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There are drawbacks to the method of Zakeri and colleagues. In particular, the method works well only when a strong hybridization of electronic states takes place at the interface, the magnetic properties of the interface layer are substantially different from the properties of other magnetic layers of the system, and the lowest-energy magnon mode is mainly localized at the interface. However, in

such cases, this electron–magnon ‘digging’ method can be used to obtain quantitative information about the strength of the magnetic exchange interaction at the buried magnetic interface. ❐

Andrei Slavin is in the Department of Physics, Oakland University, 2200 South Squirrel Road, Rochester, Michigan 48309, USA. e-mail: slavin@oakland.edu

References1. Zakeri, K. et al. Nature Nanotech. 8, 853–858 (2013).2. Vollmer, R., Etzkorn, M., Kumar, P. S. A., Ibach, H. & Kirschner, J.

Phys. Rev. Lett. 91, 147201 (2003).3. Zakeri, Kh., Zhang, Y., Chuang, T.-H. & Kirschner, J.

Phys. Rev. Lett. 108, 197205 (2012).4. Zakeri, Kh. & Kirschner, J. Probing Magnons by Spin-Polarized

Electrons (Topics in Applied Physics Magnonics From Fundamentals to Applications) Vol. 125, Ch. 7, 84–99 (Springer, 2013).

5. Ibach, H. et al. Rev. Sci. Instrum. 74, 4089–4095 (2003).6. Buczek, P., Ernst, A. & Sandratskii, L. M. Phys. Rev. B

84, 174418 (2011).

In cancer gene therapy, nucleic acids are delivered to tumour cells (a process known as transfection) to either induce

the expression of toxic proteins that are capable of killing them or to reduce the activity of vital proteins in the cells. A major obstacle to the successful translation of cancer gene therapy to the clinic is the lack of safe and efficient carrier systems. The nucleic acid carriers that are currently available are limited by issues such as immunogenicity and a lack of selectivity, that is, they transfect both tumour and normal cells1,2.

Cationic polymer-based nanoparticles are a promising alternative for such carrier applications3. These nanoparticles are formed through electrostatic interactions between anionic nucleic acids and cationic polymers. The nucleic acids trapped within nanoparticles are protected against potential degradation in the circulatory system. Nanoparticles also accumulate passively in tumours, rather than in healthy organs. This phenomenon of passive tumour targeting has the potential to limit non-specific distribution while maintaining on-target efficacy. However, many nanoparticle systems are rapidly removed from the circulation by macrophages, a specific type of immune cell that is also responsible for clearing cellular debris and infectious agents. Therefore, healthy organs (such as the liver and lungs) that have a large population of resident macrophages also demonstrate high degree of non-specific nanoparticle accumulation. As a result, off-target delivery of genes is still a significant concern with cationic nanoparticles, and

improving targeting efficiency is a key issue for cancer gene therapy research4. Writing in the Proceedings of the National Academy of Sciences, Bert Vogelstein, Shibin Zhou and colleagues at Johns Hopkins Medical Institutions and Johns Hopkins University have now developed polymer-based nanoparticles that provide a 16,000-fold increase in the ratio of tumour to non-tumour cell delivery compared with commercially available delivery formulations5.

The starting point for the work was in vivo-jetPEI, a cationic polymer-based formulation currently being used in clinical trials as a gene delivery vector for viral diseases and cancer. The researchers hypothesized that the molecular weight of the cationic polymer polyethylenimine (PEI) could be an important determinant of the in vivo performance of the vector. Therefore, they investigated a nanoparticle formulation that was composed of an 88 kDa linear PEI polymer complexed with the gene of interest. In comparison, in vivo-jetPEI is thought to be a linear PEI derivative of approximately 22 kDa; its exact composition is proprietary.

High levels of transfection were observed with these high-molecular-weight nanoparticles. However, they were also found to accumulate in the liver and lungs. Therefore, to achieve both high transfection efficiency and low toxicity, Vogelstein and colleagues synthesized a hybrid system called ‘core/pegylated shell’ nanoparticles. These nanoparticles have a core of high-molecular-weight PEI (88 kDa) complexed with DNA and also a corona of polyethylene glycol (PEG)-conjugated low-

molecular-weight PEI (2.5 kDa) (Fig. 1). The low-molecular-weight PEI helps to maintain low toxicity, while the PEG limits uptake by immune cells. Compared with in vivo-jetPEI, the core/pegylated shell nanoparticles exhibited significantly higher transfection in primary tumours and lower transfection in the lungs.

One of the most striking features of the core/pegylated shell system is its selectivity: the nanoparticles were found to selectively deliver to sites of tumour spread in the lungs and liver, but showed minimal transfection in the surrounding normal tissue. High selectivity is important not only for cancer gene therapy but also for chemotherapy. However, the selectivity experiments were conducted in immunodeficient or NOG mice. These mice lack functional cells that protect against infection such as T cells, B cells and natural killer (NK) cells and are characterized by dysfunctional macrophages. Therefore, additional studies in fully immunocompetent mice are required to confirm the high selectivity of this system.

When measuring off-target transfection of the vector at the whole-tissue level, its transfection levels were also compared with that of in vivo-jetPEI only in the lungs. This may have been because in vivo-jetPEI showed maximum transfection in this organ. As most nano-formulations often show the highest accumulation in the liver, it would be of interest to measure transfection levels in it as well. Quantitative analysis of biodistribution of the vector following systemic delivery may help confirm its tumour-specific accumulation. The researchers suggest

POLYMER NANOPARTICLES

Weighing up gene deliveryIncreasing the molecular weight of the core of a polymeric nanoparticle significantly improves its use in gene delivery.

Ameya R. Kirtane and Jayanth Panyam

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806 NATURE NANOTECHNOLOGY | VOL 8 | NOVEMBER 2013 | www.nature.com/naturenanotechnology

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that the high selectivity of the core/pegylated shell system arises from the enhanced permeability and retention effect. However, there are several other gene delivery systems that utilize this effect, but do not show such high selectivity. Hence, the mechanism of high selectivity merits further investigation.

Although the selectivity of these nanoparticles was remarkable, the number of cells that expressed the transfected gene was rather low (<1%). Such low levels of transfection could be problematic for cancer therapies that require the introduction of a specific gene into every

tumour cell to trigger cell death. On the other hand, this system would possibly be useful for the delivery of genes that encode secreted proteins capable of killing multiple surrounding tumour cells or disrupting the tumour blood supply. Thus, it remains to be seen whether such low transfection efficiency will translate into therapeutic benefit. Additionally, it would be interesting to compare the transfection efficiency and therapeutic efficacy of this new system with that of in vivo-jetPEI.

The core/pegylated shell nanoparticles performed differently in different mouse species and in different

tumour cell lines. At present, most nano-delivery systems are characterized in two-dimensional cell-culture models and in immunocompromised mouse models of human cancers. Although many nanosystems demonstrate very good preclinical activity in rodent models, there is limited clinical success. Differences in the pathophysiology of the tumour models likely contribute to this lack of translation. Therefore, there is a need to develop standardized cell culture and animal models that better mimic the human disease.

Nucleic acid-based therapies hold tremendous promise for treating cancer and various other chronic diseases. The development of formulations that demonstrate high targeted selectivity is an important step towards exploiting the full potential of such therapies. Future research focused on improving the transfection efficiency in the target tissues while maintaining low off-target effects will be highly valuable. Understanding the mechanisms behind the high target selectivity will be critical to such efforts. ❐

Ameya R. Kirtane and Jayanth Panyam are at the Department of Pharmaceutics and the Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA. e-mail: jpanyam@umn.edu

References1. McCormick, F. Nature Rev. Cancer 1, 130–141 (2001).2. Whitehead, K. A., Langer, R. & Anderson, D. G.

Nature Rev. Drug Disc. 8, 129–138 (2009).3. De Smedt, S. C., Demeester, J. & Hennink, W. E. Pharm. Res.

17, 113–126 (2000).4. Chen, Y., Zhu, X., Zhang, X., Liu, B. & Huang, L. Mol. Therapy

18, 1650–1656 (2010). 5. Yang, J. et al. Proc. Natl Acad. Sci. USA 110, 14717–14722 (2013).

Figure 1 | The selectivity of core/pegylated shell nanoparticles. The nanoparticles are composed of a high-molecular-weight PEI core (green) containing DNA, with a PEG-conjugated low-molecular-weight PEI shell (blue). In experiments with immunodeficient mice, they are found to selectively transfect tumour cells in the lungs (tumour cells, grey; transfected cells, green) while exhibiting minimal uptake in the surrounding normal tissue (orange cells). However, less than 1% of transfected cells expressed the transfected gene. DNA image, © Jezper/Alamy.

CorrectionIn the version of the News & Views article ‘Nanoparticles: Tracking protein corona over time’ originally published (Nature Nanotech. 8, 701–702; 2013), in ref. 6, the volume number was incorrect. Corrected in the PDF and HTML versions after print 4 October 2013.

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