Controlled-Release System Mediated by a Retro Diels–Alder Reaction

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Controlled-Release System Mediated by a Retro Diels Alder Reaction Induced by the Photothermal Effect of Gold Nanorods Shuji Yamashita,† Hiromitsu Fukushima,† Yasuro Niidome,† Takeshi Mori,† Yoshiki Katayama,†,‡,§ and Takuro Niidome*,†,‡,§,|| †

Department of Applied Chemistry, Faculty of Engineering, ‡International Research Center for Molecular Systems, and Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan PRESTO, Japan Science and Technology Corporation, 4-8-1 Honcho, Kawaguchi 332-0012, Japan

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ABSTRACT: Controlled-release systems that respond to external stimuli have received great interest for use in medical treatments such as for drug delivery to specific sites. Gold nanorods have an absorption band at the near-infrared region and convert the absorbed light energy into heat, which is known as a “photothermal effect”. Therefore, gold nanorods are expected to act not only as an on-demand thermal converter for photothermal therapy but also as a controller of a drug-release system capable of responding to the near-infrared light irradiation. In this study, to construct a controlled-release system that responds to nearinfrared light irradiation, we modified gold nanorods with polyethylene glycol (PEG) through Diels Alder cycloadducts. When the modified gold nanorods were irradiated by near-infrared light, the PEG chains were released from the gold nanorods because of the retro Diels Alder reaction induced by the photothermal effect. As a result of the PEG release, the gold nanorods formed aggregates. This type of controlled-release system coupled with the aggregate formation of the gold nanorods triggered by nearinfrared light could be expanded to applications of gold nanorods in medical fields such as drug and photothermal therapy.

1. INTRODUCTION Controlled-release systems that are capable of responding to the unique environments of tissues and/or external stimuli using nanoparticles, such as liposomes,1,2 polymer micelles,3 10 magnetite nanoparticles,11,12 and gold nanoparticles,13 17 have attracted much attention as a promising technique to deliver drugs into specific sites. In terms of tumor targeting, extracellular pH and protease activity are known to make up the unique environments of the tumors. The extracellular pH of tumors is slightly acidic (pH 6.5 7.2),18,19 so pH-responsive reactions or pHsensitive polymers have been incorporated into controlled-release systems.3 9,20 Proteases are implicated in various important biological processes in living cells and organisms. Among the various proteases, it is known that matrix metalloproteinase (MMP) and urokinase-type plasminogen activator (uPA) are highly expressed in tumors compared with normal tissues. Therefore, MMP and uPA have been used as triggers for controlled-release systems in response to the unique environments of tumors.21 25 External stimulation factors including radiofrequency,11,12 ultrasound,1,2 light,13 16 and heat9,10 have all been used to control drug-release systems. For example, magnetic nanoparticles were used as a heating device responding to the irradiation of radiofrequency.11,12 The produced heat not only triggered thermal damage of the irradiated tumor but also released drugs from the nanoparticles. Liposomes, which release encapsulated contents in response to ultrasound, have also been developed.1,2 Gold nanoparticles are promising agents for drug delivery because they can be readily prepared by reducing Au ion under r 2011 American Chemical Society

appropriate conditions and do not show significant toxicity in vitro or in vivo.13 17 Among them, gold nanorods, which are rodshaped gold nanoparticles, are expected to be functional nanodevices. The gold nanorods have two adsorption bands corresponding to the transverse and longitudinal surface plasmon oscillations of free electrons.26,27 In general, the longitudinal plasmon resonance of gold nanorods can be tuned from 550 nm to over 1200 nm by varying the aspect ratio of the gold nanorod. Near-infrared region between 670 and 890 nm is located in the minimum light absorption band of tissues between the absorptions of the intrinsic chromophores, hemoglobin (900 nm), resulting in the maximal penetration of light into the tissues.28 Therefore, in this study, we employed gold nanorods that show adsorption band corresponding to the longitudinal surface plasmon resonance at 885 nm. The gold nanorods also possess photothermal effects that can efficiently convert the absorbed light energy into heat.29 Therefore, gold nanorods are expected to act as a thermal converter for photothermal therapy and as a suitable controlled-release system triggered by near-infrared light irradiation.13,14,30 32 For example, nucleic acids such as plasmid DNAs and double-stranded oligonucleotides modified on the gold nanorods were released by irradiation of pulsed near-infrared light because of a shape change in the gold nanorods to a spherical form triggered by the Received: September 20, 2011 Revised: October 11, 2011 Published: October 11, 2011 14621

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Langmuir photothermal effect.33 37 Double-stranded oligonucleotides can also be used as a heat-labile linker.38 40 The induced heat from the photothermal effect could trigger dissociation of the doublestranded oligonucleotides on the gold nanorods to singlestranded oligonucleotides, thereby releasing single-stranded oligonucleotides, which can act as antisense oligonucleotides.41 The Diels Alder reaction is known as a reversible cycloaddition reaction between diene and alkene groups to form a cycloadduct. Actually, the reaction between furan and maleimide proceeds at 60 °C, and its reverse reaction, the so-called retro Diels Alder reaction, proceeds at 90 °C.42,43 Branda et al. succeeded in the release of a fluorescence group from a fluorescence group-linked Diels Alder cycloadduct modified on gold nanoshells, which can be heated by near-infrared light irradiation.44 In this study, we modified PEG-linked Diels Alder cycloadducts on gold nanorods and proposed a controlled-release system of PEG from the surface of the gold nanorods triggered by a retro Diels Alder reaction induced by the photothermal effect of the gold nanorods.

2. EXPERIMENTAL SECTION 2.1. Materials. Gold nanorods were provided by a joint research project with Mitsubishi Materials Corp. and Dai Nippon Toryo Co. Ltd. The mean size of the gold nanorods was 65 ( 5 and 11 ( 1 nm in longitudinal and transverse directions, respectively. m-PEG20 000-SH [molecular weight (MW) ca. 20 000 Da) and m-PEG20 000-maleimide (MW ca. 20 000 Da) were purchased from NOF Co. Ltd. (Tokyo, Japan). Tris (2-carboxyethyl)phosphine hydrochloride (TCEP) was purchased from Wako Pure Chemical Industries, Limited (Osaka, Japan). Furfuryl disulfide was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Dimethylformamide (DMF) was purchased from Wako Pure Chemical Industries, Limited (Osaka, Japan). 2.2. Synthesis of PEG-Linked Diels Alder Cycloadduct-SH (PEG20 000-DA-SH). PEG-linked Diels Alder cycloadduct was synthesized by mixing m-PEG20 000-maleimide (α-[3-(3-maleimide-1-oxopropyl)amino]propyl-ω-methoxy, polyoxyethylene) and furfuryl disulfide in a 1:40 molar ratio in DMF, then heating the solution at 60 °C for 3 days in an oil bath. TCEP was added to reduce the disulfide bond. After DMF was evaporated, residues were dissolved in milli-Q water. The solution was dialyzed with a dialysis membrane [molecular weight cutoff (MWCO) 10 000 Da] for 1 day and freeze-dried, resulting in the PEG-linked Diels Alder cycloadduct-SH (PEG20 000-DA-SH) in a white powder form. 2.3. Preparation of PEG-DA-Modified Gold Nanorods. An aqueous solution of the synthesized PEG20 000-DA-SH was added to the gold nanorods dispersed in a hexadecyltrimethylammonium bromide (CTAB) micelle solution (CTAB-stabilized gold nanorods) at a PEG20 000-DA-SH:Au molar ratio of 0.05. The suspension was mixed for 24 h at room temperature and dialyzed with a dialysis membrane (MWCO 10 000 Da) to remove the remaining CTAB. The solution of PEG-DA-modified gold nanorods was centrifuged at 14000g for 10 min at 25 °C, decanted, and resuspended in water to concentrate and remove excess free PEG chains. PEG-modified gold nanorods used as a control material were prepared by mixing with m-PEG20 000-SH using the same method as the PEG-DA-modified gold nanorods. 2.4. Characterization of PEG-DA-Modified Gold Nanorods. The surface modification of the gold nanorods was confirmed by a change of ζ-potential of the gold nanorods. Measurement of the

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ζ-potential was performed in Milli-Q water using a Zetasizer Nano ZS (Malvern, Worcestershire, UK). The PEG chains modified on the gold nanorods were observed by transmission electron microscopy (TEM) using a JEOL JEM-2010 (JASCO, Tokyo, Japan) after staining with 1% phosphotungstic acid. Dispersal of gold nanorods in solution was confirmed from the absorbance spectrum using a V-670 spectrophotometer (JASCO, Tokyo, Japan). 2.5. Aggregate Formation of PEG-DA-Modified Gold Nanorods. The prepared PEG- and PEG-DA-modified gold nanorod solutions [100 μL of 1.0 mM (Au atoms) in 50 mM NaCl in sodium phosphate buffer (pH 7.4)] were aliquoted into tubes. The solutions were irradiated with a continuous wave (CW) near-infrared diode laser (wavelength, 920 nm; beam diameter, 5.5 mm; Power Technology Inc., Little Rock, AR) at 500 mW for 10 min. Control samples were heated in a heat block at 80 or 90 °C for 10 min. After the CW near-infrared laser irradiation or the heat treatment, aggregate formation of the PEG- or PEG-DA-modified gold nanorods was evaluated in terms of changes in the absorbance spectra, increases in light scattering, and TEM observations. Fifty microliters of the gold nanorods solutions were diluted by 20 times, and then the absorbance spectra of the diluted samples were measured using a V-670 spectrophotometer. The light-scattering measurements were performed using a Malvern Instrument Zetasizer Nano ZS equipped with a He Ne laser (633 nm, 3 mW) and an Avalanche photodiode detector at an angle of 173°. All the data were processed on Dispersion Technology Software (Malvern Instruments). The derived count rate was used as the lightscattering date. The derived count rate values were averaged over three times. The viscosity (0.8872) and the refractive index (1.330) of water at 25 °C were entered into the software. Another 50 μL of sample solution was used for the TEM observation. 2.6. Release of PEG Chains from PEG-DA-Modified Gold Nanorods. The prepared PEG or PEG-DA-modified gold nanorod solutions [100 μL of 1.0 mM (Au atoms) in Milli-Q water] were aliquoted into tubes. The laser-irradiated or heattreated gold nanorods solutions were ultracentrifuged (79 000g for 30 min at 25 °C, Himac CS100GX II, Hitachi Koki, Tokyo, Japan) to precipitate all nanorods. PEG chains released from the gold nanorods were quantified by the barium iodine method.45 Briefly, the supernatant (40 μL) was mixed with barium chloride (10 μL, 5 wt %), iodine (5 μL, 0.1 M), and water (50 μL). The PEG contents were monitored at 535 nm and calibrated using standard solutions. The percentage of the released PEG chains was calculated using the following equation: released PEG % = {[amount of released PEG chains amount of free PEG chains (unbound PEG chains)]/[total amount of PEG chains (positive control) the amount of free PEG chains]}. The positive control was prepared as follows. In the case of the PEG-modified gold nanorods, 500 μL of the gold nanorod solution [1.0 mM (Au atoms) in Milli-Q water] was aliquoted into a tube, and then 10.6 mg (0.01 mmol) of 3-mercaptopropionic acid (MPA) was added into the solution. The solution was mixed for 2 h at room temperature. The solution was ultracentrifuged (79 000g for 30 min at 25 °C) to precipitate all nanorods and dialyzed to get rid of MPA with a dialysis membrane (MWCO 10 000 Da) for 1 day. After the dialysis, the solution was freeze-dried using an FDU1200 (Tokyo Rikakikai, Tokyo, Japan) freeze drier and resuspended in 500 μL of Milli-Q water. In the case of the PEG-DAmodified gold nanorods, 500 μL of the gold nanorod solution [1.0 mM (Au atoms) in Milli-Q water] was heated in a heat block 14622

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Figure 1. Synthesis of PEG20 000-DA-SH. PEG20 000-maleimide and furfuryl disulfide were coupled by a Diels Alder reaction, and then the disulfide bond in the resultant compound was reduced by TCEP.

at 100 °C for 120 min. The solution was ultracentrifuged (79 000g for 30 min at 25 °C) to precipitate all nanorods. The supernatants (40 μL) after the ultracentrifugation were mixed with barium chloride (10 μL, 5 wt %), iodine (5 μL, 0.1 M), and water (50 μL). The PEG contents were monitored at 535 nm and were calibrated using standard solutions. 2.7. TEM Observation. Twenty microliters of gold nanorod solution was dropped on a parafilm and then 20 μL of 2% phosphotungstic acid was mixed with the gold nanorod solution. A grid (STEM100Cu grid, Ouken, Tokyo, Japan) was put on the mixture and left to stand for 5 min. After any excess solution was removed, the samples adsorbed on the grids were dried in a desiccator for over 24 h. The samples were observed with TEM (JEOL JEM-2010).

Figure 2. Absorption spectra of the PEG-DA-modified gold nanorods (A) and their TEM image (B). The PEG layer on the gold nanorods was observed as a gray shadow in the TEM image.

Table 1. ζ-Potential of the PEG-DA-Modified Gold Nanorods

3. RESULTS AND DISCUSSION 3.1. Preparation of PEG-DA-Modified Gold Nanorods. A building block of a Diels Alder cycloadduct with a PEG and a thiol group (PEG20 000-DA-SH) was synthesized as shown in Figure 1. The Diels Alder cycloadduct was synthesized between maleimide and furan. After the disulfide bonds were reduced by TCEP, PEG20 000-DA-SH was obtained as a white powder. CTAB-stabilized gold nanorods were mixed with PEG20 000-DA-SH, and then their surfaces were modified with PEG-DA through the Au S bonds. The PEG-DA-modified gold nanorods did not form aggregates, even after removal of the CTAB, which was acting as a stabilizer of the gold nanorods. 3.2. Characterization of PEG-DA-Modified Gold Nanorods. We previously succeeded in preparing PEG5 000-SH-modified gold nanorods.46 To compare with the PEG-DA-modified gold nanorods, PEG20 000-modified gold nanorods without the Diels Alder cycloadduct part were used as a control. As shown in Figure 2A, both types of modified gold nanorods (PEG-DAmodified and PEG-modified) showed typical absorption spectra, that is, two surface plasmon bands corresponding to the longitudinal (885 nm) and transverse (520 nm) oscillation modes.26,27,46 As shown in Table 1, the ζ-potentials of the CTAB-stabilized gold nanorods were positive. In contrast, the ζ-potentials of the PEG-DA-modified gold nanorods were nearly neutral, indicating that the PEG layer makes neutral and hydrophilic layer on the gold surfaces.47,48 The PEG layer of the PEG20 000-DA-modified gold nanorods was also confirmed by TEM observation (Figure 2B). 3.3. Aggregate Formation of PEG-DA-Modified Gold Nanorods. The PEG-DA-modified gold nanorods were prepared

ζ-potential/mV

samples CTAB-stabilized gold nanorods PEG-DA-modified gold nanorods PEG-modified gold nanorods

+28.3 ( 0.4 1.32 ( 0.26 2.54 ( 0.26

Figure 3. Mechanism of release of the PEG chain from the surface of the PEG-DA-modified gold nanorods. Photothermal effect of the gold nanorods induced by the near-infrared laser light irradiation triggers a retro Diels Alder reaction, and then the PEG chain is released from the gold surface. The PEG release induces aggregate formation of the gold nanorods.

to construct the release system controlled by the Diels Alder reaction induced by the photothermal effect of the gold nanorods (Figure 3). That is, the PEG-DA-modified gold nanorods have neutral and hydrophilic surfaces maintained by 14623

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Figure 4. Absorption spectra of the PEG-DA- and PEG-modified gold nanorods after the near-infrared laser light irradiation or heat treatments. The PEG-DA-modified gold nanorod after near-infrared laser light irradiation (A), heat treatment at 90 °C (B), and heat treatment at 80 °C (C). The PEGmodified gold nanorods after near-infrared laser light irradiation (D), heat treatment at 90 °C (E), and heat treatment at 80 °C (F).

the modified PEG chains. After the laser irradiation or the heat treatment, the PEG chains are released from the surface of the gold nanorods because of the retro Diels Alder reaction induced by the heat. If a modified drug was placed on the PEG chain, a drug controlled-release system will be established. At the same time, the surface of the gold nanorods changes to hydrophobic and then forms aggregates. This means that the gold nanorods are accumulated at the irradiated site after systemic injection of the gold nanorods. If this is applied to photothermal therapy, the accumulation will enhance the heating efficiency. To evaluate the aggregate formation of the PEG-DA-modified gold nanorods, we measured the absorption spectra of the gold nanorods after near-infrared laser irradiation (CW nearinfrared laser light at 920 nm, 0.55 mm in diameter) or heat treatment at 90 or 80 °C for 10 min. As shown in Figure 4A C, remarkable decreases of the absorption band at the near-

infrared light region were observed after both cases of laser irradiation and heat treatments. Simultaneously, a new band at 700 nm appeared. The decreases were dependent on the laser exposure time or the time of heat treatment. The light scattering of the PEG-DA-modified gold nanorods increased depending upon the laser exposure time or time of heat treatment (Figure 5A). The time-dependent aggregate formation of the PEG-DA-modified gold nanorods was also observed in the TEM images (Figure 6A D). In the TEM images, aggregations like a raft were observed (Figure 6C E). The formation of aggregation was side-by-side arrangement of the gold nanorods. Coupling of the longitudinal surface plasmon oscillations in the side-by-side arrangement leads to a blue shift as previously reported by Jain et al.49 Therefore, the new band at 700 nm in Figure 4A C would be result of the blue shift of the longitudinal surface plasmon band of the gold nanorods. 14624

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Figure 5. Light-scattering analysis of the PEG- or PEG-DA-modified gold nanorods after near-infrared laser light irradiation or heat treatments. (A) Increases in light scattering in the PEG-DA-modified gold nanorods after near-infrared laser light irradiation (b), heat treatment at 90 °C (9), and heat treatment at 80 °C (2). (B) Increase in light scattering in the PEG-modified gold nanorods after near-infrared laser light irradiation (b), heat treatment at 90 °C (9), and heat treatment at 80 °C (2).

However, in the case of the PEG-modified gold nanorods, no aggregation formation was observed (Figures 3B, 4D F, 5B, and 6F,G). After the laser irradiation, the maximum temperature reached around 80 °C in both the PEG-DA-modified gold nanorods and PEG-modified gold nanorods. In the case of the PEG-DA-modified gold nanorods, the solution temperature after laser irradiation for 10 min reached 80 °C, although the aggregation formation after the laser irradiation was stronger and more rapid than the heat treatment at 80 °C. This result indicates that the actual local temperature of the gold surface was higher than the temperature of the gold nanorod solution. This result is consistent with our previous report;40 that is, even if the solution temperature of the double-stranded oligonucleotidemodified gold nanorods was lower than the melting temperature (Tm) of the modified double-stranded oligonucleotides, release of single-stranded oligonucleotides from the double-stranded oligonucleotides-modified gold nanorods after near-infrared laser light irradiation was clearly observed. 3.4. Quantification of the Release of PEG Chains from the Gold Nanorods after the Laser Irradiation. The released PEG chain was quantified by the Iodine Barium method.37,45 In the case of the PEG-DA-modified gold nanorods, 30 40% of the modified PEG chain was detected in the solution as released PEG after the laser irradiation as shown in Figure 7. This indicated that the release of the PEG chain surely triggered aggregate formation of the gold nanorods since the PEG chains on the gold surface contribute to the dispersion stability of the gold nanorods. However, in the case of the PEG-modified gold nanorods, no release of the PEG chains from the gold surface were detected similarly to what we previously observed.37 Therefore, the release of PEG chains from the PEG-DA-modified gold nanorods was most likely mediated by the retro Diels-Alder reaction induced by the

Figure 6. TEM images of the PEG-DA-modified gold nanorods after near-infrared laser light irradiation or heat treatment. Panels A D show the TEM images of the PEG-DA-modified gold nanorods after the laser irradiation at the exposure times of 0, 1, 5, and 10 min, respectively. Panel E shows the PEG-DA-modified gold nanorods after the heat treatment at 90 °C for 10 min. Panels F and G show the PEG-modified gold nanorods after near-infrared laser light irradiation at the exposure times of 10 min and heat treatment at 90 °C for 10 min, respectively.

Figure 7. Release of PEG chains from the PEG-DA-modified gold nanorods (b) and PEG-modified gold nanorods (9) after near-infrared laser light irradiation.

photothermal effect of the gold nanorods, not by dissociation of the Au S bond or other chemical bonds between the PEG part and the gold surface.

4. CONCLUSION In this study, we prepared PEG-DA-modified gold nanorods. We succeeded in construction of a controlled-release and aggregation technique by combining the cycloadduct of the 14625

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Langmuir Diels Alder reaction and the gold nanorods. Consequently, this technique will provide functional options for achieving an advanced controlled-release system using gold nanorods for drug therapy responding to external stimuli. Moreover, it may be suitable as a new accumulation system for the use of gold nanorods in tumors for effective photothermal therapy.

’ AUTHOR INFORMATION Corresponding Author

*Department of Applied Chemistry, Faculty of Engineering, Kyushu University 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. Tel./Fax: +81 92 802 2851. E-mail: niidome.takuro.655@ m.kyushu-u.ac.jp.

’ ACKNOWLEDGMENT This research was supported by a Grant-in-Aid of Scientific Research (B) (No. 22300158) from the Japan Society for the Promotion of Science (JSPS) and by a grant for Precursory Research for Embryonic Science and Technology (PRESTO) from the Japan Science and Technology Agency (JST). ’ REFERENCES (1) Hernot, S.; Klibanov, A. L. Adv. Drug Delivery Rev. 2008, 60, 1153–1166. (2) Huang, S.-L. Adv. Drug Delivery Rev. 2008, 60, 1167–1176. (3) Guo, X.; Szoka, F. C., Jr. Acc. Chem. Res. 2003, 36, 335–341. (4) Walker, G. F.; Fella, C.; Pelisek, J.; Fahrmeir, J.; Boeckle, S.; Ogris, M.; Wagner, E. Mol. Ther. 2005, 11, 418–425. (5) Freiberg, S.; Zhu., X. X. Int. J. Pharm. 2004, 282, 1–18. (6) Torchilin, V. P. J. Controlled Release 2001, 73, 137–172. (7) Bae, Y.; Fukushima, S.; Harada, A.; Kataoka, K. Angew. Chem., Int. Ed. 2003, 42, 4640–4643. (8) Lee, E. S.; Oh, K. T.; Kim, D.; Youn, Y. S.; Bae, Y. H. J. Controlled Release 2007, 123, 19–26. (9) Meng, F.; Zhong, Z.; Feijen, J. Biomacromolecules 2009, 10, 197–209. (10) Soga, O.; Van Nostrum, C. F.; Fens, M.; Rijcken, C. J. F.; Schiffelers, R. M.; Storm, G.; Hennink, W. E. J. Controlled Release 2005, 103, 341–353. (11) Brazel, C. S. Pharm. Res. 2009, 10, 644–656. (12) Liu, T.-Y.; Hu, S.-H.; Liu, D.-M.; Chen, S.-Y.; Chen, I.-W. Nanotoday 2009, 4, 52–65. (13) Pissuwan, D.; Niidome, T.; Cortie, M. B. J. Controlled Release 2011, 149, 65–71. (14) Timko, B. P.; Dvir, T.; Kohane, D. S. Adv. Mater. 2010, 22, 4925–4943. (15) Ghosh, P.; Han, G.; De, M.; Kim, C. K; Rotello, V. M. Adv. Drug Delivery Rev. 2008, 60, 1307–1315. (16) Sperling, R. A.; Gil, P. R.; Zhang, F.; Zanella, M.; Parak, W. J. Chem. Soc. Rev. 2008, 37, 1896–1908. (17) Giljohann, D. A; Seferos, D. S.; Daniel, W. L.; Massich, M. D.; Patel, P. C; Mirkin, C. A. Angew. Chem., Int. Ed. 2010, 49, 3280–3294. (18) Gerweck, L. E.; Seetharaman, K. Cancer Res. 1996, 56, 1194–1198. (19) Tannock, I. F.; Rotin, D. Cancer Res. 1989, 49, 4373–4384. (20) Ulbrich, K.; Subr, V. Adv. Drug Delivery Rev. 2004, 56, 1023–1050. (21) Hatakeyama, H.; Akita, H.; Kogure, K.; Oishi, M.; Nagasaki, Y.; Kihira, Y.; Ueno, M.; Kobayashi, H.; Kikuchi, H.; Harashima, H. Gene Ther. 2007, 14, 68–77. (22) Harris, T. J.; von Maltzahn, G.; Lord, M. E.; Park, J. H.; Agrawal, A.; Min, D. H.; Sailor, M. J.; Bhatia, S. N. Small 2008, 4, 1307–1312. (23) Lee, S.; Cha, E. J.; Park, K.; Lee, S. Y.; Hong, J. K.; Sun, I. C.; Kim, S. Y.; Choi, K.; Kwon, I. C.; Kim, K.; Ahn, C. H. Angew. Chem., Int. Ed. 2008, 47, 2804–2807.

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