Abstract
Dendrimers have attracted great interest for the design of functional materials. Because the core porphyrin unit in dendrimer porphyrin (DP) is surrounded by large poly(benzyl ether) dendritic wedges with ionic peripheries, the resulting electrostatic interaction with oppositely charged polymeric materials has been used to create various functional nano-devices. In this paper, we briefly review DP-based self-assembled biomedical nano-devices, including DP-loaded polyion complex micelles, the ternary complex systems used for gene delivery, polymer-metal complex micelles, the hollow nanocapsules used for combination cancer therapy, and the DP-immobilized surfaces used for diagnostic tools.
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Introduction
Because of their well-characterized, three-dimensional structure, dendritic macromolecules are of interest for a wide range of applications.1, 2, 3, 4, 5 For biomedical applications in particular, dendrimers are promising materials because functional nano-devices require a controlled three-dimensional architecture with appropriate functional groups at designated sites.6, 7, 8, 9, 10, 11 Because dendrimers are synthesized by precisely controlled stepwise reactions, designers have the freedom to introduce functional groups at specific sites.12, 13, 14 A typical dendrimer comprises three different topological parts: a focal core, layered building blocks, and multiple peripheral groups, which provide fascinating chemical characteristics.15, 16 The focal core can be isolated from the outer environment by large dendritic wedges, the layered building blocks provide the dendrimer with its three-dimensional structure, and the multivalent surface can integrate functionalities in a small space. In addition, only the congested surface functionalities interact with the external environment; therefore, the peripheral functional groups can be used to control the solution properties of the dendrimers.17, 18, 19 To date, a great number of dendritic macromolecules have been developed and investigated. Among them, we have designed poly(benzyl ether) dendrimers with a photofunctional porphyrin or phthalocyanine core for use in biomedical nano-devices. Herein, we review recent research on dendrimer porphyrin-based nano-devices for biomedical applications.
Structure and characteristics of dendrimer porphyrin and phthalocyanine
Synthesizing dendrimer porphyrin (DP) and dendrimer phthalocyanine (DPc) uses convergent synthetic strategies to prepare a defect-free dendritic structure (Scheme 1).20, 21 Because porphyrin and phthalocyanine have unique photofunctional properties, such as a large absorption cross-section, fluorescence emission, and photosensitizing properties, DP and DPc can be used as photofunctional nano-devices.22, 23, 24, 25 Upon excitation by light, porphyrin and phthalocyanine can fluoresce or transfer their excitation energy or an electron to an appropriate acceptor molecule.25 This unique property makes these molecules useful for probing micro-environments or as photosensitizers for photodynamic therapy (PDT).26, 27, 28, 29 However, because porphyrin and phthalocyanine are strongly hydrophobic and because they have a large π conjugation domain, they often form aggregates. Aggregated porphyrin and phthalocyanine eventually lose their photofunctional properties.30 The dendrimer forms of these molecules, DP and DPc, remain soluble in aqueous medium because of the large number of anionic functional groups on their periphery. In addition, large dendritic wedges effectively prevent aggregation.31, 32, 33, 34 The high solubility of DP and DPc permits their use in PDT, a promising technology for less invasive cancer treatments. PDT involves the systemic administration of photosensitizers (PS) followed by the irradiation of the target tissue with laser light. The irradiation excites PSs, which transfer their excitation energy or electrons to oxygen molecules in the target tissue to generate highly toxic reactive oxygen species (ROS). The ROS eventually destroy the target tissue (Figure 1). Because DP and DPc exhibit successful solubility in aqueous medium, we can utilize them as effective PSs. When DP was used as a PS, it exhibited 10–100 times higher photocytotoxicity than protoporphyrin IX, a conventional PS, for treating Lewis lung carcinoma (LLC).33 Moreover, the ionic surfaces of DP and DPc have been used to form polyion complex (PIC) micelles through electrostatic interactions. In vitro and in vivo experiments have demonstrated that PIC micelles are successful formulations for use in PDT.
Formation of DP-loaded PIC micelles
Because the peripheries of DP and DPc contain negatively charged carboxylic acid groups, PIC micelles can be formed through electrostatic interactions with positively charged block copolymers. When DP is mixed with poly(ethylene glycol)-block-poly(L-lysine) (PEG-b-PLL) in a stoichiometric charge ratio, PIC micelles form spontaneously with a diameter of approximately 60 nm (Figure 2).35 The PIC micelles prepared from DP and PEG-b-PLL have an extremely narrow size distribution in physiological saline solution. The spherical shape of DP-incorporated micelles was confirmed by atomic force microscopy (AFM) and field emission-transmission electron microscopy (FE-TEM). Static light scattering (SLS) revealed that each PIC micelle contains an average of 38 DP molecules.35 The PIC micelles remain stable in remarkably high NaCl concentrations. Although the local DP concentration is high in the micellar core, the PIC micelles did not exhibit fluorescent quenching.34 Moreover, fluorescent quenching did not occur when PIC micelles containing DP were incubated with cells, suggesting an effective photochemical reaction in the living cells. These unique photochemical properties might not be achieved with other conventional PSs. We have investigated the efficiency of oxygen depletion under light irradiation. PIC micelles containing DP exhibited an oxygen depletion rate comparable to that of free DP in PBS containing fetal bovine serum (FBS) as a singlet oxygen acceptor, suggesting that the singlet oxygen molecules produced by DP effectively escape the micellar structure and react with proteins in FBS (Figure 3).34 DP-loaded PIC micelles exhibited approximately 280 times higher photocytotoxicity against LLC cells than free, anionic DP, although the cells only take up 6–8 times more DP-incorporated PIC micelles than free anionic DP (Figure 4).34 This strong photocytotoxicity can be explained by a high local concentration of singlet oxygen generation at the local site.
The formation of PIC micelles was again investigated using different generations of DPs. Using small dendrimers to form PIC micelles resulted in aggregates with a large size distribution, indicating that the relatively open architectures and small dendritic wedges may not completely prevent π-π interactions between the porphyrin cores.36 Additionally, aggregates of small dendrimers had shorter fluorescence lifetimes and decreased oxygen depletion. Therefore, we conclude that the dendritic wedges in third-generation DPs might be sufficiently large to prevent focal photosensitizing units in the micellar core from self-quenching. The in vitro PDT effect of various sized DP-loaded micelles has been tested for HeLa (human cervical adenocarcinoma) cells.36 Micelles loaded with third-generation DPs exhibited the highest photocytotoxicity.
To evaluate PDT with DP-loaded micelles in vivo, animal models of exclusive age-related macular degeneration (AMD) were prepared by photocoagulation using semiconductor laser irradiation. AMD, which is caused by abnormal neovascularization (CNV) from the choroidal membrane to the macula, is a major cause of vision loss in developed countries.37 For PDT to be effective against AMD, PSs need to selectively accumulate in CNV lesions.38 PDT was performed using DP-loaded PIC micelles in an AMD model.39 After 7 days of photocoagulation in rats, 400 μl of DP-loaded PIC micelles or free DP (including 1.5 mg ml−1 of DP) was administered by tail vein injection.39 When DP fluorescence was observed in the eyes, DP-loaded micelles effectively and selectively accumulated in the CNV lesions. The selective accumulation of DP-loaded micelles indicates that the CNV lesions may have features similar to solid tumor vasculatures, such as hyperpermeability and impaired lymphatic drainage.40, 41, 42, 43 Additionally, DP-loaded micelle accumulation in CNV lesions significantly enhanced PDT, as confirmed by fluorescein angiography. When the laser irradiation was performed after 15 min of the DP-loaded micelle injection, 78% of fluorescein leakage in the CNV lesions was blocked after 1 day of PDT.39 More importantly, no macroscopic photodamage was observed on the skin when the rats were exposed to broadband visible light after 4 h of the DP-loaded micelles injection (a Xenon lamp equipped with a 377 to 700 nm bandpass filter with power of 30 mW cm−2). In sharp contrast, administering Photofrin, a conventional PS, has resulted in severe skin burns under the same conditions, indicating that DP-loaded micelles may not be hypersensitive to light exposure.
Corneal neovascularization is another major cause of vision loss. A wide range of inflammatory, infectious, degenerative, and traumatic disorders can induce corneal neovascularization. Similar to AMD, DP-loaded micelles selectively accumulate in neovascular corneal tissue. PDT using a fluence of 10 J cm−2 after injecting DP-loaded PIC micelles resulted in complete regression of neovascular lesions after 7 days. From these in vivo results, we conclude that DP has great potential as a PS to treat several ophthalmologic diseases.
Formation of DPc-loaded PIC micelles
Although the aforementioned results indicate that DP has great potential as a PS for PDT in transparent ophthalmologic diseases, the absorption maximum of DP, 430 nm (soret band) and 560 nm (Q band), might limit its use in solid tumors because of problems with light delivery. Melanin dyes in the skin absorb short wavelength light to prevent genetic disorders, and heme proteins in the blood also absorb light in the visible range. Therefore, PSs for solid tumors must absorb long wavelength light that can penetrate deeper lesions. DPc-loaded PIC micelles were prepared and tested in a solid tumor model.28, 44, 45, 46 DPc-loaded micelles, approximately 50 nm in diameter, were prepared from DPc and PEG-b-PLL in a manner similar to the DP-loaded micelles.47 Unlike DP, loading DPc into micelles shifted the absorption maximum from 685 to 630 nm, indicating possible interactions between the phthalocyanine units in the micellar core. The relatively small dendritic wedges in DPc may not be sufficient to prevent such interactions. Consequently, DPc-loaded micelles consume less oxygen than DPc alone.47
DPc-loaded micelles, however, significantly enhanced photocytotoxicity, which relies on the photoirradiation time. DPc-loaded micelles exhibited approximately 100 times higher photocytotoxicity than free DPc upon 60 min of photoirradiation. DPc-loaded PIC micelles were 3.9 times more effective than Photofrin, as indicated by the number of photosensitizing units. Significant differences in the light-induced morphological changes of the cells were observed when the cells were treated with IC99 of DPc or DPc-loaded micelles.48 DPc-loaded PIC micelles induced rapid cell death accompanied by morphological changes, including swelling and membrane blebbing, whereas free DPc induced gradual shrinkage of the cells.
The morphological changes induced by DPc-loaded micelles are characteristic of oncosis, which is induced by several pathological conditions, such as hypoxia, inhibition of ATP production, and increased permeability of the plasma membrane.48 Through detailed observation with a fluorescence microscope, we observed that DPc-loaded micelles induce photodamage to mitochondria, which results in oncosis-like cell death through exhaustion of ATP. In addition to the unique intracellular localization and photochemical reactions, the high local concentration of DPc in the micellar core may also contribute to the high PDT efficiency. The high local concentration of DPc might generate a high local concentration of ROS, generating enough photochemical oxidation to exceed the threshold of cell death.49
To test phototoxicity induced by DPc-loaded micelles in vivo, mice with subcutaneous A549 tumors received DPc-loaded micelles (0.37 μmol kg−1), free DPc, or Photofrin (2.7 μmol kg−1) through tail vain injection.49 The tumor volumes were monitored after the PDT treatment. DPc-loaded micelles exhibited significantly higher antitumor activity than DPc or Photofrin. Furthermore, the DPc-loaded micelle dose, in PS units, was 7.3 times lower than that of Photofrin (Figure 5). The enhanced PDT efficacy of DPc-loaded micelles might be attributed to their increased accumulation in tumors and enhanced photocytotoxicity. Similar to DP-loaded micelles, DPc-loaded micelles resulted in minimal skin toxicity upon broadband white light irradiation. DP- and DPc-loaded micelles may produce low phototoxicity in the skin because fewer of the micelles accumulate in the skin and other normal organs.
Irradiating PSs with light generates ROS, which disrupt tissues and organelles. PSs then accumulate in endo/lysosomal compartments, and photoirradiation selectively disrupts the endo/lysosomal lipid bilayer. Recently, this concept has been applied to drug delivery.50 Because the endosomal escape of drugs is a major obstacle in drug delivery for drugs that are taken up by endocytosis, light-induced drug delivery would allow for site-specific drug delivery. Cells take up DPc-loaded PIC micelles through endocytosis; therefore, DPc-loaded PIC micelles are preferentially localized in the endo/lysosomes. Upon photoirradiation, DPc-loaded PIC micelles disrupt the endo/lysosomal membranes and translocate to other organelles.
This concept has been used for the light-induced delivery of several compounds, including plasmid DNA (pDNA) and camptothecin (CPT), to the cytoplasm. The light dose for light-induced drug delivery is much lower than that for PDT. Light-induced transfection was performed using a combination of micelles loaded with DPc and pDNA. Transgene expression increased 100-fold while maintaining 80% cell viability.50 More recently, a polymeric micelle containing CPT, a hydrophobic anticancer agent, was designed as a stimulus-responsive drug carrier. CPT is covalently conjugated to block copolymers via a disulfide bond, which is cleaved under reductive conditions in the cytosol. To evaluate in vitro cytotoxicity, HeLa cells were incubated with CPT-loaded micelles and a non-toxic concentration of DPc-loaded PIC micelles.51 Upon light irradiation, the CPT-loaded micelles internalized and the disulfide bonds were cleaved, significantly enhancing the cytotoxicity of the CPT (Figure 6). Photo-induced drug delivery has an added benefit of controlling drug localization in the body. In addition, a strong potential exists for overcoming the multidrug resistance present in many in vivo tumor models.
Ternary complex system for gene delivery
To deliver genes, ternary complexes composed of pDNA, quadruple cationic Tat peptide (CP4), and DPc have been designed (Figure 7).52 The ternary complex was prepared by simply adding DPc to the cationic pDNA–CP4 complex, which was obtained by mixing pDNA and CP4 with negative and positive charge in a 1:2 ratio. Adding DPc to the cationic pDNA–CP4 complex creates a ternary complex 130 nm in diameter with a narrow size distribution.52 In contrast, linear poly(aspartic acid) (degree of polymerization=26) does not form spherical nanoparticles when added to pDNA–CP4 complexes, suggesting that the three-dimensional structure of DPc plays an essential role in forming the ternary complex. The ternary complex enhanced in vitro transgene expression more than 100-fold following light irradiation, without severe photocytotoxicity. In contrast, AlPcS2a (aluminum phthalocyanine with two sulfonate groups) mixed with the pDNA–CP4 complex, causing severe cytotoxicity, possibly because of the non-selective adhesion of AlPcS2a to cells. The ternary complex was used for subconjunctival injection in rats and was irradiated with a semiconductor laser (689 nm) 2 h after injection. The gene, encoding a fluorescent protein, was only expressed at the laser-irradiated site in the conjunctiva, indicating that we can control gene expression in a light-directed manner.
Transgene expression by the ternary complex can be explained by the following mechanism (Figure 8): Cells internalize the ternary complex through endocytosis. Once internalized, DPc is released from the ternary complex as its peripheral carboxyl groups are protonated under the acidic conditions in the endosome. The hydrophobic nature of the dendritic framework causes DPc to then associate with the endosomal membrane. Finally, light-induced disruption of the endosomal membrane allows the pDNA–CP4 complex to escape to the cytosol. The Tat peptides in CP4 then transport the pDNA to the nucleus.
Polymer-metal complex micelle
Although PDT is a promising technology to treat malignant tumors, improving its effectiveness could expand its application to a wide range of cancer modalities. In this regard, several nano-devices have been designed for combination cancer therapy. Recently, we designed polymer-metal complex micelles (PMCM) by coordinating cisplatin [cis-dichlorodiammineplatinum (II); CDDP] with DPc and poly(ethylene glycol)-block-poly(L-aspartic acid) (PEG-b-PLA, n; molecular weight of the PEG segment=12 000 g mol−1; polymerization degrees of the aspartic acid segment n=68, 96).45, 53, 54 The formation of PMCMs was confirmed by TEM and LLS, where PMCM68 and PMCM96 were 97 and 140 nm in diameter, respectively (Figure 9).54 The PMCMs were highly stable in 10 mM PBS without NaCl and maintained their shape and size for over a month. The PMCMs slowly released CDDP in physiological PBS at 37 °C. Under pulsed laser light (615 nm), the PMCMs generated singlet oxygen, which was evidenced by the photo-luminescence from the singlet oxygen at 1270 nm (Figure 9). Because the PMCMs exhibited sustained release of CDDP with generation of singlet oxygen, they are potential biomedical nano-device for combination therapy.
LbL nanocapsules for combination therapy
Recently, we reported a new hollow nanocapsule (NC) as a biomedical nano-device for combination cancer therapy.55 Hollow NCs were designed using layer-by-layer (LbL) deposition of polyelectrolytes on a sacrificial template.56, 57 DP and poly(allylamine hydrochloride) (PAH) were used as negative and positive electrolytes, respectively.58 PAH and DP were alternatively deposited on a negatively charged polystyrene (PS) nanoparticle, which was removed to form a hollow structure (Figure 10). The stepwise formation of multilayer shells on PS was monitored by the ζ-potential of the particles after each deposition. The deposition of PAH and DP results in discrete ζ-potential values, alternatively positive or negative, depending on the outermost layer.58 Formation of the multilayer can also be monitored by changes in the UV-Vis absorbance and FL emission because of the strong UV-Vis absorption and fluorescence emission properties of DP. TEM and FE-SEM were used to directly observe the formation of the multilayered hollow NCn (n=numbers of LbL bilayer) (Figure 11). Even a single bilayer had sufficient stability to maintain its globular shape after the template PS nanoparticle was removed. Drug encapsulation was tested using doxorubicin hydrochloride (DOX). Through a simple diffusion method, a large amount of DOX was encapsulated in a time-dependent manner. To control the drug release, the shells were crosslinked using N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). As a result, the release rate of DOX depended on the degree of cross-linking. When light irradiated this NC, it was strongly photocytotoxic, indicating that NCs can be successfully used as photosensitizers for PDT. When light irradiated NCs with DOX, they were much more cytotoxic than either chemotherapy or PDT alone, indicating that NCs are possible nano-devices for combinational cancer therapy.
DP-immobilized surfaces for diagnostic tools
Protein microarrays are a promising technology for protein-based high-throughput assays to analyze interactions between proteins and analytes.59, 60, 61, 62, 63 To design protein microarrays, we used DP as a protein support because the many carboxylic acid moieties on the periphery can effectively immobilize target proteins. DP-coated surfaces can load more proteins and more protein activity than planar surfaces.64, 65, 66, 67 Furthermore, we determined the relative amounts of dendrimer immobilized on the surface and monitored the enzyme-catalyzed reactions using fluorescence microscopy by means of the fluorescent properties of the DP.66 To prepare a DP-coated surface, the surface of a silicon wafer was covered with positively charged amine groups using 3-aminopropyltriethoxysilane deposited DP via electrostatic interaction in a silanization reaction (Figure 12). FITC-labeled bovine serum albumin (FITC-BSA) or glucose oxidase (GOx) was then immobilized on the DP-coated surface using EDC/NHS chemistry. The DP-coated surface had a higher loading efficacy than the linear poly(acrylic acid)-immobilized surface control. More interestingly, we could directly observe GOx activity from the fluorescence emission intensity of DP. Increasing the glucose concentration caused a gradual decrease in the fluorescence emission intensity of DP. This unique property can be used to develop glucose sensors for medical and industrial applications.
As another application, we prepared patterned protein microarrays for immunoassays using the LbL technique and used DP to immobilize the proteins on the substrate (Figure 13).67
By combining spin-assisted LbL self-assembly and the lift-off method, micropatterns can be fabricated that consist of multilayer films. DP was immobilized on these micropatterns via electrostatic adsorption, and the fluorescence intensity was confirmed by microscopy and AFM. Finally, immunoglobulin was immobilized on the DP-immobilized micropatterns using EDC/NHS chemistry. The DP-immobilized micropatterns exhibited significantly enhanced protein-loading efficacy.67 Furthermore, the microarray prepared by combining the multilayer micropatterns and DP exhibited drastically improved sensitivity as immunosensors compared with conventional systems.
Conclusions
In this paper, we have briefly reviewed recent research related to DP and DPc applications in biomedical fields. Owing to the unique photophysical properties of porphyrin and phthalocyanine in the cores, we have successfully used DP and DPc as photosensitizers for PDT. Moreover, the multivalent functionality on the periphery can be used to build up various nano-devices, including PIC micelles, ternary complexes, PMCMs, hollow NCs, and protein arrays. These unique applications of DP and DPc cannot be achieved using linear polymeric materials. We expect that the continuous effort in designing dendritic materials will be justified and will open a new paradigm in the design of biomedical nano-devices.
References
Newkome, G. R., Moorefield, C. N. & Voegtle, F. Dendrimers and Dendrons: Concepts, Syntheses, Applications, Wiley-VCH, Weinheim, (2001).
Fréchet, J. M. J. & Tomalia, D. A. Dendrimers and other Dendritic Polymers, Wiley-VCH, New York, (2001).
Bosman, A. W., Janssen, H. M. & Meijer, E. W. About dendrimers: structure, physical properties, and applications. Chem. Rev. 99, 1665–1688 (1999).
Lee, I., Athey, B. D., Wetzel, A. W., Meixner, W. & Baker, J. R. Structural molecular dynamics studies on polyamidoamine dendrimers for a therapeutic application: effects of pH and generation. Macromolecules 35, 4510–4520 (2002).
Roy, R., Zanini, D., Meunier, S. J. & Romanowska, A. Solid-phase synthesis of dendritic sialoside inhibitors of influenza A virus haemagglutinin. J. Chem. Soc. Chem. Commun. 1869–1872 (1993).
Jang, W.-D. & Kataoka, K. Bioinspired applications of functional dendrimers. J. Drug Del. Sci. Tech 15, 19–30 (2005).
Wiener, E. C., Brechbiel, M. W., Brothers, H., Magin, R. L., Gansow, O. A., Tomalia, D. A. & Lauterbur, P. C. Dendrimer-based metal chelates: a new class of magnetic resonance imaging contrast agents. Magn. Reson. Med. 31, 1–8 (1994).
Aulenta, F., Hayes, W. & Rannard, S. Dendrimers: a new class of nanoscopic containers and delivery devices. Eur. Polym. J. 39, 1741–1771 (2003).
Stiriba, S.-E., Frey, H. & Haag, R. Dendritic polymers in biomedical applications: from potential to clinical use in diagnostics and therapy. Angew. Chem. Int. Ed. 41, 1329–1334 (2002).
Patri, A. K., Majoros, I. J. & Baker, J. R. Dendritic polymer macromolecular carriers for drug delivery. Curr. Opin. Chem. Biol. 6, 466–471 (2002).
Boas, U. & Heegaard, P. M. H. Dendrimers in drug research. Chem. Soc. Rev. 33, 43–63 (2004).
Gorman, C. Metallodendrimers: Structural diversity and functional behavior. Adv. Mater. 10, 295–309 (1998).
Zeng, F. & Zimmerman, S. C. Dendrimers in supramolecular chemistry: From molecular recognition to self-assembly. Chem. Rev. 97, 1681–1712 (1997).
Fischer, M. & Vögtle, F. Dendrimers: From design to application—A progress report. Angew. Chem., Int. Ed. 38, 884–905 (1999).
Tekade, R. K., Kumar, P. V. & Jain, N. K. Dendrimers in oncology: an expanding horizon. Chem. Rev. 109, 49–87 (2009).
Mintzer, M. A. & Grinstaff, M. W. Biomedical applications of dendrimers: a tutorial. Chem. Soc. Rev. 40, 173–190 (2011).
Liu, M., Kono, K. & Fréchet, J. M. J. Water-soluble dendritic unimolecular micelles: Their potential as drug delivery agents. J. Control. Release 65, 121–131 (2000).
Stevelmans, S., van Hest, J. C. M., Jansen, J. F. G. A., van Boxtel, D. A. F. J., de Brabander-van den Berg, E. M. M. & Meijer, E. W. Synthesis, characterization, and guest–host properties of inverted unimolecular dendritic micelles. J. Am. Chem. Soc. 118, 7398–7399 (1996).
Gupta, U., Agashe, H. B., Asthana, A. & Jain, N. K. Dendrimers: novel polymeric nanoarchitectures for solubility enhancement. Biomacromolecules 7, 649–658 (2006).
Grayson, S. M. & Fréchet, J. M. J. Convergent dendrons and dendrimers: From synthesis to applications. Chem. Rev. 101, 3819–3867 (2001).
Sadamoto, R., Tomioka, N. & Aida, T. Photoinduced electron transfer reactions through dendrimer architecture. J. Am. Chem. Soc. 118, 3978–3979 (1996).
Pushpan, S. K., Venkatraman, S., Anand, V. G., Sankar, J., Parmeswaran, D., Ganesan, S. & Chandrashekar, T. K. Porphyrins in photodynamic therapy—A search for ideal photosensitizer. Curr. Med. Chem.: Anti-Cancer Agents 2, 187–207 (2002).
Sessler, J. L. & Weghorn, S. J. Expanded, Contracted and Isomeric Porphyrins, Elsevier, Oxford, (1997) and references therein.
Sessler, J. L., Gebauer, A. & Weghorn, S. J. in Expanded Porphyrins in the Porphyrin Handbook eds. K. M. Kadish, K. M. Smith, R. Guilard Vol. 2, 157–230 Academic Press, New York, (2000).
Martinez-Diaz, M. V., de la Torre, G. & Torres, T. Lighting porphyrins and phthalocyanines for molecular photovoltaics. Chem. Commun. 46, 7090–7108 (2010).
O’Connor, A. E., Byrne, A. T. & Gallagher, W. M. Porphyrin and non-porphyrin photosensitizers in oncology: pre-clinical and clinical advances in photodynamic therapy. Photochem. Photobiol. 85, 1053–1074 (2009).
Macdonald, I. J. & Dougherty, T. J. Basic principles of photodynamic therapy. J. Porphyr. Phthalocya. 5, 105–129 (2001).
Lukyanets, E. A. Phthalocyanines as photosensitizers in the photodynamic therapy of cancer. J. Porphyr. Phthalocya. 3, 424–432 (1999).
Ethirajan, M., Chen, Y., Joshi, P. & Pandey, R. K. The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem. Soc. Rev. 40, 340–362 (2011).
Gerhardt, S. A., Lewis, J. W., Kliger, D. S., Zhang, J. Z. & Simonis, U. Effect of micelles on oxygen-quenching processes of triplet-state para-substituted tetraphenylporphyrin photosensitizers. J. Phys. Chem. A 107, 2763–2767 (2003).
Sato, T., Jiang, D. L. & Aida, T. A. Blue-luminescent dendritic rod: Poly(phenyleneethynylene) within a light-harvesting dendritic envelope. J. Am. Chem. Soc. 121, 10658–10659 (1999).
Nishiyama, N., Stapert, H. R., Zhang, G.-D., Takasu, D., Jiang, D.-L., Nagano, T., Aida, T. & Kataoka, K. Light-harvesting ionic dendrimer porphyrins as new photosensitizers for photodynamic therapy. Bioconjugate Chem. 14, 58–66 (2003).
Zhang, G.-D., Harada, A., Nishiyama, N., Jiang, D.-L., Koyama, H., Aida, T. & Kataoka, K. Polyion complex micelles entrapping cationic dendrimer porphyrin: effective photosensitizer for photodynamic therapy of cancer. J. Controlled Release 93, 141–150 (2003).
Jang, W.-D., Nishiyama, N., Zhang, G.-D., Harada, A., Jiang, D.-L., Kawauchi, S., Morimoto, Y., Kikuchi, M., Koyama, H., Aida, T. & Kataoka, K. Supramolecular nanocarrier of anionic dendrimer porphyrins with pegylated cationic block copolymer to enhance intracellular photodynamic efficacy. Angew. Chem., Int. Ed. 44, 419–423 (2005).
Stapert, H. R., Nishiyama, N., Jiang, D.-L., Aida, T. & Kataoka, K. Polyion complex micelles encapsulating light-harvesting ionic dendrimer zinc porphyrins. Langmuir 16, 8182–8188 (2000).
Li, Y., Jang, W.-D., Nishiyama, N., Kishimura, A., Kawauchi, S., Morimoto, Y., Miake, S., Yamashita, T., Kikuchi, M., Aida, T. & Kataoka, K. Dendrimer generation effects on photodynamic efficacy of dendrimer porphyrins and dendrimer-loaded supramolecular nanocarriers. Chem. Mater. 19, 5557–5562 (2007).
Renno, R. Z. & Miller, J. W. Photosensitizer delivery for photodynamic therapy of choroidal neovascularization. Adv. Drug. Deliv. Rev. 52, 63–78 (2001).
TAP and VIP Study Group. Guidelines for using Verteporfin in photodynamic therapy to treat choroidal neovascularization due to age related macular degeneration and other causes. Retina 22, 6–18 (2002).
Ideta, R., Tasaka, F., Jang, W.-D., Nishiyama, N., Zhang, G.-D., Harada, A., Yanagi, Y., Tamaki, Y., Aida, T. & Kataoka, K. Nanotechnology-based photodynamic therapy for neovascular disease using a supramolecular nanocarrier loaded with a dendritic photosensitizer. Nano Lett. 5, 2426–2431 (2005).
Nishiyama, N., Okazaki, S., Cabral, H., Miyamoto, M., Kato, Y., Sugiyama, Y., Nishio, K., Matsumura, Y. & Kataoka, K. Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. Cancer Res. 63, 8977–8983 (2003).
Kwon, G., Suwa, S., Yokoyama, M., Okano, T., Sakurai, Y. & Kataoka, K. Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly(ethylene oxide-aspartate) block copolymer-adriamycin conjugates. J. Control. Release 29, 17–23 (1994).
Yokoyama, M., Okano, T., Sakurai, Y., Fukushima, S., Okamoto, K. & Kataoka, K. Selective delivery of adiramycin to a solid tumor using a polymeric micelle carrier system. J. Drug Target 7, 171–186 (1999).
Ideta, R., Yanagi, Y., Tamaki, Y., Tasaka, F., Harada, A. & Kataoka, K. Effective accumulation of polyion complex micelle to experimental choroidal neovascularization in rats. FEBS Letters 557, 21–25 (2004).
Lo, P.-C., Huang, J.-D., Cheng, D. Y. Y., Chan, E. Y. M., Fong, W.–P., Ko, W.-H. & Ng, D. K. P. New amphiphilic silicon(IV) phthalocyanines as efficient photosensitizers for photodynamic therapy: Synthesis, photophysical properties, and in vitro photodynamic activities. Chem. Eur. J. 10, 4831–4838 (2004).
Ng, A. C. H., Li, X. & Ng, D. K. P. Synthesis and photophysical properties of nonaggregated phthalocyanines bearing dendritic substituents. Macromolecules 32, 5292–5298 (1999).
Sheng, Z., Ye, X., Zheng, Z., Yu, S., Ng, D. K. P., Ngai, T. & Wu, C. Transient absorption and fluorescence studies of disstacking phthalocyanine by poly(ethylene oxide). Macromolecules 35, 3681–3685 (2002).
Jang, W.-D., Nakagishi, Y., Nishiyama, N., Kawauchi, S., Morimoto, Y., Kikuchi, M. & Kataoka, K. Polyion complex micelles for photodynamic therapy: incorporation of dendritic photosensitizer excitable at long wavelength relevant to improved tissue-penetrating property. J. Control. Release 113, 73–79 (2006).
Nishiyama, N., Nakagishi, Y., Morimoto, Y., Lai, P.-S., Miyazaki, K., Urano, K., Horie, S., Kumagai, M., Fukushima, S., Cheng, Y., Jang, W.-D., Kikuchi, M. & Kataoka, K. Enhanced photodynamic cancer treatment by supramolecular nanocarriers charged with dendrimer phthalocyanine. J. Control. Release 133, 245–251 (2009).
Majno, G. & Joris, I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am. J. Phathol 146, 3–15 (1995).
Nishiyama, N. Photochemical enhancement of transgene expression by polymeric micelles incorporating plasmid DNA and dendrimer-based photosensitizer. J. Drug Targeting 14, 413–424 (2006).
Cabral, H., Nakanishi, M., Kumagai, M., Jang, W.-D., Nishiyama, N. & Kataoka, K. A photo-activated targeting chemotherapy using glutathione sensitive camptothecin-loaded polymeric micelles. Pharm. Res. 26, 82–92 (2009).
Nishiyama, N., Iriyama, A., Jang, W.-D., Miyata, K., Itaka, K., Inoue, Y., Takahashi, H., Yanagi, Y., Koyama, H. & Kataoka, K. Light-induced gene transfer from packaged DNA enveloped in a dendrimeric photosensitizer. Nat. Mater. 4, 934–941 (2005).
Koide, A., Kishimura, A., Osada, K., Jang, W.-D., Yamasaki, Y. & Kataoka, K. Semipermeable polymer vesicle (PICsome) self-assembled in aqueous medium from a pair of oppositely charged block copolymers: physiologically stable Micro-/Nano-Containers of water-soluble macromolecules. J. Am. Chem. Soc. 128, 5988–5989 (2006).
Kim, J., Yoon, H.-J., Kim, S., Wang, K., Ishii, T., Kim, Y.-R. & Jang, W.-D. Polymer-metal complex micelles for the combination of sustained drug releasing and photodynamic therapy. J. Mater. Chem. 19, 4627–4632 (2009).
Liu, X. Y., Gao, C. Y., Shen, J. C. & Mohwald, H. Multilayer microcapsules as anti-cancer drug delivery vehicle: deposition, sustained release, and in vitro bioactivity. Macromol. Biosci. 5, 1209–1219 (2005).
De Cock, L. J., De Koker, S., De Geest, B. G., Grooten, J., Vervaet, C., Remon, J. P., Sukhorukov, G. B. & Antipina, M. N. Polymeric multilayer capsules in drug delivery. Angew. Chem., Int. Ed. 49, 6954–6973 (2010).
Delcea, M., Yashchenok, A., Videnova, K., Kreft, O., Mohwald, H. & Skirtach, A. G. Multicompartmental micro- and nanocapsules: Hierarchy and applications in biosciences. Macromol. Biosci. 10, 465–474 (2010).
Son, K. J., Yoon, H.-J., Kim, J.-H., Jang, W.-D., Lee, Y. & Koh, W.-G. Photosensitizing hollow nanocapsules for combination cancer therapy. Angew. Chem., Int. Ed. 50, 11968–11971 (2011).
Hartmann, M., Roeraade, J., Stoll, D., Templin, M. & Joos, T. Protein microarrays for diagnostic assays. Anal. Bioanal. Chem. 393, 1407–1416 (2009).
Hu, Y., Uttamchandani, M. & Yao, S. Q. Microarray: a versatile platform for high-throughput functional proteomics. Comb. Chem. High Throughput Screening 9, 203–212 (2006).
MacBeath, G. & Schreiber, S. L. Printing proteins as microarrays for high-throughput function determination. Science 289, 1760–1763 (2000).
Mitchell, P. A perspective on protein microarrays. Nat. Biotechnol. 20, 225–229 (2002).
Arenkov, P., Kukhtin, A., Gemmell, A., Voloshchuk, S., Chupeeva, V. & Mirzabekov, A. Protein microchips: use for immunoassay and enzymatic reactions. Anal. Biochem. 278, 123–131 (2000).
Ajikumar, P. K., Kiat, J., Tang, Y. C., Lee, J. Y., Stephanopoulos, G. & Too, H. P. Carboxyl-terminated dendrimer-coated bioactive interface for protein microarray: High-sensitivity detection of antigen in complex biological samples. Langmuir 23, 5670–5677 (2007).
Pathak, S., Singh, A. K., McElhanon, J. R. & Dentinger, P. M. Dendrimer-activated surfaces for high density and high activity protein chip applications. Langmuir 20, 6075–6079 (2004).
Lee, Y., Kim, J., Kim, S., Jang, W.-D., Park, S. & Koh, W.-G. Protein-conjugated, glucose-sensitive surface using fluorescent dendrimer porphyrin. J. Mater. Chem. 19, 5643–5647 (2009).
Son, K. J., Kim, S., Kim, J.-H., Jang, W.-D., Lee, Y. & Koh, W.-G. Dendrimer porphyrin-terminated polyelectrolyte multilayer micropatterns for a protein microarray with enhanced sensitivity. J. Mater. Chem. 20, 6531–6538 (2010).
Acknowledgements
This work was supported by a National Research Foundation (NRF) grant funded by the Korean government (MEST) (no. 2011-0001126). Y.-H. Jeong and H.-J. Yoon acknowledge fellowships from the BK21 program supported by MEST, Korea.
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Jeong, YH., Yoon, HJ. & Jang, WD. Dendrimer porphyrin-based self-assembled nano-devices for biomedical applications. Polym J 44, 512–521 (2012). https://doi.org/10.1038/pj.2012.20
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DOI: https://doi.org/10.1038/pj.2012.20