anti-tumor activity through the targeting of polymer nanoparticles to deliver a combination of nitric oxide and cisplatin [17]. The group also developed hydrophobic biodegradable acetalated dextran as a targeting delivery system for therapeutic molecules such as doxorubicin [18] and stable multifunctional soft core–shell nanoparticles via the self-assembly of predesigned diblock copolymers [19]. An future science group
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objective of this work is to demonstrate controlled release in response to biologically relevant chemical environments. The listed company Starpharma is focused on exploiting dendrimers. It has developed a range of lysine- and hydrogel-based drug delivery technologies and has a product (VivaGel®; designed to combat bacterial vaginosis and sexually transmitted viral infections) at an advanced stage of clinical testing. An anticancer product containing docetaxel is reported to be imminently approaching the clinical trial phase. Dendrimers are also a theme at the Monash Institute of Pharmaceutical Sciences where a group is evaluating novel doxorubicin-conjugated PEGylated polylysine dendrimers [20,21]. There is also research into polymer nano particles at the University of Western Australia. For example, one group demonstrated improved intracellular delivery of paclitaxel to colon cancer cells after conjugation of loaded poly(d,l-lacticco-glycolic acid) nanoparticles with wheat germ agglutinin as a tumor-targeting ligand [22]. In other work, paclitaxel-loaded nanoparticles were synthesized with an amphiphilic aminocalixarene carrier [23]. A detailed correlative microscopy study from the same university of the endocytotic pathways followed by polymer nanoparticles into neural cells is also of interest [24]. A therapeutic substance can of course be encapsulated inside another particle; for example, Caruso and colleagues at the University of Melbourne have developed a means to immobilize a pH-cleavable doxorubicin–polymer conjugate in a polydopamine capsule [25]. Researchers at the School of Pharmacy, Curtin University (Perth, Australia) are interested in polymeric nanoparticles as a potential means to deliver peptides to the brain. Both chitosan and poly(d,l-lactic-co-glycolic acid) nanoparticles have been studied for the delivery of dalargin, a model hydrophilic hexapeptide, to the CNS [26,27]. High entrapment efficiency and peptide stability, together with sustained drug release were achieved with both formulations. Inorganic nanoparticles of various types are also topical. The company pSivida is commercializing drug delivery systems based on nanoporous silicon scaffolds and has several products targeting the ophthalmology market, with some already US FDA approved. There is also interest in drug delivery from composites of porous silicon and polymers at the University of South Australia [28]. A recent research collaboration between University of Queensland and University of Wollongong in Australia has developed future science group
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mesoporous silica nanoparticles modified with hyaluronic acid for targeting doxorubicin delivery to CD44-overexpressing cancer cells [29]. These nanoparticles demonstrated improved cellular uptake and superior antiproliferative action on human colon cancer cells over free doxorubicin or nonmodified encapsulated silica nanoparticles. Researchers at the Ian Wark Research Institute of the University of South Australia have been working on hybrid silica/lipid nanoparticles with a view to enhancing encapsulation, protection and controlled release of insulin, proteins and peptides [30]. Recently, they demonstrated enhanced chemical stability of all trans-retinol, a model water-sensitive molecule, after coating submicron oil-in-water emulsions with silica nanoparticles in solid state [31]. Previously, silicacoated oil-in-water emulsion showed potential for topical targeting, resulting in improved dermal delivery of lipophilic drugs [32]. Layered double-hydroxide nanoparticles of magnesium and aluminium provide a flexible platform for the intercalation of various payloads. For example, an antirestenotic compound, low-molecular-weight heparin, intercalated into such particles has been targeted to injured arteries with the aid of antibodies by individuals at the AIBN [33]. Researchers at AIBN have also proposed a novel nanocomposite film for sustained release of anionic drugs: layered doublehydroxide nanoparticles containing ketorolac were dispersed into a hydrogel matrix to produce drug-loaded contact lenses [34]. On a somewhat different note, there is the intriguing suggestion that a modified form of lactoferrin, a milk protein, could be exploited as an anticancer nutraceutical when delivered to tumors using a calcium phosphate nanoparticle vector [35]. Finally, there have been several investigations across Australia on the functionalization and biological interactions of gold nanoparticles. One aspect that has garnered attention is the response of the immunological system to such nanoparticles. Minchin’s group at University of Queensland has investigated interfacial reactions in serum and confirmed that cytokine release is usually triggered, although interesting exceptions occur; for example, particles that are positively charged or coated with human plasma proteins are inert [36]. An intriguing but different phenomenon was recently uncovered by three of the current authors (Chen, Valenzuela and Cortie) in which it was found that citrate-stabilized gold nano particles could exert a significant downregulation of cytokine production within the adipose tissue www.futuremedicine.com
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of mice [37]. This was associated with a decrease in body fat but not appetite. Similarly, Brown et al. found that macrophage activity in arthritic rats was advantageously suppressed under some circumstances [38]. The mechanism of these curious phenomena appears to involve targeting, but not destruction, of the macrophages by the gold nanoparticles. Other types of nanoparticle are also being investigated; for example, the prospect of the nanoparticle itself being made substantially of the active ingredient has been considered. A group at CSIRO has developed a novel oral nanochemotherapeutic with sustained release properties and target-selective activation. Researchers have produced self-assembled nanostructured nanoparticles consisting of 5-fluorouracil lipid prodrugs [39]. These lipid prodrug nanoparticles inhibit the growth of a highly aggressive mouse breast tumor while avoiding systemic toxicity. The Advanced Drug Delivery group (University of Sydney) is currently focusing on tailoring drug nanoparticle architecture to enhance aerosol performance. The group succeeded in producing micron-sized aggregates of proteins (‘nanomatrix’ particles) with controlled surface roughness by spray-drying nanosuspensions [40]. The same group also developed improved lipo somal nanoparticles to overcome rapid clearance of antibiotics, such as ciprofloxacin from the lungs, with obvious applications in the treatment of respiratory infections [41]. Pulmonary delivery of nanosized particles produced in supercritical fluids is being pursued by a UNSW start up, Bioparticle Technologies (Sydney, Australia). A multifunctional hybrid nanoparticle, built on a rhodamine B/polyglycidol methacrylate core containing Fe3O4 nanocrystals, has recently been used as a vector to deliver an ion channeltargeting peptide by a group at the University of Western Australia [42]. This group has also published a detailed study on the uptake of polyethylenimine (PEI)-decorated nanoparticles by neural cells [24], with a spin-out company, Eridan Technology (Perth, Australia), established to pursue the technology. A generic method to coat nanoparticles or nanocapsules of various compositions has recently been published by Caruso’s group at University of Melbourne. In this approach a coordination complex of natural polyphenols and iron ions is induced to self-assemble on an existing substrate or particle. The advantage is that the method is rapid and versatile and the coatings are generally biocompatible. Caruso and his group are already well-known 2002
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internationally for their ongoing development of the ‘layer-by-layer’ method for producing hollow nanoparticles, for example [43]. Nanoparticle delivery systems have been used to enhance cell-mediated immune responses against purified antigens, indicating their potential for use in intranasal immunization. Researchers at the School of Pharmacy, Curtin University have developed a biodegradable nano particulate system based on chitosan–dextran sulfate nanoparticles for this role [44]. Finally, capsules suitable for drug delivery can also be manufactured by bacteria. For example, drug delivery using bacterially expressed vesicles (‘caveolae’) formed by the polymerization of the prokaryotic protein caveolin has recently been investigated by Parton’s group at the University of Queensland [45]. This vehicle offers intriguing flexibility in so far as its production is genetically encoded, allowing for ready manipulation of the surface properties or morphology. On a related note, although slightly out of the scope of this review, bacterially derived ‘minicells’ have been considered for encapsulating drugs by the Sydney-based company EnGeneIC Ltd (Australia) [46].
Nucleic acid delivery Nonviral vectors for transfection and gene therapy are being investigated by several laboratories. For example, delivery of DNA and RNA from porous silica nanospheres is being pursued by Ceramisphere, a company with its origins at the Australian Nuclear Science and Technology Organisation. RNAi has potential in the treatment of various diseases via targeted gene silencing. However, systemic delivery of naked siRNAs is ineffective owing to their susceptibility to nuclease degradation and net negative charge under physiological conditions. Therefore, development of biocompatible, synthetic nanoparticle-based RNAi vehicles would provide protection of encapsulated sensitive molecules and promote their cellular uptake [47]. Delivery of siRNA using a biodegradable star polymer has been investigated by Boyer et al. at the Australian Centre for Nanomedicine at UNSW [48], while Davis and coworkers, at the same center, developed novel PEG-coated iron oxide nanoparticles for the efficient delivery of siRNA [49]. The PEG layer provided charge shielding and hence limited protein adsorption onto nanoparticles without compromising their siRNA transfection efficiency or their magnetic properties. Davis has now relocated to the Monash Institute of Pharmaceutical Sciences, future science group
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to join the rapidly growing nanomedicine activities there. There is also research at the ARC Centre of Excellence for Functional Nanomaterials and the AIBN focused on the synthesis of layered double-hydroxide nanoparticles for siRNA delivery. Owing to the size and positive surface charge of nanoparticles, they were able to bind nucleic acids and facilitate uptake into mammalian cells via endocytosis. Moreover, researchers designed functionalized mesoporous silica nanoparticles with large pores and a cubic mesostructure as a new carrier material for delivery of model oligo-DNA [47,50]. In the same ARC Centre of Excellence, but based in UNSW, Arsianti et al. functionalized PEI onto magnetic iron oxide nanoparticles to transfect pDNA. Their study has shown that it is necessary to protect pDNA with PEI cationic polymers. In addition, uptake of nanoparticles was aided by gravitational and magnetic sedimentation onto adherent cells [51]. Monteiro and coworkers at the AIBN and the Queensland University of Technology have achieved an influenza virus-inspired polymer system for the controlled release of siRNA, allowing potential for multiple repeat doses and long-term treatment of diseases [52]. An ingenious method to engineer the release of siRNA therapeutics was described by Cass et al. at the CSIRO. siRNA was electrostatically bonded to a cationic block copolymer that also contained disulfide bridges. Upon uptake into the reductive environment of an endosome, chain scission at the disulfide bridges occurred, weakening the polyplexes and releasing nucleic acid payload [53]. Finally, at Griffith University in Queensland, the use of liposomes was employed by McCaskill and coworkers to knockdown targeted genes in a proposed treatment for lung epithelium diseases [54]. Clearly, the delivery of nucleic acid using nonviral vectors is a rapidly developing field in Australia, as it is elsewhere.
Regenerative medicine & emerging applications An important objective of regenerative techno logies is to accelerate tissue repair. For example, patient recovery after insertion of orthopedic implants can be facilitated by careful attention to the bio–nano interface. In this context, the use of porous materials derived from coral and other marine exoskeletons has been pursued for some years at the University of Technology, Sydney, Australia. As an example, a recent report describes how such material can be used to deliver simvastatin [55]. Modification of the surfaces of future science group
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cardiovascular and other implants has been a theme at the nearby University of Sydney, with treatment by a high-voltage gas plasma being a favored route [56], while at the UNSW, there has been research into the general effects of surface nanostructure on cell–material interactions for some years [57,58]. Artificial materials for transduction or transmission of neural signals have also been a recurring research theme, probably inspired by the success of the ‘bionic ear’. Part of this research is conducted by, or with, Cochlear ® (Sydney, Australia), the manufacturer of the successful cochlear ear implant, or by the Bionics Institute in Melbourne (Australia). Research into the use of conductive polymers in this arena has been ongoing at the University of Wollongong, and forms a program within the multi-institutional Australian Centre of Excellence for Electromaterials Science. A recent paper on coating electrodes with nanoscale layers of various conducting polymers is an example [59]. The exploitation of localized heat generation in nanoparticles (generated by plasmonic heating in gold nanoparticles or fluctuating magnetic fields iron oxide nanoparticles) has also caught the attention of a number of researchers. Gold nanospheres or nanorods, for example, have been investigated for potential therapeutic applications at the University of Technology Sydney. In vitro studies have shown how the particles can be selectively targeted to murine macrophages or to the infectious protozoan Toxoplasmosis gondii, either of which can then be destroyed using relatively low-power laser irradiation [60,61]. The convenient localization of radiotherapy dose enhancement using heavy element nano particles such as gold or bismuth oxide is being pursued by a group at RMIT University (Melbourne, Australia) [62]. The mechanism of this phenomenon seems to be the radiation-induced generation of free radicals on the surface of the nanoparticle – a phenomenon known since the 1950s – but the use of gold nanoparticles for this purpose may represent a new approach. Another interesting line of research has been the possible use of cerium oxide nanoparticles as scavengers for intracellular reactive oxygen species. It has been shown that the particles are taken up by monocyte cells (but not endothelial cells), for example, and a reduction in reactive oxygen species is possible [63].
Conclusion The ‘nanomedicine’ community in Australia and New Zealand is small but active, reflecting www.futuremedicine.com
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the fact that it is based in a relatively prosperous market of less than 30 million people. There are particularly well-developed research strengths for polymer therapeutics and biosensors, and other interesting activities in many other areas of nanomedicine. Some of this research has already led to commercial developments, such as the companies Starpharma (polymer therapeutic products) or pSivida (porous silicon). Although there are several larger research groupings, such as the Australian Centre for Nanomedicine, the nanomedicine research community more generally operates on a dispersed and laissez-faire basis. Australia has not benefited from targeted national support for nanomedicine research within a multi-institutional grouping; however, if this were to occur, it would no doubt be strongly beneficial in terms of activity and output. The funding model does not discourage fundamental research, and most of the current projects underway are still several years away from preclinical consideration. Another attribute of nanomedical research in the antipodes is that many of the groups are closely linked to collaborators in the northern hemisphere, distance apparently not presenting an obstacle to activity.
Future perspective The larger part of the nanomedicine community in Australia and New Zealand is focused
on developing a range of drug delivery strategies. Some of these initiatives have led to spinoff companies and commercial products; however, the local market is very small. This has the inevitable consequence that most products must eventually be pitched to northern hemisphere markets and investors. The community also has internationally competitive research strengths in respect of fundamental surface chemistry and polymer science. Links with other groups around the world are sought after and welcomed. The future trajectory of the local research community in nanomedicine will probably be strongly influenced by the success or otherwise of the pioneering commercial ventures mentioned above. If they are successful, this will no doubt inspire further spinoffs, a factor that, in turn, encourages more government investment and a new generation of nanomedical researchers and products. Financial & competing interests disclosure SRS Ting acknowledges a National Health and Medical Research Council Early Career Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Executive summary Australia and New Zealand have a small but active nanomedicine community. There is considerable interest in various strategies for targeted delivery of drugs and nucleic acids. There is a strong focus on polymer-based pharmaceutical technologies. Some nanomedical products are already on the market and several others are in trials. The local market is small and, therefore, an international perspective is necessary.
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