新型树状大分子前药的设计与合成
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摘要
树状大分子由于其独特的结构与性能，如单分散性、纳米级尺寸、规整的结构、丰富的表面官能团和特定的内部空穴，使其在催化、光电材料、药物传递等众多领域受到了广泛的关注。作为药物载体，树状大分子有其独特的优势，它们可以通过多种途径与药物分子作用，如包合、表面键连等。本论文的工作就是利用上述优点来制备树状大分子前药。
1.我们对整个树状大分子研究领域做了广泛的调研，对树状大分子的结构与性质、合成方法以及应用，特别是在医药和生物技术领域中的应用做了回顾与总结。在此基础上，我们提出了课题设计的主体框架。
2.为了能够更有效地合成所需要的树状大分子前药，我们对合成方法和合成途径做了探索性试验。以邻甲氧基苯甲酸为药物模拟物，合成了3代的树枝元和3代的树状大分子，并对合成过程中的关键酯化步骤做了充分的条件筛选，找到了酯化的最佳条件，即DCC/DPTS体系。此外，发散法被证明更有利于得到高代数的树状大分子。
3.非甾体抗炎药树状大分子前药的合成。首先，将布洛芬或者阿司匹林连接到酒石酸二苄酯的其中一个羟基上，得到单羟基酯，然后用该结构单体与多元酸中心核反应，再经去保护与偶联反应，得到了两种2代的布洛芬树状大分子前药和一种2代的阿司匹林树状大分子前药；另外，我们还对两种1代的布洛芬树状大分子前药的表面基团做了修饰，得到了载药量更高的前药。值得指出的是，酒石酸的多官能团特点赋予了结构单体的多样性，这样不仅可以得到许多内外连有相同药物分子的树状大分子前药，而且还可以依据药物拼合原理将不同的药物连接到树状大分子的骨架上，且能很方便地调控药物分子在树状大分子骨架结构中的位置。这种基于酒石酸的树状大分子前药的设计思想未见文献报道，使得我们所合成的这些树状大分子前药具有一定的新颖性。
4.一氧化氮释放型非甾体抗炎药树状大分子前药的合成。采用三组分的Passerini反应将表面为羧基的树状大分子、布洛芬或者阿司匹林的醛类衍生物以及连有硝酸酯基团的异腈化合物经“一锅法”组合到一起，得到了4个一氧化氮释放型非甾体抗炎药树状大分子前药。多组分反应是获得分子多样性的有效途径，已经被用于组合化学中药物库的合成。然而，以树状大分子或者是其它高分子为载体，通过多组分反应来构建大分子或者高分子前药却未见文献报道。通过这一途径，我们可以将药物拼合原理、前药原理和载体药物设计理论融合到一步反应中，从而极大地促进新药，特别是新型药物传递系统的开发进程。因此，不管是从研究价值还是从应用前景来看，开展基于多组分反应的树状大分子前药的研究都具有深远的意义。
Dendrimers have attracted much attention in the fields of, for example, catalysis,electrooptic materials and drug delivery due to their unique properties such asmonodispersity, nanoscale sizes, well-defined structures, plenty of terminal surfacegroups and specific cavities in the interior. As drug carriers, dendrimers havedistinctive advantages and can interact with drugs via encapsulation, attachment ontothe surface etc. This thesis focuses on the preparation of dendritic prodrugs.
1. An extensive survey has been done for dendrimers, in which the profiles ofstructures, chemophysical properties, synthetic approaches, and applicationsespecially in medicine and biotechnology have been reviewed. Thereafter, a projecton dendritic prodrugs was proposed based on this survey.
2. In order to get these desired dendritic prodrugs some preliminary experimentswere carried out to find out the optimized routes and methods. In the exploration, onethird-generation dendron and one dendrimer with the same generation were obtainedusing2-methoxybenzoic acid as a drug surrogate. Meanwhile, it was found thatDCC/DPTS was the optimum condition for the key esterification step. Moreover, incontrast to the convergent approach, the divergent one proved itself a better way tosynthesize higher generation dendrimers.
3. Synthesis of dendritic prodrugs incorpoarting non-steroidal anti-inflammatorydrugs (NSAIDs). Initially, the reaction of dibenzyl tartrate with ibuprofen or aspirinyielded a certain monomer with only one hydroxyl group which was subsequentlycoupled to the multi-carboxylic acid core, and then the product obtained wassubjected to hydrogenolysis and coupled with the monomer again. In this iterativeway, two ibuprofen dendritic prodrugs of generation2and one aspirin dendriticprodrugs of the same generation were produced. At the same time, two dendriticprodrugs with higher drug payload were obtained through the reaction ofbromomethyl ibuprofen with the carboxyl groups on the surface of two kinds offirst-generation ibuprofen dendritic prodrugs. It is noteworthy that themulti-functionality of tartaric acid makes itself versatile, which allows for thepreparation of dendritic prodrugs with the same drugs in the interior and at theperiphery of dendrimers, as well as dendritic prodrugs with different drugsincorporated into the dendrimer scaffolds just by using different monomers. So far the dendritic prodrugs based on tartaric acid have not been reported.
4. Synthesis of dendritic prodrugs conjugated with both nitric oxide(NO)-releasing moieties and non-steroidal anti-inflammatory drugs (also referred toas NO-NSAID dendritic prodrugs). Four NO-NSAID dendritic prodrugs weresynthesized through the way that dendrimers with surface carboxyl groups,aldehydes derived from ibuprofen or aspirin and the isocyanide coupled to anorganic nitrate were combined together via Passerini reaction, a “one-pot” reactioninvolving three components. Now multi-component reactions are among the mostefficient tools for the construction of drug candidate library in combinatorialchemistry. However, there is no report on the preparation of dendritic ormacromolecular prodrugs via a multi-component reaction using dendrimers or anyother macromolecules as carriers. Admittedly, this strategy can take combinationprinciples, prodrug principles and theory of drug-carrier design into a single reaction,which will probably boost the drug development, and particularly the research anddevelopment of drug delivery systems. To sum up, it deserves to make efforts toapply more multi-component reactions to the synthesis of dendritic prodrugs fromthe views of both academics and industry.
1.我们对整个树状大分子研究领域做了广泛的调研，对树状大分子的结构与性质、合成方法以及应用，特别是在医药和生物技术领域中的应用做了回顾与总结。在此基础上，我们提出了课题设计的主体框架。
2.为了能够更有效地合成所需要的树状大分子前药，我们对合成方法和合成途径做了探索性试验。以邻甲氧基苯甲酸为药物模拟物，合成了3代的树枝元和3代的树状大分子，并对合成过程中的关键酯化步骤做了充分的条件筛选，找到了酯化的最佳条件，即DCC/DPTS体系。此外，发散法被证明更有利于得到高代数的树状大分子。
3.非甾体抗炎药树状大分子前药的合成。首先，将布洛芬或者阿司匹林连接到酒石酸二苄酯的其中一个羟基上，得到单羟基酯，然后用该结构单体与多元酸中心核反应，再经去保护与偶联反应，得到了两种2代的布洛芬树状大分子前药和一种2代的阿司匹林树状大分子前药；另外，我们还对两种1代的布洛芬树状大分子前药的表面基团做了修饰，得到了载药量更高的前药。值得指出的是，酒石酸的多官能团特点赋予了结构单体的多样性，这样不仅可以得到许多内外连有相同药物分子的树状大分子前药，而且还可以依据药物拼合原理将不同的药物连接到树状大分子的骨架上，且能很方便地调控药物分子在树状大分子骨架结构中的位置。这种基于酒石酸的树状大分子前药的设计思想未见文献报道，使得我们所合成的这些树状大分子前药具有一定的新颖性。
4.一氧化氮释放型非甾体抗炎药树状大分子前药的合成。采用三组分的Passerini反应将表面为羧基的树状大分子、布洛芬或者阿司匹林的醛类衍生物以及连有硝酸酯基团的异腈化合物经“一锅法”组合到一起，得到了4个一氧化氮释放型非甾体抗炎药树状大分子前药。多组分反应是获得分子多样性的有效途径，已经被用于组合化学中药物库的合成。然而，以树状大分子或者是其它高分子为载体，通过多组分反应来构建大分子或者高分子前药却未见文献报道。通过这一途径，我们可以将药物拼合原理、前药原理和载体药物设计理论融合到一步反应中，从而极大地促进新药，特别是新型药物传递系统的开发进程。因此，不管是从研究价值还是从应用前景来看，开展基于多组分反应的树状大分子前药的研究都具有深远的意义。
Dendrimers have attracted much attention in the fields of, for example, catalysis,electrooptic materials and drug delivery due to their unique properties such asmonodispersity, nanoscale sizes, well-defined structures, plenty of terminal surfacegroups and specific cavities in the interior. As drug carriers, dendrimers havedistinctive advantages and can interact with drugs via encapsulation, attachment ontothe surface etc. This thesis focuses on the preparation of dendritic prodrugs.
1. An extensive survey has been done for dendrimers, in which the profiles ofstructures, chemophysical properties, synthetic approaches, and applicationsespecially in medicine and biotechnology have been reviewed. Thereafter, a projecton dendritic prodrugs was proposed based on this survey.
2. In order to get these desired dendritic prodrugs some preliminary experimentswere carried out to find out the optimized routes and methods. In the exploration, onethird-generation dendron and one dendrimer with the same generation were obtainedusing2-methoxybenzoic acid as a drug surrogate. Meanwhile, it was found thatDCC/DPTS was the optimum condition for the key esterification step. Moreover, incontrast to the convergent approach, the divergent one proved itself a better way tosynthesize higher generation dendrimers.
3. Synthesis of dendritic prodrugs incorpoarting non-steroidal anti-inflammatorydrugs (NSAIDs). Initially, the reaction of dibenzyl tartrate with ibuprofen or aspirinyielded a certain monomer with only one hydroxyl group which was subsequentlycoupled to the multi-carboxylic acid core, and then the product obtained wassubjected to hydrogenolysis and coupled with the monomer again. In this iterativeway, two ibuprofen dendritic prodrugs of generation2and one aspirin dendriticprodrugs of the same generation were produced. At the same time, two dendriticprodrugs with higher drug payload were obtained through the reaction ofbromomethyl ibuprofen with the carboxyl groups on the surface of two kinds offirst-generation ibuprofen dendritic prodrugs. It is noteworthy that themulti-functionality of tartaric acid makes itself versatile, which allows for thepreparation of dendritic prodrugs with the same drugs in the interior and at theperiphery of dendrimers, as well as dendritic prodrugs with different drugsincorporated into the dendrimer scaffolds just by using different monomers. So far the dendritic prodrugs based on tartaric acid have not been reported.
4. Synthesis of dendritic prodrugs conjugated with both nitric oxide(NO)-releasing moieties and non-steroidal anti-inflammatory drugs (also referred toas NO-NSAID dendritic prodrugs). Four NO-NSAID dendritic prodrugs weresynthesized through the way that dendrimers with surface carboxyl groups,aldehydes derived from ibuprofen or aspirin and the isocyanide coupled to anorganic nitrate were combined together via Passerini reaction, a “one-pot” reactioninvolving three components. Now multi-component reactions are among the mostefficient tools for the construction of drug candidate library in combinatorialchemistry. However, there is no report on the preparation of dendritic ormacromolecular prodrugs via a multi-component reaction using dendrimers or anyother macromolecules as carriers. Admittedly, this strategy can take combinationprinciples, prodrug principles and theory of drug-carrier design into a single reaction,which will probably boost the drug development, and particularly the research anddevelopment of drug delivery systems. To sum up, it deserves to make efforts toapply more multi-component reactions to the synthesis of dendritic prodrugs fromthe views of both academics and industry.
引文
[1] Autumn, K.; Liang, Y. A.; Hsieh, S. T. et al. Adhesive force of a single geckofoot-hair. Nature2000,405,681–685.
[2] Buhleier, E.; Wehner, W.; V gtle, F.“Cascade”-and “nonskid-chain-like”syntheses of molecular cavity topologies. Synthesis1978,155–158.
[3] Denkewalter, R. G.; Kolc, J.; Lukasavage, W. J. Macromolecular highly branchedhomogeneous compound based on lysine units. U.S. Pat.4289872, Sept.15,1981.
[4] Denkewalter, R. G.; Kolc, J.; Lukasavage, W. J. Preparation of lysine basedmacromolecular highly branched homogeneous compound. U.S. Pat.4360646, Nov.23,1982.
[5] Denkewalter, R. G.; Kolc, J.; Lukasavage, W. J. Macromolecular highly branchedhomogeneous compound. U.S. Pat.4410688, Oct.18,1983.
[6] Tomalia, D. A.; Baker, H.; Dewald, J. R. et al. A new class of polymers: starbust-dendritic macromolecules. Polym. J.(Tokyo)1985,17,117–132.
[7] Tomalia, D. A.; Baker, H.; Dewald, J. R. et al. Dendritic macromolecules:synthesis of starbust dendrimers. Macromolecules1986,19,2466–2468.
[8] Newkome, G. R.; Yao, Z. Q.; Baker, G. R. et al. Part1. Cascade molecules: a newapproach to micelles. A [27]-arborol. J. Org. Chem.1985,50,2003–2004.
[9] W rner, C.; Mülhaupt, R. Polynitrile-and polyamine-functional poly(trimethyleneimine) dendrimers. Angew. Chem. Int. Ed.1993,32,1306–1308.
[10] De Brabander-van Den Berg, E. M. M.; Meijer, E. W. Poly(propylene imine)dendrimers: large-scale synthesis by heterogeneously catalyzed hydrogenations.Angew. Chem. Int. Ed.199332,1308–1311.
[11] Esfand, R.; Tomalia, D. A. Poly(amidoamine)(PAMAM) dendrimers: frombiomimicry to drug delivery and biomedical applications. Drug Discov. Today2001,6,427–436.
[12] Majoros, I. J.; Myc, A.; Thomas, T. et al. PAMAM dendrimer-based multi-functional conjugate for cancer therapy: synthesis, characterization, and functionality.Biomacromolecules2006,7,572–579.
[13] Majoros, I. J.; Thomas, T.; Mehta, C. B. et al. Poly(amidoamine) dendrimer-based multifunctional engineered nanodevice for cancer therapy. J. Med. Chem.2005,48,5892–5899.
[14] Haba, Y.; Harada, A.; Takagishi, T. et al. Rendering poly(amidoamine) orpoly(propylenimine) dendrimers temperature sensitive. J. Am. Chem. Soc.2004,126,12760–12761.
[15] Szalai, M. S.; Kevwitch, R. M.; McGrath, D. V. Geometric disassembly ofdendrimers: dendritic amplification. J. Am. Chem. Soc.2003,125,15688–15689.
[16] Cheng, Y.; Xu, T. Dendrimers as potential drug carriers. Part I. Solubilization ofnon-steroidal anti-inflammatory drugs in the presence of polyamidoamine dendrimers.Eur. J. Med. Chem.2005,40,1188–1192.
[17] Man, N.; Cheng, Y.; Xu, T. et al. Dendrimers as potential drug carriers. Part II.Prolonged delivery of ketoprofen by in vitro and in vivo studies. Eur. J. Med. Chem.2006,41,670–674.
[18] Cheng, Y.; Xu, T.; Fu, R. Polyamidoamine dendrimers used as solubilityenhancers of ketoprofen. Eur. J. Med. Chem.2005,40,1390–1393.
[19] Cheng, Y.; Man, N.; Xu, T. et al. Transdermal delivery of nonsteroidalanti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers. J.Pharm. Sci.2007,96,595–602.
[20] Kannan, S.; Kolhe, P.; Raykova, V. et al. Dynamics of cellular entry and drugdelivery by dendritic polymers into human lung epithelial carcinoma cells. J.Biomater. Sci., Polym. Ed.2004,15,311–330.
[21] Newkome, G. R.; Shreiner, C. D. Poly(amidoamine), polypropylenimine, andrelated dendrimers and dendrons possessing different1→2branching motifs: Anoverview of the divergent procedures. Polymer2008,49,1–173.
[22] Hawker, C. J.; Fréchet, J. M. J. Preparation of polymers with controlledmolecular architecture. A new convergent approach to dendritic macromolecules. J.Am. Chem. Soc.,1990112,7638–7647.
[23] Hawker, C. J.; Fréchet, J. M. J. A new convergent approach to monodispersedendritic macromolecules. J. Chem. Soc., Chem. Commun.1990,1010–1013.
[24] Aulenta, F.; Hayes, W.; Rannard, S. Dendrimers: A new class of nanoscopiccontainers and delivery devices. Eur. Polym. J.2003,39,1741–1771.
[25] Caminade, A.; Laurent, R.; Majoral, J. Characterization of dendrimers. Adv.Drug Deliv. Rev.2005,57,2130–2146.
[26] Lee, C. C.; MacKay, J. A.; Fréchet, J. M. J. et al. Designing dendrimers forbiological applications. Nat. Biotechnol.2005,23,1517–1526.
[27] Farin, D.; Avnir, D. Surface fractality of dendrimers. Angew. Chem. Int. Ed.1991,30,1379–1380.
[28] Jansen, J. F. G. A.; De Brabander-van Den Berg, E. M. M.; Meijer, E. W.Encapsulation of guest molecules into a dendritic box. Science1994,266,1226–1229.
[29] Butler, J. E.; Ni, L.; Nessler, R. et al. The physical and functional behavior ofcapture antibodies adsorbed on polystyrene. J. Immunol. Methods1992,150,77–90.
[30] De Backer, S.; Prinzie, Y.; Verheijen, W. et al. Solvent dependence of thehydrodynamical volume of dendrimers with a rubicene core. J. Phys. Chem. A1998,102,5451–5455.
[31] Elshakre, M.; Atallah, A. S.; Santos, S. et al. A structural study of carbosilanedendrimers versus polyamidoamine. Comput. Theor. Polym. Sci.2000,10,21–28.
[32] Lee, I.; Athey, B. D.; Wetzel, A. W. et al. Structural molecular dynamics studieson polyamidoamine dendrimers for a therapeutic application: Effects of pH andgeneration. Macromolecules2002,35,4510–4520.
[33] Welch, P.; Muthukumar, M. Tuning the density profile of dendriticpolyelectrolytes. Macromolecules1998,31,5892–5897.
[34] Ramzi, A.; Scherrenberg, R.; Joosten, J. et al. Structure-property relations indendritic polyelectrolyte solutions at different ionic strength. Macromolecules2002,35,827–833.
[35] Bosman, A. W.; Janssen, H. M.; Meijer, E. W. About dendrimers: structure,physical Properties, and applications. Chem. Rev.1999,99,1665–1688.
[36] http://www.ninger.com/dendrimer/
[37] Newkome, G. R.; Moorefield, C. N.; Baker, G. R. et al. Alkane cascade polymerswith a micellar topology: micelle acid derivatives. Angew. Chem. Int. Ed.1991,30,1176–1178.
[38] Newkome, G. R.; Moorefield, C. N.; Baker, G. R. et al. Unimolecular micelles.Angew. Chem. Int. Ed.1991,30,1178–1180.
[39] Newkome, G. R.; Behera, R. K.; Moorefield, C. N. et al. Cascade polymers:synthesis and characterization of one-directional arborols based on adamantane. J.Org. Chem.1991,56,7162–7167.
[40]. Newkome, G. R.; Nayak, A.; Behera, R. K. et al. Cascade polymers: synthesisand characterization of four-directional spherical dendritic macromolecules based onadamantane. J. Org. Chem.1992,57,358–362.
[41] Newkome, G. R.; Young, J. K.; Baker, G. R. et al. Cascade polymers. pHdependence of hydrodynamic radii of acid-terminated dendrimers. Macromolecules1993,26,2394–2396.
[42] Launay, N.; Caminade, A. M.; Lahana, R. et al. A general synthetic strategy forneutral phosphorous-containing dendrimers. Angew. Chem. Int. Ed.1994,33,1589–1592.
[43] Launay, N.; Caminade, A. M.; Majoral, J. P. Synthesis and reactivity of unusualphosphorous dendrimers. A useful divergent growth approach upto the seventhgeneration. J. Am. Chem. Soc.1995,117,3282–3283.
[44] Majoral, J. P.; Caminade, A. M. Divergent approaches to phosphorus-containingdendrimers and their functionalization. Top. Curr. Chem.1998,197,79–124.
[45] Marcos, M.; Martin-Rapún, R.; Omenat, A. et al. Highly congested liquid crystalstructures: dendrimers, dendrons, dendronized and hyperbranched polymers. Chem.Soc. Rev.2007,36,1889–1901.
[46] Wooley, K. L.; Hawker, C. J.; Fréchet, J. M. J. Unsymmetrical three-dimensionalmacromolecules: Preparation and characterization of strongly dipolar dendriticmacromolecules. J. Am. Chem. Soc.,1993115,11496–11505.
[47] Gillies, E. R.; Fréchet, J. M. J. Designing macromolecules for therapeuticapplications: polyester dendrimer–poly(ethylene oxide)“bow-tie” hybrids withtunable molecular weight and architecture. J. Am. Chem. Soc.2002,124,14137–14146.
[48] Steffensen, M. B.; Simanek, E. E. Synthesis and manipulation of orthogonallyprotected dendrimers: building blocks for library synthesis. Angew. Chem. Int. Ed.2004,43,5178–5180.
[49] Miller, T. M.; Neenan, T. X. Convergent synthesis of monodisperse dendrimersbased upon1,3,5-trisubstituted benzenes. Chem. Mater.1990,2,346–349.
[50] Miller, T. M.; Neenan, T. X.; Zayas, R. et al. Synthesis and characterization of aseries of monodisperse,1,3,5-phenylene-based hydrocarbon dendrimers includingC276H186and their fluorinated analogs. J. Am. Chem. Soc.1992,114,1018–1025.
[51] Pillow, J. N. G.; Halim, M.; Lupton, J. M. et al. A facile iterative procedure forthe preparation of dendrimers containing luminescent cores and stilbene dendrons.Macromolecules1999,32,5985–5993.
[52] Pillow, J. N. G.; Burn, P. L.; Samuel, I. D. W. et al. Synthetic routes to phenylenevinylene dendrimers. Synth. Met.1999,102,1468–1469.
[53] Miller, T. M.; Kwock, E. W.; Neenan, T. X. Synthesis of four generations ofmonodisperse aryl ester dendrimers based on1,3,5-benzenetricarboxylic acid.Macromolecules1992,25,3143–3148.
[54] Kwock, E. W.; Neenan, T. X.; Miller, T. M. Convergent synthesis ofmonodisperse aryl ester dendrimers. Chem. Mater.1991,3,775–777.
[55] Kadei, K.; Moors, R.; V gtle, F. Dendrimers and dendrimer building blocks withtrisubstituted benzene and ‘hexacyclene’ as core units. Chem. Ber.1994,127,897–903.
[56] Louie, J.; Hartwig, J. F.; Fry, A. J. Discrete high molecular weight triarylaminedendrimers prepared by palladium-catalyzed amination. J. Am. Chem. Soc.1997,119,11695–11696.
[57] Sadalapure, K.; Lindhorst, T. K. A general entry into glycopeptide dendrons.Angew. Chem. Int. Ed.2000,39,2010–2013.
[58] Wooley, K. L.; Hawker, C. J.; Fréchet, J. M. J. Hyperbranched macromoleculesvia a novel double-stage convergent growth approach. J. Am. Chem. Soc.1991,113,4252–4261.
[59] Xu, Z. F.; Kahr, M.; Walker, K. L. et al. Phenylacetylene dendrimers by thedivergent, convergent, and double-stage convergent methods. J. Am. Chem. Soc.1994,116,4537–4550.
[60] Kawaguchi, T.; Walker, K. L.; Wilkins, C. L. et al. Double exponentialdendrimer growth. J. Am. Chem. Soc.1995,117,2159–2165.
[61] Spindler, R.; Fréchet, J. M. J. Two-step approach towards the acceleratedsynthesis of dendritic macromolecules. J. Chem. Soc., Perkin Trans.11993,913–918.
[62] Zeng, F.; Zimmerman, S. C. Rapid synthesis of dendrimers by an orthogonalcoupling strategy. J. Am. Chem. Soc.1996,118,5326–5327.
[63] Deb, S. K.; Maddux, T. M.; Yu, L. A simple orthogonal approach topoly(phenylenevinylene) dendrimers. J. Am. Chem. Soc.1997,119,9079–9080.
[64] Ishida, Y.; Jikei, M.; Kakimoto, M. Rapid synthesis of aromatic polyamidedendrimers by an orthogonal and a double-stage convergent approach.Macromolecules2000,33,3202–3211.
[65] Maraval, V.; Pyzowski, J.; Caminade, A. M. et al.“Lego” chemistry for thestraightforward synthesis of dendrimers. J. Org. Chem.2003,68,6043–6046.
[66] Maraval, V.; Caminade, A. M; Majoral, J. P. et al. Dendrimer design: how tocircumvent the dilemma of a reduction of steps or an increase of function multiplicity?Angew. Chem. Int. Ed.2003,42,1822–1826.
[67] Maraval, V.; Laurent, R.; Marchand, P. et al. Accelerated methods of synthesis ofphosphorus-containing dendrimers. J. Organomet. Chem.2005,690,2458–2471.
[68] Mathias, J. P.; Stoddart, F. Constructing a molecular LEGO set. Chem. Soc. Rev.1992,21,215–225.
[69] Ashton, P. R.; Brown, G. R.; Isaacs, N. S. et al. Molecular LEGO.1. Substrate-directed synthesis via stereoregular Diels-Alder oligomerizations. J. Am. Chem. Soc.1992,114,6330–6353.
[70] B rner, H. G. Multifuctional polymer-bioconjugates as molecular LEGO bricks.Macromol. Chem. Phys.2007,208,124–130.
[71] Bolz, I.; May, C.; Spange, S. Solvatochromic properties of Schiff bases derivedfrom5-aminobarbituric acid: chromophores with hydrogen bonding pattens ascomponents for coupled structures. New J. Chem.2007,31,1568–1571.
[72] Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click chemistry: Diverse chemicalfunction from a few good reactions. Angew. Chem. Int. Ed.2001,40,2004–2021.
[73] Wu, P.; Feldman, A. K.; Nugent, A. K. et al. Efficiency and fidelity in aclick-chemistry route to triazole dendrimers by the copper(I)-catalyzed ligation ofazides and alkynes. Angew. Chem. Int. Ed.2004,43,3928–3932.
[74] Wu, P.; Malkoch, M.; Hunt, J. N. et al. Multivalent, bifunctional dendrimersprepared by click chemistry. Chem. Commun.2005,46,5775–5777.
[75] Touaibia, M.; Wellens, A.; Shiao, T. C. et al. Mannosylated G(0) dendrimers withnanomolar affinities to Escherichia coli FimH. ChemMedChem2007,8,1190–1201.
[76] Dijkgraaf, I.; Rijnders, A. Y.; Soede, A. et al. Synthesis of DOTA-conjugatedmultivalent cyclic-RGD peptide dendrimers via1,3-dipolar cycloaddition and theirbiological evaluation: implications for tumor targeting and tumor imaging purposes.Org. Biomol. Chem.2007,6,935–944.
[77] Gopin, A.; Ebner, E.; Attali, B. et al. Enzymatic activation of second-generationdendritic prodrugs: conjugation of self-immolative dendrimers with poly(ethyleneglycol) via click chemistry. Bioconjugate Chem.2006,17,1432–1440.
[78] Ornelas, C.; Aranzaes, J. R.; Clouter, E. et al. Click assembly of1,2,3-triazole-linked dendrimers, including ferrocenyl dendrimers, which sense both oxo anions andmetal cations. Angew. Chem. Int. Ed.2007,46,872–877.
[79] Ornelas, C.; Aranzaes, J. R.; Salmon, L. et al.“Click” dendrimers: synthesis,redox sensing of Pd(OAc)2and remarkable catalytic hydrogenation activity of precisePd nanoparticles stabilized by1,2,3-triazole-containing dendrimers. Chem. Eur. J.2008,14,50–64.
[80] Killops, K. L.; Campos, L. M.; Hawker, C. J. Robust, efficient, and orthogonalsynthesis of dendrimers via thiol-ene “click” chemistry. J. Am. Chem. Soc.2008,130,5062–5064.
[81] Bhyrappa, P.; Young, J. K.; Moore., J. S. et al. Dendrimer-metalloporphyrins:synthesis and catalysis. J. Am. Chem. Soc.1996,118,5708–5711.
[82] Ouali, A.; Laurent, R.; Caminade, A.-M. et al. Enhanced catalytic properties ofcopper in O-and N-arylation and vinylation reactions, using phosphorus dendrimersas ligands. J. Am. Chem. Soc.2006,128,15990–15991.
[83] Zhao, M.; Helms, B.; Slonkina, E. et al. Iron complexes of dendrimer-appendedcarboxylates for activating dioxygen and oxidizing hydrocarbons. J. Am. Chem. Soc.2008,130,4352–4363.
[84] Karakhanov, E. A.; Maximov, A. L.; Tarasevich, B. N. et al. Dendrimer-basedcatalysts in Wacker-oxidation: Unexpected selectivity to terminal double bonds. J.Mol. Catal. A: Chem.2009,297,73–79.
[85] Pittelkow, M.; Brock-Nannestad, T.; Moth-Poulsen, K. et al. Chiral dendrimerencapsulated Pd and Rh nanoparticles. Chem. Commun.2008,2358–2368.
[86] Ma, C.-Q.; Mena-Osteritz, E.; Debaerdemaeker, T. et al. Functionalized3Doligothiophene dendrons and dendrimers—Novel macromolecules for organicelectronics. Angew. Chem. Int. Ed.2007,46,1679–1683.
[87] Samoc, M.; Morrall, J. P.; Dalton, G. T. et al. Two-photon and three-photonabsorption in an organometallic dendrimer. Angew. Chem. Int. Ed.2007,46,731–733.
[88] Zhou, G.; Wong, W.-Y.; Yao, B. et al. Triphenylamine-dendronized pure rediridium phosphors with superior OLED efficiency/color purity trade-offs. Angew.Chem. Int. Ed.2007,46,1149–1151.
[89] Adhikari, R. M.; Mondal, R.; Shah, B. K. et al. Synthesis and photophysicalproperties of carbazole-based blue light-emitting dendrimers. J. Org. Chem.2007,72,4727–4732.
[90] Sanji, T.; Shiraishi, K.; Tanaka, M. Synthesis and photophysical properties ofphosphole-cored dendrimers. Org. Lett.2007,9,3611–3614.
[91] Taranekar, P.; Fulghum, T.; Patton, D. et al. Investigating carbazole jacketedprecursor dendrimers: Sonochemical synthesis, characterization, and electrochemicalcrosslinking properties. J. Am. Chem. Soc.2007,129,12537–12548.
[92] Won, K.-T.; Yu-Hsien, L.; Wu, H.-H. Synthesis and properties of dumbbell-shaped dendrimers containing9-phenylcarbazole dendrons. Org. Lett.2007,9,4531–4534.
[93] Jiang, Y.; Lu, Y.-X.; Cui, Y.-X. et al. Synthesis of giant rigid π-conjugateddendrimers. Org. Lett.2007,9,4539–4542.
[94] Jayamurugan, G.; Umesh, C. P.; Jayaraman, N. Inherent photoluminescenceproperties of poly(propyl ether ether imine) dendrimers. Org. Lett.2008,10,9-12.
[95] Xu, T.; Lu, R.; Liu, X. et al. Synthesis and characterization of subporphyrinswith dendritic carbazole arms. Eur. J. Org. Chem.2008,1065–1071.
[96] Giansante, C.; Ceroni, P.; Balzani, V. et al. Self-assembly of a light-harvestingantenna formed by a dendrimer, a RuIIcomplex, and a NdIIIion. Angew. Chem. Int.Ed.2008,47,5422–5425.
[97] Fernández, G.; Pérez, E. M.; Sánchez, L. et al. An electroactive dynamicallypolydisperse supramolecular dendrimer. J. Am. Chem. Soc.2008,130,2410–2411.
[98] Gillies, E. R.; Fréchet, J. M. J. Dendrimers and dendritic polymers in drugdelivery. Drug Discov. Today2005,10,35–43.
[99] Cheng, Y.; Wang, J.; Rao, T. et al. Pharmaceutical applications of dendrimers:Promising nanocarriers for drug delivery. Front. Biosci.2008,13,1447–1471.
[100] Cheng, Y.; Xu, Z.; Ma, M. et al. Dendrimers as drug carriers: Applications indifferent routes of drug administration. J. Pharm. Sci.2008,97,123–143.
[101] Cheng, Y.; Gao, Y.; Rao, T. et al. Dendrimer-based prodrugs: Design, synthesis,screening and biological evaluation. Comb. Chem. High Throughput Screen.2007,10,336–349.
[102] Villalonga-Barber, C.; Micha-Screttas, M.; Steele, B. R. et al. Dendrimers asbiopharmaceuticals: Synthesis and properties. Curr. Top. Med. Chem.2008,8,1294–1309.
[103] Yang, W.; Cheng, Y.; Xu, T. et al. Targeting cancer cells with biotin-dendrimerconjugates. Eur. J. Med. Chem.2009,44,862–868.
[104] Hong, S.; Bielinska, A. U.; Mecke, A. et al. Interaction of poly(amidoamine)dendrimers with supported lipid bilayers and cells: Hole formation and the relation totransport. Bioconjugate Chem.2004,15,774–782.
[105] Chen, H.-T.; Neerman, M. F.; Parrish, A. R. et al. Cytotoxicity, hemolysis, andacute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drugdelivery. J. Am. Chem. Soc.2004,126,10044–10048.
[106] Malik, N.; Wiwattanapatapee, R.; Klopsch, R. et al. Dendrimers: Relationshipbetween structure and biocompatibility in vitro, and preliminary studies on thebiodistribution of125I-labelled polyamidoamine dendrimers in vivo. J. ControlledRelease2000,65,133–148.
[107] Roberts, J. C.; Bhalgat, M. K.; Zera, R. T. Preliminary biological evaluation ofpolyamidoamine (PAMAM) Starburst dendrimers. J. Biomed. Mater. Res.1996,30,53–65.
[108] Fischer, D.; Li, Y.; Ahlemeyer, B. et al. In vitro cytotoxicity testing ofpolycations: Influence of polymer structure on cell viability and hemolysis.Biomaterials2003,24,1121–1131.
[109] Kobayashi, H.; Kawamoto, S.; Saga, T. et al. Positive effects of polyethyleneglycol conjugation to generation-4polyamidoamine dendrimers as macromolecularMR contrast agents. Magn. Res. Med.2001,46,781–788.
[110] Plank, C.; Mechtler, K.; Szoka, F. C. Jr. et al. Activation of the complementsystem by synthetic DNA complexes: A potential barrier for intravenous genedelivery. Human Gene Ther.1996,7,1437–1446.
[111] Kobayashi, H.; Sato, N.; Kawamoto, S. et al. Comparison of the macro-molecular MR contrast agents with ethylenediamine-core versus ammonia-coregeneration-6polyamidoamine dendrimer. Bioconjugate Chem.2001,12,100–107.
[112] Brem, H.; Walter, K. A.; Langer, R. Polymers as controlled drug deliverydevices for the treatment of malignant brain tumors. Eur. J. Pharm. Biopharm.1993,39,2–7.
[113] Batz, H. G.; Franzmann, G.; Ringsdorf, H. Model reactions for synthesis ofpharmacologically active polymers by way of monomeric and polymeric reactiveesters. Angew. Chem. Int. Ed.1972,11,1103–1104.
[114] Ringsdorf, H. Structure and properties of pharmacologically active polymers. J.Polym. Sci. Polym. Symp.1975,5,135–153.
[115] Shatayeva, L. K.; Samsonov, G. V.; Vacik, J. et al. Permeability of hetero-generous membrances based on methacrylic acid. J. Appl. Polym. Sci.1979,23,2245–2251.
[116] Duncan, R. Drug-polymer conjugates: Potential for improved chemotherapy.Anti-Cancer Drugs1992,3,175–210.
[117] Gillies, E. R.; Dy, E.; Fréchet, J. M. J. et al. Biological evaluation of polyesterdendrimer: Poly(ethylene oxide)“bow-tie” hybrids with tunable molecular weightand architecture. Mol. Pharm.2005,2,129–138.
[118] Cheng, Y.; Xu, T. The effect of dendrimers on the pharmacodynamic andpharmacokinetic behaviors of non-covalently or covalently attached drugs. Eur. J.Med. Chem.2008,43,2291–2297.
[119] Newkome, G. R.; Lin, X.; Yaxiong, C. et al. Two-directional cascade polymersynthesis: Effects of core variation. J. Org. Chem.1993,58,3123–3129.
[120] Moorefield, C. N.; Newkome, G. R. Unimolecular micelles: Supramolecular useof dendritic constructs to create versatile molecular containers. Compt. Rend. Chim.2003,6,715–724.
[121] Hawker, C. J.; Wooley, K. L.; Fréchet, J. M. J. Unimolecular micelles andglobular amphiphiles: Dendritic macromolecules as novel recyclable solubilizationagents. J. Chem. Soc., Perkin Trans.11993,12,1287–1297.
[122] Twyman, L. J.; Beezer, A. E.; Esfand, R. et al. The synthesis of water solubledendrimers, and their application as possible drug delivery systems. Tetrahedron Lett.1999,40,1743–1746.
[123] Beezer, A. E.; King, A. S. H.; Martin, I. K. et al. Dendrimers as potential drugcarriers; encapsulation of acidic hydrophobes within water soluble PAMAMderivatives. Tetrahedron2003,59,3873–3880.
[124] Wallimann, P.; Seiler, P.; Diederich, F. Dendrophanes: Novel steroid-recognizing dendritic receptors: Preliminary communication. Helv. Chim. Acta1996,79,779–788.
[125] Kolhe, P.; Misra, E.; Kannan, R. M. et al. Drug complexation, in vitro releaseand cellular entry of dendrimers and hyperbranched polymers. Int. J. Pharm.2003,259,143–160.
[126] Baars, M. W. P. L.; Karlsson, A. J.; Sorokin, V. et al. Supramolecular modifica-tion of the periphery of dendrimers resulting in rigidity and functionality. Angew.Chem. Int. Ed.2000,39,4262–4265.
[127] Boas, U.; Karlsson, A. J.; De Waal, B. F. M. et al. Synthesis and properties ofnew thiourea-functionalized poly(propylene imine) dendrimers and their role as hostsfor urea functionalized guests. J. Org. Chem.2001,66,2136–2145.
[128] Uhrich, K.; Cannizzaro, S.; Langer, R. et al. Polymeric systems for controlleddrug release. Chem. Rev.1999,99,3181–3198.
[129] Kolhe, P.; Khandare, J.; Pillai, O. et al. Preparation, cellular transport, andactivity of polyamidoamine-based dendritic nanodevices with a high drug payload.Biomaterials2006,27,660–669.
[130] Milhem, O. M.; Myles, C.; McKeown, N. B. et al. Polyamidoamine Starburstdendrimers as solubility enhancers. Int. J. Pharm.2000,197,239–241.
[131] Gurdag, S.; Khandare, J.; Stapels, S. et al. Activity of dendrimer-methotrexateconjugates on methotrexate-sensitive and-resistant cell lines. Bioconjugate Chem.2006,17,275–283.
[132] Roy, R.; Baek, M. G. Glycodendrimers: novel glycotope isosteres unmaskingsugar coding. Case study with T-antigen markers from breast cancer MUC1glycoprotein. Rev. Mol. Biotechnol.2002,90,291–309.
[133] Thomas, T. P.; Majoros, I. J.; Kotlyar, A. et al. Targeting and inhibition of cellgrowth by an engineered dendritic nanodevice. J. Med. Chem.2005,48,3729–3735.
[134] Barth, R. F.; Adams, D. M.; Soloway, A. H. et al. Boronated starburstdendrimer-monoclonal antibody immunoconjugates: Evaluation as a potentialdelivery system for neutron capture therapy. Bioconjugate Chem.1994,5,58–66.
[135] Yang, W. L.; Barth, R. F.; Adams, D. M. et al. Intratumoral delivery ofboronated epidermal growth factor for neutron capture therapy of brain tumors.Cancer Res.1997,57,4333–4339.
[136] Thomas, T. P.; Patri, A. K.; Myc, A. et al. In vitro targeting of synthesizedantibody-conjugated dendrimer nanoparticles. Biomacromolecules2004,5,2269–2274.
[137] Shaunak, S.; Thomas, S.; Gianasi, E. et al. Polyvalent dendrimer glucosamineconjugates prevent scar tissue formation. Nat. Biotechnol.2004,22,977–984.
[138] Liu, M.; Kono, K.; Fréchet, J. M. J. Water-soluble dendrimer-poly(ethyleneglycol) starlike conjugates as potential drug carriers. J. Polym. Sci., Part A: Polym.Chem.1999,37,3492–3503.
[139] Amir, R. J.; Pessah, N.; Shamis, M. et al. Self-immolative dendrimers. Angew.Chem. Int. Ed.2003,42,4494–4499.
[140] de Groot, F. M. H.; Albrecht, C.; Koekkoek, R. et al.“Cascade-releasedendrimers” liberate all end groups upon a single triggering event in the dendriticcore. Angew. Chem. Int. Ed.2003,42,4490–4494.
[141] Shamis, M.; Lode, H. N.; Shabat, D. Bioactivation of self-immolative dendriticprodrugs by catalytic antibody38C2. J. Am. Chem. Soc.2004,126,1726–1731.
[142] Sagi, A.; Segal, E.; Satchi-Fainaro, R. et al. Remarkable drug-releaseenhancement with an elimination-based AB3self-immolative dendritic amplifier.Bioorg. Med. Chem.2007,15,3720–3727.
[143] Amir, R. J.; Danieli, E.; Shabat, D. Receiver–amplifier, self-immolativedendritic device. Chem. Eur. J.2007,13,812–821.
[144] Malik, N.; Evagorou, E. G.; Duncan, R. Dendrimer-platinate: A novel approachto cancer chemotherapy. Anti-Cancer Drugs1999,10,767–776.
[145] Howell, B. A.; Fan, D.; Rakesh, L. Thermal decomposition of a generation4.5PAMAM dendrimer platinum drug conjugate. J. Therm. Anal. Calorim.2006,85,17–20.
[146] Tang, S.; Martinez, L. J.; Sharma, A. et al. Synthesis and characterization ofwater-soluble and photostable L-DOPA dendrimers. Org. Lett.2006,8,4421–4424.
[147] Tang, S.; June, S. M.; Howell, B. A. et al. Synthesis of salicylate dendriticprodrugs. Tetrahedron Lett.2006,47,7671–7675.
[148] Wiener, E. C.; Brechbiel, M. W.; Brothers, H. et al. Dendrimer-based metalchelates: a new class of magnetic resonance imaging contrast agents. Magn. Reson.Med.1994,31,1–8.
[149] Longmire, M.; Choyke, P. L.; Kobayashi, H. Dendrimer-based contrast agentsfor molecular imaging. Curr. Top. Med. Chem.2008,8,1180–1186.
[150] Kobayashi, H.; Brechbiel, M. W. Nano-sized MRI contrast agents withdendrimer cores. Adv. Drug Deliv. Rev.2005,57,2271–2286.
[151] Kobayashi, H.; Kawamoto, S.; Jo, S.-K. et al. Macromolecular MRI contrastagents with small dendrimers: pharmacokinetic differences between sizes and cores.Bioconjugate Chem.2003,14,388–394.
[152] Talanov, V. S.; Regino, C. A. S.; Kobayashi, H. et al. Dendrimer-basednanoprobe for dual modality magnetic resonance and fluorescence imaging. NanoLett.2006,6,1459–1463.
[153] Kobayashi, H.; Kawamoto, S.; Choyke, P. L. et al. Comparison of dendrimer-based macromolecular contrast agents for dynamic micro-magnetic resonancelymphangiography. Magn. Reson. Med.2003,50,758–766.
[154] Kobayashi, H.; Kawamoto, S.; Star, R. A. et al. Micro-magnetic resonancelymphangiography in mice using a novel dendrimer-based magnetic resonanceimaging contrast agent. Cancer Res.2003,63,271–276.
[155] Kobayashi, H.; Brechbiel, M. W. Dendrimer-based macromolecular MRIcontrast agents: characteristics and application. Mol. Imaging2003,2,1–10.
[156] Dijkgraaf, I.; Rijnders, A. Y.; Soede, A. et al. Synthesis of DOTA-conjugatedmultivalent cyclic-RGD peptide dendrimers via1,3-dipolar cycloaddition and theirbiological evaluation: Implications for tumor targeting and tumor imaging purposes.Org. Biomol. Chem.2007,5,935–944.
[157] Regino, C. A. S.; Walbridge, S.; Bernardo, M. et al. A dual CT-MR dendrimercontrast agent as a surrogate marker for convection-enhanced delivery of intracerebralmacromolecular therapeutic agents. Contrast Media Mol. Imaging2008,3,2–8.
[158] Heinen, S.; Walder, L. Generation-dependent intramolecular CT complexationin a dendrimer electron sponge consisting of a viologen skeleton. Angew. Chem. Int.Ed.2000,39,806–809.
[159] Subbarayan, M.; Shetty, S. J.; Srivastava, T. S. et al. Water-soluble99mTc-labeled dendritic novel porphyrins tumor imaging and diagnosis. Biochem. Biophys.Res. Commun.2001,281,32–36.
[160] Balzani, V.; Ceroni, P.; Gestermann, S. et al. Effect of protons and metal ions onthe fluorescence properties of a polylysin dendrimer containing twenty four dansylunits. J. Chem. Soc., Dalton Trans.2000,3765–3771.
[161] Zheng, J.; Dickson, R. M. Individual water-soluble dendrimer-encapsulatedsilver nanodot fluorescence. J. Am. Chem. Soc.2002,124,13982–13983.
[162] Paulo, P. M. R.; Gronheid, R.; De Schryver, F. C. et al. Porphyrin-dendrimerassemblies studied by electronic absorption spectra and time-resolved fluorescence.Macromolecules2003,36,9135–9144.
[163] Lee, J. W.; Kim, H. J.; Han, S. C. et al. Synthesis and characterization ofpoly(amido amine) dendrimer containing fluorene as a core chromophore. J. Nanosci.Nanotech.2008,8,4635–4639.
[164] Dufès, C.; Uchegbu, I. F.; Sch tzlein, A. G. Dendrimers in gene delivery. Adv.Drug Deliv. Rev.2005,57,2177–2202
[165] Parekh, H. S. The advance of dendrimers—A versatile targeting-platform forgene/drug delivery. Cur. Pharm. Des.2007,13,2837–2850.
[166] Luo, D.; Haverstick, K.; Belcheva, N. et al. Poly(ethylene glycol)-conjugatedPAMAM dendrimer for biocompatible, high-efficiency DNA delivery.Macromolecules2002,35,3456–3462.
[167] Wada, K.; Arima, H.; Tsutsumi, T. et al. Improvement of gene deliverymediated by mannosylated dendrimer/α-cyclodextrin conjugates. J. ControlledRelease2005,104,397–413.
[168] Kim, J.-B.; Choi, J. S.; Nam, K. et al. Enhanced transfection of primary corticalcultures using arginine-grafted PAMAM dendrimer, PAMAM-Arg. J. ControlledRelease2006,114,110–117.
[169] Choi, J. S.; Ko, K. S.; Park, J. S. et al. Dexamethasone conjugatedpoly(amidoamine) dendrimer as a gene carrier for efficient nuclear translocation. Int.J. Pharm.2006,320,171–178.
[170] Maiti, P. K.; Bagchi, B. Structure and dynamics of DNA-dendrimercomplexation: Role of counterions, water, and base pair sequence. Nano Lett.2006,6,2478–2485.
[171] Kim, T.-i.; Baek, J.-u.; Bai, C. Z. et al. Arginine-conjugated polypropyleniminedendrimer as a non-toxic and efficient gene delivery carrier. Biomaterials2007,28,2061–2067.
[172] Tsutsumi, T.; Hirayama, F.; Uekama, K. et al. Evaluation of polyamidoaminedendrimer/α-cyclodextrin conjugate (generation3, G3) as a novel carrier for smallinterfering RNA (siRNA). J. Controlled Release2007,119,349–359.
[173] Rozkiewicz, D. I.; Brugman, W.; Kerkhoven, R. M. et al. Dendrimer-mediatedtransfer printing of DNA and RNA microarrays. J. Am. Chem. Soc.2007,129,11593–11599.
[174] Pasupathy, K.; Lin, S.; Hu, Q. et al. Direct plant gene delivery with apoly(amidoamine) dendrimer. Biotechnol. J.2008,3,1078–1082.
[175] Arotiba, O.; Owino, J.; Songa, E. et al. An electrochemical DNA biosensordeveloped on a nanocomposite platform of gold and poly(propyleneimine) dendrimer.Sensors2008,8,6791–6809.
[176] Nam, H. Y.; Nam, K.; Hahn, H. J. et al. Biodegradable PAMAM ester forenhanced transfection efficiency with low cytotoxicity. Biomaterials2009,30,665–673.
[177] Mintzer, M. A.; Simanek, E. E. Nonviral vectors for gene delivery. Chem. Rev.2009,109,259–302.
[178] Grinstaff, M. W. Dendritic macromers for hydrogel formation: Tailoredmaterials for ophthalmic, orthopedic, and biotech applications. J. Polym. Sci., Part A:Polym. Chem.2008,46,383–400.
[179] Grinstaff, M. W. Biodendrimers: New polymeric biomaterials for tissueengineering. Chem. Eur. J.2002,8,2838–2846.
[180] Duan, X.; Sheardown, H. Dendrimer crosslinked collagen as a corneal tissueengineering scaffold: Mechanical properties and corneal epithelial cell interactions.Biomaterials2006,27,4608–4617.
[181] Cai, Q.; Zhao, Y.; Bei, J. et al. Synthesis and properties of star-shapedpolylactide attached to poly(amidoamine) dendrimer. Biomacromolecules2003,4,828–834.
[182] S ntjens, S. H. M.; Nettles, D. L.; Carnahan, M. A. et al. Biodendrimer-basedhydrogel scaffolds for cartilage tissue repair. Biomacromolecules2006,7,310–316.
[183] Langer, R. Drug delivery and targeting. Nature1998,392(6679SUPPL.),5–10.
[184] Ihre, H.; Hult, A.; Fréchet, J. M. J. et al. Double-stage convergent approach forthe synthesis of functionalized dendritic aliphatic polyesters based on2,2-bis(hydroxymethyl)propionic acid. Macromolecules1998,31,4061–4068.
[185] Padilla De Jesús, O. L.; Ihre, H. R.; Gagne, L. et al. Polyester dendritic systemsfor drug delivery applications: In vitro and in vivo evaluation. Bioconjugate Chem.2002,13,453–461.
[186] Ihre, H. R.; Padilla De Jesús, O. L.; Szoka, F. C. Jr. et al. Polyester dendriticsystems for drug delivery applications: Design, synthesis, and characterization.Bioconjugate Chem.2002,13,443–452.
[187] Luman, N. R.; Kim, T.; Grinstaff, M. W. Dendritic polymers composed ofglycerol and succinic acid: Synthetic methodologies and medical applications. PureAppl. Chem.2004,76,1375–1385.
[188] Hirayama, Y.; Sakamoto, Y.; Yamaguchi, K. et al. Synthesis of polyesterdendrimers and dendrons starting from Michael reaction of acrylates with3-hydroxyacetophenone. Tetrahedron Lett.2005,46,1027–1030.
[189] Carnahan, M. A.; Grinstaff, M. W. Synthesis of generational polyesterdendrimers derived from glycerol and succinic or adipic acid. Macromolecules2006,39,609–616.
[190] Gingras, M.; Raimundo, J.-M.; Chabre, Y. M. Cleavable dendrimers. Angew.Chem. Int. Ed.2007,46,1010–1017.
[191] Satija, J.; Gupta, U.; Jain, N. K. Pharmaceutical and biomedical potential ofsurface engineered dendrimers. Crit. Rev. Ther. Drug Carrier Syst.2007,24,257–306.
[192] Darbre, T.; Reymond, J.-L. Peptide dendrimers as artificial enzymes, receptors,and drug-delivery agents. Acc. Chem. Res.2006,39,925–934.
[193] Crespo, L.; Sanclimens, G.; Pons, M. et al. Peptide and amide bond-containingdendrimers. Chem. Rev.2005,105,1663–1681.
[194] Chow, H.-F.; Mak, C. C. Synthesis and chiroptical properties of layer-blockdendrimers. Pure Appl. Chem.1997,69,483–488.
[195] Chow, H.-F.; Mak, C. C. Synthesis and structure-optical rotation relationshipsof homochiral, monodisperse, tartaric acid-based dendrimers. J. Chem. Soc., PerkinTrans.11994,2223–2228.
[196] Chow, H.-F.; Mak, C. C. Facile preparation of optically active dendriticfragments containing multiple tartrate-derived chiral units. Tetrahedron Lett.1996,37,5935–5938.
[197] Chow, H.-F.; Mak, C. C. Preparation and structure-chiroptical relationships oftartaric acid-based layer-block chiral dendrimers. J. Chem. Soc., Perkin Trans.11997,91–95.
[198] Buschhaus, B.; Bauer, W.; Hirsch, A. Synthesis and chiroptical properties of anew type of chiral depsipeptide dendrons. Tetrahedron2003,59,3899–3915.
[199] Maurer, K.; Hager, K.; Hirsch, A. Self-assembly and chiroptical properties ofchiral dendrimers consisting of a Hamilton receptor substituted porphyrin anddepsipeptide cyanurates. Eur. J. Org. Chem.2006,3338–3347.
[200] Ghosh, S.; Banthia, A. K. Toward chiral polyamidoamine (PAMAM) dendriticarchitecture with tartaric acid core. J. Indian Chem. Soc.2002,79,442–443.
[201] Singh, G.; Triadafilopoulos, G. Epidemiology of NSAID induced gastro-intestinal complications. J. Rheumatol. Suppl.1999,56,18–24.
[202] Cena, C.; Lolli, M. L.; Lazzarato, L. et al. Antiinflammatory, gastrosparing, andantiplatelet properties of new NO-donor esters of aspirin. J. Med. Chem.2003,46,747–754.
[203] Yumiko, N.; Kozo, T.; Kimio, H. Promoting effect of o-ethylmenthol on thepercutaneous absorption of ketoprofen. Int. J. Pharm.1996,145,29–36.
[204] Makiko, F.; Naohide, H.; Kumi, S. Effect of fatty acid esters on permeation ofketoprofen through hairless rat skin. Int. J. Pharm.2000,205,117–125.
[205] Vergote, G. J.; Vervaet, C.; Driessche, I. V. An oral controlled release matrixpellet formulation containing nanocrystalline ketoprofen. Int. J. Pharm.2001,219,81–87.
[206] Sloan, K.B.; Wasdo, S. Designing for topical delivery: Prodrugs can make thedifference. Med. Res. Rev.2003,23,763–793.
[207] Ahuja, M.; Dhake, A. S.; Sharma, S. K. et al. Topical ocular delivery ofNSAIDs. AAPS J.2008,10,229–241.
[208] MacNaughton, W. K.; Cirino, G.; Wallace, J. L. Endothelium-derived relaxingfactor (nitric oxide) has protective actions in the stomach. Life Sci.1989,45,1869–1876.
[209] Kitagawa, H., Takeda, F., Kohei, H. Effect of endothelium-derived relaxingfactor on the gastric lesion induced by HCl in rats. J. Pharmacol. Exp. Ther.1990,253,1133–1137.
[210] Wallace, J. L.; Granger, D. N. The cellular and molecular basis of gastricmucosal defence. FASEB J.1996,10,731–740.
[211] Fiorucci, S.; Santucci, L.; Gresele, P. et al. Gastrointestinal safety of NO-aspirin(NCX-4016) in healthy human volunteers: A proof of concept endoscopic study.Gastroenterology2003,124,600–607.
[212] Davies, N. M.; Roseth, A. G.; Appleyard, C. B. et al. NO-naproxen vs. naproxen:Ulcerogenic, analgesic and anti-inflammatory effects. Aliment. Pharmacol. Ther.1997,11,69–79.
[213] Lanas, A.; Bajador, E.; Serrano, P. et al. Nitrovasodilators, low-dose aspirin,nonsteroidal anti-inflammatory drugs, and the risk of upper gastrointestinal bleeding.New Engl. J. Med.2000,343,834–839.
[214] Lanas, A.; García-Rodríguez, L. A.; Arroyo, M. T. et al. Effect of antisecretorydrugs and nitrates on the risk of ulcer bleeding associated with nonsteroidalanti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am. J. Gastroenterol.2007,102,507–515.
[215] Schoenfeld, P.; Kimmey, M. B.; Scheiman, J. et al. Review article: Nonsteroidalanti-inflammatory drug-associated gastrointestinal complications—Guidelines forprevention and treatment. Aliment. Pharmacol. Ther.1999,13,1273–1285.
[216] Ranatunge, R. R.; Augustyniak, M. E.; Dhawan, V. et al. Synthesis andanti-inflammatory activity of a series of N-substituted naproxen glycolamides: Nitricoxide-donor naproxen prodrugs. Bioorg. Med. Chem.2006,14,2589–2599.
[217] Ongini, E.; Bolla, M. Nitric-oxide based nonsteroidal anti-inflammatory agents.Drug Discov. Today: Ther. Strat.2006,3,395–400.
[218] Cena, C.; Lolli, M. L.; Lazzarato, L. et al. Antiinflammatory, gastrosparing, andantiplatelet properties of new NO-donor esters of aspirin. J. Med. Chem.2003,46,747–754.
[219] Chiroli, V.; Benedini, F.; Ongini, E. et al. Nitric oxide-donating non-steroidalanti-inflammatory drugs: The case of nitroderivatives of aspirin. Eur. J. Med. Chem.2003,38,441–446.
[220] Fiorucci, S.; Santucci, L.; Distrutti, E. NSAIDs, coxibs, CINOD andH2S-releasing NSAIDs: What lies beyond the horizon. Digest. Liver Dis.2007,39,1043–1051.
[221] Velázquez, C. A.; Praveen Rao, P. N.; Citro, M. L. et al. O2-Acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs): Synthesis, nitric oxiderelease, and biological evaluation studies. Bioorg. Med. Chem.2007,15,4767–4774.
[222] Abadi, A. H.; Hegazy, G. H.; El-Zaher, A. A. Synthesis of novel4-substituted-7-trifluoromethylquinoline derivatives with nitric oxide releasing properties and theirevaluation as analgesic and anti-inflammatory agents. Bioorg. Med. Chem.2005,13,5759–5765.
[223] Ziakas, G. N.; Rekka, E. A.; Gavalas, A. M. et al. Nitric oxide releasingderivatives of tolfenamic acid with anti-inflammatory activity and safegastrointestinal profile. Bioorg. Med. Chem.2005,13,6485–6492.
[224] Hulsman, N.; Medema, J. P.; Bos, C. et al. Chemical insights in the concept ofhybrid drugs: The antitumor effect of nitric oxide-donating aspirin involves a quinonemethide but not nitric oxide nor aspirin. J. Med. Chem.2007,50,2424–2431.
[225] Kashfi, K.; Rigas, B. The mechanism of action of nitric oxide-donating aspirin.Biochem. Biophys. Res. Commun.2007,358,1096–1101.
[226] Rigas, B.; Williams, J. L. NO-donating NSAIDs and cancer: An overview witha note on whether NO is required for their action. Nitric Oxide Biol. Chem.2008,19,199–204.
[227] Dunlap, T.; Abdul-Hay, S. O.; Chandrasena, R. E. P. et al. Nitrates and NO-NSAIDs in cancer chemoprevention and therapy: In vitro evidence querying the NOdonor functionality. Nitric Oxide Biol. Chem.2008,19,115–124.
[228] Stasko, N. A.; Schoenfisch, M. H. Dendrimers as a scaffold for nitric oxiderelease. J. Am. Chem. Soc.2006,128,8265–8271.
[229] Taite, L. J.; West, J. L. Poly(ethylene glycol)-lysine dendrimers for targeteddelivery of nitric oxide. J. Biomater. Sci., Polym. Ed.2006,17,1159–1172.
[230] Stasko, N. A.; Fischer, T. H.; Schoenfisch, M. H. S-Nitrosothiol-modifieddendrimers as nitric oxide delivery vehicles. Biomacromolecules2008,9,834–841.
[231] ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P. et al. Removal of benzyl-typeprotecting groups from peptides by catalytic transfer hydrogenation with formic acid.J. Org. Chem.1979,44,3442–3444.
[232] Smith, H. L.; Brown, E. S.; Smith, J. D. et al. Hydrogenolysis of benzyl esterswith palladiumon-carbon catalysts. J. Pharm. Sci.1965,54,1269–1273.
[233] Zagorevskii1, V. A.; Tsvetkova1, I. D.; Orlova1, é. K. et al. Pyran, its analogs,and related compounds. Chem. Heterocycl. Compd.1971,7,14–18.
[234] Rainsford, K. D. Anti-inflammatory drugs in the21st century. Sub-cell.biochem.2007,42,3–27.
[235] Rephaeli, A.; Zhuk, R.; Nudelman, A. Prodrugs of butyric acid from bench tobedside: Synthetic design, mechanisms of action, and clinical applications. Drug Dev.Res.2000,50,379–391.
[236] Muramatsu, I.; Murakami, M.; Takahiro Yoneda, T. et al. The formylation ofamino acids with acetic formic anhydride. Bull. Chem. Soc. Jpn.1965,38,244–246.
[2] Buhleier, E.; Wehner, W.; V gtle, F.“Cascade”-and “nonskid-chain-like”syntheses of molecular cavity topologies. Synthesis1978,155–158.
[3] Denkewalter, R. G.; Kolc, J.; Lukasavage, W. J. Macromolecular highly branchedhomogeneous compound based on lysine units. U.S. Pat.4289872, Sept.15,1981.
[4] Denkewalter, R. G.; Kolc, J.; Lukasavage, W. J. Preparation of lysine basedmacromolecular highly branched homogeneous compound. U.S. Pat.4360646, Nov.23,1982.
[5] Denkewalter, R. G.; Kolc, J.; Lukasavage, W. J. Macromolecular highly branchedhomogeneous compound. U.S. Pat.4410688, Oct.18,1983.
[6] Tomalia, D. A.; Baker, H.; Dewald, J. R. et al. A new class of polymers: starbust-dendritic macromolecules. Polym. J.(Tokyo)1985,17,117–132.
[7] Tomalia, D. A.; Baker, H.; Dewald, J. R. et al. Dendritic macromolecules:synthesis of starbust dendrimers. Macromolecules1986,19,2466–2468.
[8] Newkome, G. R.; Yao, Z. Q.; Baker, G. R. et al. Part1. Cascade molecules: a newapproach to micelles. A [27]-arborol. J. Org. Chem.1985,50,2003–2004.
[9] W rner, C.; Mülhaupt, R. Polynitrile-and polyamine-functional poly(trimethyleneimine) dendrimers. Angew. Chem. Int. Ed.1993,32,1306–1308.
[10] De Brabander-van Den Berg, E. M. M.; Meijer, E. W. Poly(propylene imine)dendrimers: large-scale synthesis by heterogeneously catalyzed hydrogenations.Angew. Chem. Int. Ed.199332,1308–1311.
[11] Esfand, R.; Tomalia, D. A. Poly(amidoamine)(PAMAM) dendrimers: frombiomimicry to drug delivery and biomedical applications. Drug Discov. Today2001,6,427–436.
[12] Majoros, I. J.; Myc, A.; Thomas, T. et al. PAMAM dendrimer-based multi-functional conjugate for cancer therapy: synthesis, characterization, and functionality.Biomacromolecules2006,7,572–579.
[13] Majoros, I. J.; Thomas, T.; Mehta, C. B. et al. Poly(amidoamine) dendrimer-based multifunctional engineered nanodevice for cancer therapy. J. Med. Chem.2005,48,5892–5899.
[14] Haba, Y.; Harada, A.; Takagishi, T. et al. Rendering poly(amidoamine) orpoly(propylenimine) dendrimers temperature sensitive. J. Am. Chem. Soc.2004,126,12760–12761.
[15] Szalai, M. S.; Kevwitch, R. M.; McGrath, D. V. Geometric disassembly ofdendrimers: dendritic amplification. J. Am. Chem. Soc.2003,125,15688–15689.
[16] Cheng, Y.; Xu, T. Dendrimers as potential drug carriers. Part I. Solubilization ofnon-steroidal anti-inflammatory drugs in the presence of polyamidoamine dendrimers.Eur. J. Med. Chem.2005,40,1188–1192.
[17] Man, N.; Cheng, Y.; Xu, T. et al. Dendrimers as potential drug carriers. Part II.Prolonged delivery of ketoprofen by in vitro and in vivo studies. Eur. J. Med. Chem.2006,41,670–674.
[18] Cheng, Y.; Xu, T.; Fu, R. Polyamidoamine dendrimers used as solubilityenhancers of ketoprofen. Eur. J. Med. Chem.2005,40,1390–1393.
[19] Cheng, Y.; Man, N.; Xu, T. et al. Transdermal delivery of nonsteroidalanti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers. J.Pharm. Sci.2007,96,595–602.
[20] Kannan, S.; Kolhe, P.; Raykova, V. et al. Dynamics of cellular entry and drugdelivery by dendritic polymers into human lung epithelial carcinoma cells. J.Biomater. Sci., Polym. Ed.2004,15,311–330.
[21] Newkome, G. R.; Shreiner, C. D. Poly(amidoamine), polypropylenimine, andrelated dendrimers and dendrons possessing different1→2branching motifs: Anoverview of the divergent procedures. Polymer2008,49,1–173.
[22] Hawker, C. J.; Fréchet, J. M. J. Preparation of polymers with controlledmolecular architecture. A new convergent approach to dendritic macromolecules. J.Am. Chem. Soc.,1990112,7638–7647.
[23] Hawker, C. J.; Fréchet, J. M. J. A new convergent approach to monodispersedendritic macromolecules. J. Chem. Soc., Chem. Commun.1990,1010–1013.
[24] Aulenta, F.; Hayes, W.; Rannard, S. Dendrimers: A new class of nanoscopiccontainers and delivery devices. Eur. Polym. J.2003,39,1741–1771.
[25] Caminade, A.; Laurent, R.; Majoral, J. Characterization of dendrimers. Adv.Drug Deliv. Rev.2005,57,2130–2146.
[26] Lee, C. C.; MacKay, J. A.; Fréchet, J. M. J. et al. Designing dendrimers forbiological applications. Nat. Biotechnol.2005,23,1517–1526.
[27] Farin, D.; Avnir, D. Surface fractality of dendrimers. Angew. Chem. Int. Ed.1991,30,1379–1380.
[28] Jansen, J. F. G. A.; De Brabander-van Den Berg, E. M. M.; Meijer, E. W.Encapsulation of guest molecules into a dendritic box. Science1994,266,1226–1229.
[29] Butler, J. E.; Ni, L.; Nessler, R. et al. The physical and functional behavior ofcapture antibodies adsorbed on polystyrene. J. Immunol. Methods1992,150,77–90.
[30] De Backer, S.; Prinzie, Y.; Verheijen, W. et al. Solvent dependence of thehydrodynamical volume of dendrimers with a rubicene core. J. Phys. Chem. A1998,102,5451–5455.
[31] Elshakre, M.; Atallah, A. S.; Santos, S. et al. A structural study of carbosilanedendrimers versus polyamidoamine. Comput. Theor. Polym. Sci.2000,10,21–28.
[32] Lee, I.; Athey, B. D.; Wetzel, A. W. et al. Structural molecular dynamics studieson polyamidoamine dendrimers for a therapeutic application: Effects of pH andgeneration. Macromolecules2002,35,4510–4520.
[33] Welch, P.; Muthukumar, M. Tuning the density profile of dendriticpolyelectrolytes. Macromolecules1998,31,5892–5897.
[34] Ramzi, A.; Scherrenberg, R.; Joosten, J. et al. Structure-property relations indendritic polyelectrolyte solutions at different ionic strength. Macromolecules2002,35,827–833.
[35] Bosman, A. W.; Janssen, H. M.; Meijer, E. W. About dendrimers: structure,physical Properties, and applications. Chem. Rev.1999,99,1665–1688.
[36] http://www.ninger.com/dendrimer/
[37] Newkome, G. R.; Moorefield, C. N.; Baker, G. R. et al. Alkane cascade polymerswith a micellar topology: micelle acid derivatives. Angew. Chem. Int. Ed.1991,30,1176–1178.
[38] Newkome, G. R.; Moorefield, C. N.; Baker, G. R. et al. Unimolecular micelles.Angew. Chem. Int. Ed.1991,30,1178–1180.
[39] Newkome, G. R.; Behera, R. K.; Moorefield, C. N. et al. Cascade polymers:synthesis and characterization of one-directional arborols based on adamantane. J.Org. Chem.1991,56,7162–7167.
[40]. Newkome, G. R.; Nayak, A.; Behera, R. K. et al. Cascade polymers: synthesisand characterization of four-directional spherical dendritic macromolecules based onadamantane. J. Org. Chem.1992,57,358–362.
[41] Newkome, G. R.; Young, J. K.; Baker, G. R. et al. Cascade polymers. pHdependence of hydrodynamic radii of acid-terminated dendrimers. Macromolecules1993,26,2394–2396.
[42] Launay, N.; Caminade, A. M.; Lahana, R. et al. A general synthetic strategy forneutral phosphorous-containing dendrimers. Angew. Chem. Int. Ed.1994,33,1589–1592.
[43] Launay, N.; Caminade, A. M.; Majoral, J. P. Synthesis and reactivity of unusualphosphorous dendrimers. A useful divergent growth approach upto the seventhgeneration. J. Am. Chem. Soc.1995,117,3282–3283.
[44] Majoral, J. P.; Caminade, A. M. Divergent approaches to phosphorus-containingdendrimers and their functionalization. Top. Curr. Chem.1998,197,79–124.
[45] Marcos, M.; Martin-Rapún, R.; Omenat, A. et al. Highly congested liquid crystalstructures: dendrimers, dendrons, dendronized and hyperbranched polymers. Chem.Soc. Rev.2007,36,1889–1901.
[46] Wooley, K. L.; Hawker, C. J.; Fréchet, J. M. J. Unsymmetrical three-dimensionalmacromolecules: Preparation and characterization of strongly dipolar dendriticmacromolecules. J. Am. Chem. Soc.,1993115,11496–11505.
[47] Gillies, E. R.; Fréchet, J. M. J. Designing macromolecules for therapeuticapplications: polyester dendrimer–poly(ethylene oxide)“bow-tie” hybrids withtunable molecular weight and architecture. J. Am. Chem. Soc.2002,124,14137–14146.
[48] Steffensen, M. B.; Simanek, E. E. Synthesis and manipulation of orthogonallyprotected dendrimers: building blocks for library synthesis. Angew. Chem. Int. Ed.2004,43,5178–5180.
[49] Miller, T. M.; Neenan, T. X. Convergent synthesis of monodisperse dendrimersbased upon1,3,5-trisubstituted benzenes. Chem. Mater.1990,2,346–349.
[50] Miller, T. M.; Neenan, T. X.; Zayas, R. et al. Synthesis and characterization of aseries of monodisperse,1,3,5-phenylene-based hydrocarbon dendrimers includingC276H186and their fluorinated analogs. J. Am. Chem. Soc.1992,114,1018–1025.
[51] Pillow, J. N. G.; Halim, M.; Lupton, J. M. et al. A facile iterative procedure forthe preparation of dendrimers containing luminescent cores and stilbene dendrons.Macromolecules1999,32,5985–5993.
[52] Pillow, J. N. G.; Burn, P. L.; Samuel, I. D. W. et al. Synthetic routes to phenylenevinylene dendrimers. Synth. Met.1999,102,1468–1469.
[53] Miller, T. M.; Kwock, E. W.; Neenan, T. X. Synthesis of four generations ofmonodisperse aryl ester dendrimers based on1,3,5-benzenetricarboxylic acid.Macromolecules1992,25,3143–3148.
[54] Kwock, E. W.; Neenan, T. X.; Miller, T. M. Convergent synthesis ofmonodisperse aryl ester dendrimers. Chem. Mater.1991,3,775–777.
[55] Kadei, K.; Moors, R.; V gtle, F. Dendrimers and dendrimer building blocks withtrisubstituted benzene and ‘hexacyclene’ as core units. Chem. Ber.1994,127,897–903.
[56] Louie, J.; Hartwig, J. F.; Fry, A. J. Discrete high molecular weight triarylaminedendrimers prepared by palladium-catalyzed amination. J. Am. Chem. Soc.1997,119,11695–11696.
[57] Sadalapure, K.; Lindhorst, T. K. A general entry into glycopeptide dendrons.Angew. Chem. Int. Ed.2000,39,2010–2013.
[58] Wooley, K. L.; Hawker, C. J.; Fréchet, J. M. J. Hyperbranched macromoleculesvia a novel double-stage convergent growth approach. J. Am. Chem. Soc.1991,113,4252–4261.
[59] Xu, Z. F.; Kahr, M.; Walker, K. L. et al. Phenylacetylene dendrimers by thedivergent, convergent, and double-stage convergent methods. J. Am. Chem. Soc.1994,116,4537–4550.
[60] Kawaguchi, T.; Walker, K. L.; Wilkins, C. L. et al. Double exponentialdendrimer growth. J. Am. Chem. Soc.1995,117,2159–2165.
[61] Spindler, R.; Fréchet, J. M. J. Two-step approach towards the acceleratedsynthesis of dendritic macromolecules. J. Chem. Soc., Perkin Trans.11993,913–918.
[62] Zeng, F.; Zimmerman, S. C. Rapid synthesis of dendrimers by an orthogonalcoupling strategy. J. Am. Chem. Soc.1996,118,5326–5327.
[63] Deb, S. K.; Maddux, T. M.; Yu, L. A simple orthogonal approach topoly(phenylenevinylene) dendrimers. J. Am. Chem. Soc.1997,119,9079–9080.
[64] Ishida, Y.; Jikei, M.; Kakimoto, M. Rapid synthesis of aromatic polyamidedendrimers by an orthogonal and a double-stage convergent approach.Macromolecules2000,33,3202–3211.
[65] Maraval, V.; Pyzowski, J.; Caminade, A. M. et al.“Lego” chemistry for thestraightforward synthesis of dendrimers. J. Org. Chem.2003,68,6043–6046.
[66] Maraval, V.; Caminade, A. M; Majoral, J. P. et al. Dendrimer design: how tocircumvent the dilemma of a reduction of steps or an increase of function multiplicity?Angew. Chem. Int. Ed.2003,42,1822–1826.
[67] Maraval, V.; Laurent, R.; Marchand, P. et al. Accelerated methods of synthesis ofphosphorus-containing dendrimers. J. Organomet. Chem.2005,690,2458–2471.
[68] Mathias, J. P.; Stoddart, F. Constructing a molecular LEGO set. Chem. Soc. Rev.1992,21,215–225.
[69] Ashton, P. R.; Brown, G. R.; Isaacs, N. S. et al. Molecular LEGO.1. Substrate-directed synthesis via stereoregular Diels-Alder oligomerizations. J. Am. Chem. Soc.1992,114,6330–6353.
[70] B rner, H. G. Multifuctional polymer-bioconjugates as molecular LEGO bricks.Macromol. Chem. Phys.2007,208,124–130.
[71] Bolz, I.; May, C.; Spange, S. Solvatochromic properties of Schiff bases derivedfrom5-aminobarbituric acid: chromophores with hydrogen bonding pattens ascomponents for coupled structures. New J. Chem.2007,31,1568–1571.
[72] Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click chemistry: Diverse chemicalfunction from a few good reactions. Angew. Chem. Int. Ed.2001,40,2004–2021.
[73] Wu, P.; Feldman, A. K.; Nugent, A. K. et al. Efficiency and fidelity in aclick-chemistry route to triazole dendrimers by the copper(I)-catalyzed ligation ofazides and alkynes. Angew. Chem. Int. Ed.2004,43,3928–3932.
[74] Wu, P.; Malkoch, M.; Hunt, J. N. et al. Multivalent, bifunctional dendrimersprepared by click chemistry. Chem. Commun.2005,46,5775–5777.
[75] Touaibia, M.; Wellens, A.; Shiao, T. C. et al. Mannosylated G(0) dendrimers withnanomolar affinities to Escherichia coli FimH. ChemMedChem2007,8,1190–1201.
[76] Dijkgraaf, I.; Rijnders, A. Y.; Soede, A. et al. Synthesis of DOTA-conjugatedmultivalent cyclic-RGD peptide dendrimers via1,3-dipolar cycloaddition and theirbiological evaluation: implications for tumor targeting and tumor imaging purposes.Org. Biomol. Chem.2007,6,935–944.
[77] Gopin, A.; Ebner, E.; Attali, B. et al. Enzymatic activation of second-generationdendritic prodrugs: conjugation of self-immolative dendrimers with poly(ethyleneglycol) via click chemistry. Bioconjugate Chem.2006,17,1432–1440.
[78] Ornelas, C.; Aranzaes, J. R.; Clouter, E. et al. Click assembly of1,2,3-triazole-linked dendrimers, including ferrocenyl dendrimers, which sense both oxo anions andmetal cations. Angew. Chem. Int. Ed.2007,46,872–877.
[79] Ornelas, C.; Aranzaes, J. R.; Salmon, L. et al.“Click” dendrimers: synthesis,redox sensing of Pd(OAc)2and remarkable catalytic hydrogenation activity of precisePd nanoparticles stabilized by1,2,3-triazole-containing dendrimers. Chem. Eur. J.2008,14,50–64.
[80] Killops, K. L.; Campos, L. M.; Hawker, C. J. Robust, efficient, and orthogonalsynthesis of dendrimers via thiol-ene “click” chemistry. J. Am. Chem. Soc.2008,130,5062–5064.
[81] Bhyrappa, P.; Young, J. K.; Moore., J. S. et al. Dendrimer-metalloporphyrins:synthesis and catalysis. J. Am. Chem. Soc.1996,118,5708–5711.
[82] Ouali, A.; Laurent, R.; Caminade, A.-M. et al. Enhanced catalytic properties ofcopper in O-and N-arylation and vinylation reactions, using phosphorus dendrimersas ligands. J. Am. Chem. Soc.2006,128,15990–15991.
[83] Zhao, M.; Helms, B.; Slonkina, E. et al. Iron complexes of dendrimer-appendedcarboxylates for activating dioxygen and oxidizing hydrocarbons. J. Am. Chem. Soc.2008,130,4352–4363.
[84] Karakhanov, E. A.; Maximov, A. L.; Tarasevich, B. N. et al. Dendrimer-basedcatalysts in Wacker-oxidation: Unexpected selectivity to terminal double bonds. J.Mol. Catal. A: Chem.2009,297,73–79.
[85] Pittelkow, M.; Brock-Nannestad, T.; Moth-Poulsen, K. et al. Chiral dendrimerencapsulated Pd and Rh nanoparticles. Chem. Commun.2008,2358–2368.
[86] Ma, C.-Q.; Mena-Osteritz, E.; Debaerdemaeker, T. et al. Functionalized3Doligothiophene dendrons and dendrimers—Novel macromolecules for organicelectronics. Angew. Chem. Int. Ed.2007,46,1679–1683.
[87] Samoc, M.; Morrall, J. P.; Dalton, G. T. et al. Two-photon and three-photonabsorption in an organometallic dendrimer. Angew. Chem. Int. Ed.2007,46,731–733.
[88] Zhou, G.; Wong, W.-Y.; Yao, B. et al. Triphenylamine-dendronized pure rediridium phosphors with superior OLED efficiency/color purity trade-offs. Angew.Chem. Int. Ed.2007,46,1149–1151.
[89] Adhikari, R. M.; Mondal, R.; Shah, B. K. et al. Synthesis and photophysicalproperties of carbazole-based blue light-emitting dendrimers. J. Org. Chem.2007,72,4727–4732.
[90] Sanji, T.; Shiraishi, K.; Tanaka, M. Synthesis and photophysical properties ofphosphole-cored dendrimers. Org. Lett.2007,9,3611–3614.
[91] Taranekar, P.; Fulghum, T.; Patton, D. et al. Investigating carbazole jacketedprecursor dendrimers: Sonochemical synthesis, characterization, and electrochemicalcrosslinking properties. J. Am. Chem. Soc.2007,129,12537–12548.
[92] Won, K.-T.; Yu-Hsien, L.; Wu, H.-H. Synthesis and properties of dumbbell-shaped dendrimers containing9-phenylcarbazole dendrons. Org. Lett.2007,9,4531–4534.
[93] Jiang, Y.; Lu, Y.-X.; Cui, Y.-X. et al. Synthesis of giant rigid π-conjugateddendrimers. Org. Lett.2007,9,4539–4542.
[94] Jayamurugan, G.; Umesh, C. P.; Jayaraman, N. Inherent photoluminescenceproperties of poly(propyl ether ether imine) dendrimers. Org. Lett.2008,10,9-12.
[95] Xu, T.; Lu, R.; Liu, X. et al. Synthesis and characterization of subporphyrinswith dendritic carbazole arms. Eur. J. Org. Chem.2008,1065–1071.
[96] Giansante, C.; Ceroni, P.; Balzani, V. et al. Self-assembly of a light-harvestingantenna formed by a dendrimer, a RuIIcomplex, and a NdIIIion. Angew. Chem. Int.Ed.2008,47,5422–5425.
[97] Fernández, G.; Pérez, E. M.; Sánchez, L. et al. An electroactive dynamicallypolydisperse supramolecular dendrimer. J. Am. Chem. Soc.2008,130,2410–2411.
[98] Gillies, E. R.; Fréchet, J. M. J. Dendrimers and dendritic polymers in drugdelivery. Drug Discov. Today2005,10,35–43.
[99] Cheng, Y.; Wang, J.; Rao, T. et al. Pharmaceutical applications of dendrimers:Promising nanocarriers for drug delivery. Front. Biosci.2008,13,1447–1471.
[100] Cheng, Y.; Xu, Z.; Ma, M. et al. Dendrimers as drug carriers: Applications indifferent routes of drug administration. J. Pharm. Sci.2008,97,123–143.
[101] Cheng, Y.; Gao, Y.; Rao, T. et al. Dendrimer-based prodrugs: Design, synthesis,screening and biological evaluation. Comb. Chem. High Throughput Screen.2007,10,336–349.
[102] Villalonga-Barber, C.; Micha-Screttas, M.; Steele, B. R. et al. Dendrimers asbiopharmaceuticals: Synthesis and properties. Curr. Top. Med. Chem.2008,8,1294–1309.
[103] Yang, W.; Cheng, Y.; Xu, T. et al. Targeting cancer cells with biotin-dendrimerconjugates. Eur. J. Med. Chem.2009,44,862–868.
[104] Hong, S.; Bielinska, A. U.; Mecke, A. et al. Interaction of poly(amidoamine)dendrimers with supported lipid bilayers and cells: Hole formation and the relation totransport. Bioconjugate Chem.2004,15,774–782.
[105] Chen, H.-T.; Neerman, M. F.; Parrish, A. R. et al. Cytotoxicity, hemolysis, andacute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drugdelivery. J. Am. Chem. Soc.2004,126,10044–10048.
[106] Malik, N.; Wiwattanapatapee, R.; Klopsch, R. et al. Dendrimers: Relationshipbetween structure and biocompatibility in vitro, and preliminary studies on thebiodistribution of125I-labelled polyamidoamine dendrimers in vivo. J. ControlledRelease2000,65,133–148.
[107] Roberts, J. C.; Bhalgat, M. K.; Zera, R. T. Preliminary biological evaluation ofpolyamidoamine (PAMAM) Starburst dendrimers. J. Biomed. Mater. Res.1996,30,53–65.
[108] Fischer, D.; Li, Y.; Ahlemeyer, B. et al. In vitro cytotoxicity testing ofpolycations: Influence of polymer structure on cell viability and hemolysis.Biomaterials2003,24,1121–1131.
[109] Kobayashi, H.; Kawamoto, S.; Saga, T. et al. Positive effects of polyethyleneglycol conjugation to generation-4polyamidoamine dendrimers as macromolecularMR contrast agents. Magn. Res. Med.2001,46,781–788.
[110] Plank, C.; Mechtler, K.; Szoka, F. C. Jr. et al. Activation of the complementsystem by synthetic DNA complexes: A potential barrier for intravenous genedelivery. Human Gene Ther.1996,7,1437–1446.
[111] Kobayashi, H.; Sato, N.; Kawamoto, S. et al. Comparison of the macro-molecular MR contrast agents with ethylenediamine-core versus ammonia-coregeneration-6polyamidoamine dendrimer. Bioconjugate Chem.2001,12,100–107.
[112] Brem, H.; Walter, K. A.; Langer, R. Polymers as controlled drug deliverydevices for the treatment of malignant brain tumors. Eur. J. Pharm. Biopharm.1993,39,2–7.
[113] Batz, H. G.; Franzmann, G.; Ringsdorf, H. Model reactions for synthesis ofpharmacologically active polymers by way of monomeric and polymeric reactiveesters. Angew. Chem. Int. Ed.1972,11,1103–1104.
[114] Ringsdorf, H. Structure and properties of pharmacologically active polymers. J.Polym. Sci. Polym. Symp.1975,5,135–153.
[115] Shatayeva, L. K.; Samsonov, G. V.; Vacik, J. et al. Permeability of hetero-generous membrances based on methacrylic acid. J. Appl. Polym. Sci.1979,23,2245–2251.
[116] Duncan, R. Drug-polymer conjugates: Potential for improved chemotherapy.Anti-Cancer Drugs1992,3,175–210.
[117] Gillies, E. R.; Dy, E.; Fréchet, J. M. J. et al. Biological evaluation of polyesterdendrimer: Poly(ethylene oxide)“bow-tie” hybrids with tunable molecular weightand architecture. Mol. Pharm.2005,2,129–138.
[118] Cheng, Y.; Xu, T. The effect of dendrimers on the pharmacodynamic andpharmacokinetic behaviors of non-covalently or covalently attached drugs. Eur. J.Med. Chem.2008,43,2291–2297.
[119] Newkome, G. R.; Lin, X.; Yaxiong, C. et al. Two-directional cascade polymersynthesis: Effects of core variation. J. Org. Chem.1993,58,3123–3129.
[120] Moorefield, C. N.; Newkome, G. R. Unimolecular micelles: Supramolecular useof dendritic constructs to create versatile molecular containers. Compt. Rend. Chim.2003,6,715–724.
[121] Hawker, C. J.; Wooley, K. L.; Fréchet, J. M. J. Unimolecular micelles andglobular amphiphiles: Dendritic macromolecules as novel recyclable solubilizationagents. J. Chem. Soc., Perkin Trans.11993,12,1287–1297.
[122] Twyman, L. J.; Beezer, A. E.; Esfand, R. et al. The synthesis of water solubledendrimers, and their application as possible drug delivery systems. Tetrahedron Lett.1999,40,1743–1746.
[123] Beezer, A. E.; King, A. S. H.; Martin, I. K. et al. Dendrimers as potential drugcarriers; encapsulation of acidic hydrophobes within water soluble PAMAMderivatives. Tetrahedron2003,59,3873–3880.
[124] Wallimann, P.; Seiler, P.; Diederich, F. Dendrophanes: Novel steroid-recognizing dendritic receptors: Preliminary communication. Helv. Chim. Acta1996,79,779–788.
[125] Kolhe, P.; Misra, E.; Kannan, R. M. et al. Drug complexation, in vitro releaseand cellular entry of dendrimers and hyperbranched polymers. Int. J. Pharm.2003,259,143–160.
[126] Baars, M. W. P. L.; Karlsson, A. J.; Sorokin, V. et al. Supramolecular modifica-tion of the periphery of dendrimers resulting in rigidity and functionality. Angew.Chem. Int. Ed.2000,39,4262–4265.
[127] Boas, U.; Karlsson, A. J.; De Waal, B. F. M. et al. Synthesis and properties ofnew thiourea-functionalized poly(propylene imine) dendrimers and their role as hostsfor urea functionalized guests. J. Org. Chem.2001,66,2136–2145.
[128] Uhrich, K.; Cannizzaro, S.; Langer, R. et al. Polymeric systems for controlleddrug release. Chem. Rev.1999,99,3181–3198.
[129] Kolhe, P.; Khandare, J.; Pillai, O. et al. Preparation, cellular transport, andactivity of polyamidoamine-based dendritic nanodevices with a high drug payload.Biomaterials2006,27,660–669.
[130] Milhem, O. M.; Myles, C.; McKeown, N. B. et al. Polyamidoamine Starburstdendrimers as solubility enhancers. Int. J. Pharm.2000,197,239–241.
[131] Gurdag, S.; Khandare, J.; Stapels, S. et al. Activity of dendrimer-methotrexateconjugates on methotrexate-sensitive and-resistant cell lines. Bioconjugate Chem.2006,17,275–283.
[132] Roy, R.; Baek, M. G. Glycodendrimers: novel glycotope isosteres unmaskingsugar coding. Case study with T-antigen markers from breast cancer MUC1glycoprotein. Rev. Mol. Biotechnol.2002,90,291–309.
[133] Thomas, T. P.; Majoros, I. J.; Kotlyar, A. et al. Targeting and inhibition of cellgrowth by an engineered dendritic nanodevice. J. Med. Chem.2005,48,3729–3735.
[134] Barth, R. F.; Adams, D. M.; Soloway, A. H. et al. Boronated starburstdendrimer-monoclonal antibody immunoconjugates: Evaluation as a potentialdelivery system for neutron capture therapy. Bioconjugate Chem.1994,5,58–66.
[135] Yang, W. L.; Barth, R. F.; Adams, D. M. et al. Intratumoral delivery ofboronated epidermal growth factor for neutron capture therapy of brain tumors.Cancer Res.1997,57,4333–4339.
[136] Thomas, T. P.; Patri, A. K.; Myc, A. et al. In vitro targeting of synthesizedantibody-conjugated dendrimer nanoparticles. Biomacromolecules2004,5,2269–2274.
[137] Shaunak, S.; Thomas, S.; Gianasi, E. et al. Polyvalent dendrimer glucosamineconjugates prevent scar tissue formation. Nat. Biotechnol.2004,22,977–984.
[138] Liu, M.; Kono, K.; Fréchet, J. M. J. Water-soluble dendrimer-poly(ethyleneglycol) starlike conjugates as potential drug carriers. J. Polym. Sci., Part A: Polym.Chem.1999,37,3492–3503.
[139] Amir, R. J.; Pessah, N.; Shamis, M. et al. Self-immolative dendrimers. Angew.Chem. Int. Ed.2003,42,4494–4499.
[140] de Groot, F. M. H.; Albrecht, C.; Koekkoek, R. et al.“Cascade-releasedendrimers” liberate all end groups upon a single triggering event in the dendriticcore. Angew. Chem. Int. Ed.2003,42,4490–4494.
[141] Shamis, M.; Lode, H. N.; Shabat, D. Bioactivation of self-immolative dendriticprodrugs by catalytic antibody38C2. J. Am. Chem. Soc.2004,126,1726–1731.
[142] Sagi, A.; Segal, E.; Satchi-Fainaro, R. et al. Remarkable drug-releaseenhancement with an elimination-based AB3self-immolative dendritic amplifier.Bioorg. Med. Chem.2007,15,3720–3727.
[143] Amir, R. J.; Danieli, E.; Shabat, D. Receiver–amplifier, self-immolativedendritic device. Chem. Eur. J.2007,13,812–821.
[144] Malik, N.; Evagorou, E. G.; Duncan, R. Dendrimer-platinate: A novel approachto cancer chemotherapy. Anti-Cancer Drugs1999,10,767–776.
[145] Howell, B. A.; Fan, D.; Rakesh, L. Thermal decomposition of a generation4.5PAMAM dendrimer platinum drug conjugate. J. Therm. Anal. Calorim.2006,85,17–20.
[146] Tang, S.; Martinez, L. J.; Sharma, A. et al. Synthesis and characterization ofwater-soluble and photostable L-DOPA dendrimers. Org. Lett.2006,8,4421–4424.
[147] Tang, S.; June, S. M.; Howell, B. A. et al. Synthesis of salicylate dendriticprodrugs. Tetrahedron Lett.2006,47,7671–7675.
[148] Wiener, E. C.; Brechbiel, M. W.; Brothers, H. et al. Dendrimer-based metalchelates: a new class of magnetic resonance imaging contrast agents. Magn. Reson.Med.1994,31,1–8.
[149] Longmire, M.; Choyke, P. L.; Kobayashi, H. Dendrimer-based contrast agentsfor molecular imaging. Curr. Top. Med. Chem.2008,8,1180–1186.
[150] Kobayashi, H.; Brechbiel, M. W. Nano-sized MRI contrast agents withdendrimer cores. Adv. Drug Deliv. Rev.2005,57,2271–2286.
[151] Kobayashi, H.; Kawamoto, S.; Jo, S.-K. et al. Macromolecular MRI contrastagents with small dendrimers: pharmacokinetic differences between sizes and cores.Bioconjugate Chem.2003,14,388–394.
[152] Talanov, V. S.; Regino, C. A. S.; Kobayashi, H. et al. Dendrimer-basednanoprobe for dual modality magnetic resonance and fluorescence imaging. NanoLett.2006,6,1459–1463.
[153] Kobayashi, H.; Kawamoto, S.; Choyke, P. L. et al. Comparison of dendrimer-based macromolecular contrast agents for dynamic micro-magnetic resonancelymphangiography. Magn. Reson. Med.2003,50,758–766.
[154] Kobayashi, H.; Kawamoto, S.; Star, R. A. et al. Micro-magnetic resonancelymphangiography in mice using a novel dendrimer-based magnetic resonanceimaging contrast agent. Cancer Res.2003,63,271–276.
[155] Kobayashi, H.; Brechbiel, M. W. Dendrimer-based macromolecular MRIcontrast agents: characteristics and application. Mol. Imaging2003,2,1–10.
[156] Dijkgraaf, I.; Rijnders, A. Y.; Soede, A. et al. Synthesis of DOTA-conjugatedmultivalent cyclic-RGD peptide dendrimers via1,3-dipolar cycloaddition and theirbiological evaluation: Implications for tumor targeting and tumor imaging purposes.Org. Biomol. Chem.2007,5,935–944.
[157] Regino, C. A. S.; Walbridge, S.; Bernardo, M. et al. A dual CT-MR dendrimercontrast agent as a surrogate marker for convection-enhanced delivery of intracerebralmacromolecular therapeutic agents. Contrast Media Mol. Imaging2008,3,2–8.
[158] Heinen, S.; Walder, L. Generation-dependent intramolecular CT complexationin a dendrimer electron sponge consisting of a viologen skeleton. Angew. Chem. Int.Ed.2000,39,806–809.
[159] Subbarayan, M.; Shetty, S. J.; Srivastava, T. S. et al. Water-soluble99mTc-labeled dendritic novel porphyrins tumor imaging and diagnosis. Biochem. Biophys.Res. Commun.2001,281,32–36.
[160] Balzani, V.; Ceroni, P.; Gestermann, S. et al. Effect of protons and metal ions onthe fluorescence properties of a polylysin dendrimer containing twenty four dansylunits. J. Chem. Soc., Dalton Trans.2000,3765–3771.
[161] Zheng, J.; Dickson, R. M. Individual water-soluble dendrimer-encapsulatedsilver nanodot fluorescence. J. Am. Chem. Soc.2002,124,13982–13983.
[162] Paulo, P. M. R.; Gronheid, R.; De Schryver, F. C. et al. Porphyrin-dendrimerassemblies studied by electronic absorption spectra and time-resolved fluorescence.Macromolecules2003,36,9135–9144.
[163] Lee, J. W.; Kim, H. J.; Han, S. C. et al. Synthesis and characterization ofpoly(amido amine) dendrimer containing fluorene as a core chromophore. J. Nanosci.Nanotech.2008,8,4635–4639.
[164] Dufès, C.; Uchegbu, I. F.; Sch tzlein, A. G. Dendrimers in gene delivery. Adv.Drug Deliv. Rev.2005,57,2177–2202
[165] Parekh, H. S. The advance of dendrimers—A versatile targeting-platform forgene/drug delivery. Cur. Pharm. Des.2007,13,2837–2850.
[166] Luo, D.; Haverstick, K.; Belcheva, N. et al. Poly(ethylene glycol)-conjugatedPAMAM dendrimer for biocompatible, high-efficiency DNA delivery.Macromolecules2002,35,3456–3462.
[167] Wada, K.; Arima, H.; Tsutsumi, T. et al. Improvement of gene deliverymediated by mannosylated dendrimer/α-cyclodextrin conjugates. J. ControlledRelease2005,104,397–413.
[168] Kim, J.-B.; Choi, J. S.; Nam, K. et al. Enhanced transfection of primary corticalcultures using arginine-grafted PAMAM dendrimer, PAMAM-Arg. J. ControlledRelease2006,114,110–117.
[169] Choi, J. S.; Ko, K. S.; Park, J. S. et al. Dexamethasone conjugatedpoly(amidoamine) dendrimer as a gene carrier for efficient nuclear translocation. Int.J. Pharm.2006,320,171–178.
[170] Maiti, P. K.; Bagchi, B. Structure and dynamics of DNA-dendrimercomplexation: Role of counterions, water, and base pair sequence. Nano Lett.2006,6,2478–2485.
[171] Kim, T.-i.; Baek, J.-u.; Bai, C. Z. et al. Arginine-conjugated polypropyleniminedendrimer as a non-toxic and efficient gene delivery carrier. Biomaterials2007,28,2061–2067.
[172] Tsutsumi, T.; Hirayama, F.; Uekama, K. et al. Evaluation of polyamidoaminedendrimer/α-cyclodextrin conjugate (generation3, G3) as a novel carrier for smallinterfering RNA (siRNA). J. Controlled Release2007,119,349–359.
[173] Rozkiewicz, D. I.; Brugman, W.; Kerkhoven, R. M. et al. Dendrimer-mediatedtransfer printing of DNA and RNA microarrays. J. Am. Chem. Soc.2007,129,11593–11599.
[174] Pasupathy, K.; Lin, S.; Hu, Q. et al. Direct plant gene delivery with apoly(amidoamine) dendrimer. Biotechnol. J.2008,3,1078–1082.
[175] Arotiba, O.; Owino, J.; Songa, E. et al. An electrochemical DNA biosensordeveloped on a nanocomposite platform of gold and poly(propyleneimine) dendrimer.Sensors2008,8,6791–6809.
[176] Nam, H. Y.; Nam, K.; Hahn, H. J. et al. Biodegradable PAMAM ester forenhanced transfection efficiency with low cytotoxicity. Biomaterials2009,30,665–673.
[177] Mintzer, M. A.; Simanek, E. E. Nonviral vectors for gene delivery. Chem. Rev.2009,109,259–302.
[178] Grinstaff, M. W. Dendritic macromers for hydrogel formation: Tailoredmaterials for ophthalmic, orthopedic, and biotech applications. J. Polym. Sci., Part A:Polym. Chem.2008,46,383–400.
[179] Grinstaff, M. W. Biodendrimers: New polymeric biomaterials for tissueengineering. Chem. Eur. J.2002,8,2838–2846.
[180] Duan, X.; Sheardown, H. Dendrimer crosslinked collagen as a corneal tissueengineering scaffold: Mechanical properties and corneal epithelial cell interactions.Biomaterials2006,27,4608–4617.
[181] Cai, Q.; Zhao, Y.; Bei, J. et al. Synthesis and properties of star-shapedpolylactide attached to poly(amidoamine) dendrimer. Biomacromolecules2003,4,828–834.
[182] S ntjens, S. H. M.; Nettles, D. L.; Carnahan, M. A. et al. Biodendrimer-basedhydrogel scaffolds for cartilage tissue repair. Biomacromolecules2006,7,310–316.
[183] Langer, R. Drug delivery and targeting. Nature1998,392(6679SUPPL.),5–10.
[184] Ihre, H.; Hult, A.; Fréchet, J. M. J. et al. Double-stage convergent approach forthe synthesis of functionalized dendritic aliphatic polyesters based on2,2-bis(hydroxymethyl)propionic acid. Macromolecules1998,31,4061–4068.
[185] Padilla De Jesús, O. L.; Ihre, H. R.; Gagne, L. et al. Polyester dendritic systemsfor drug delivery applications: In vitro and in vivo evaluation. Bioconjugate Chem.2002,13,453–461.
[186] Ihre, H. R.; Padilla De Jesús, O. L.; Szoka, F. C. Jr. et al. Polyester dendriticsystems for drug delivery applications: Design, synthesis, and characterization.Bioconjugate Chem.2002,13,443–452.
[187] Luman, N. R.; Kim, T.; Grinstaff, M. W. Dendritic polymers composed ofglycerol and succinic acid: Synthetic methodologies and medical applications. PureAppl. Chem.2004,76,1375–1385.
[188] Hirayama, Y.; Sakamoto, Y.; Yamaguchi, K. et al. Synthesis of polyesterdendrimers and dendrons starting from Michael reaction of acrylates with3-hydroxyacetophenone. Tetrahedron Lett.2005,46,1027–1030.
[189] Carnahan, M. A.; Grinstaff, M. W. Synthesis of generational polyesterdendrimers derived from glycerol and succinic or adipic acid. Macromolecules2006,39,609–616.
[190] Gingras, M.; Raimundo, J.-M.; Chabre, Y. M. Cleavable dendrimers. Angew.Chem. Int. Ed.2007,46,1010–1017.
[191] Satija, J.; Gupta, U.; Jain, N. K. Pharmaceutical and biomedical potential ofsurface engineered dendrimers. Crit. Rev. Ther. Drug Carrier Syst.2007,24,257–306.
[192] Darbre, T.; Reymond, J.-L. Peptide dendrimers as artificial enzymes, receptors,and drug-delivery agents. Acc. Chem. Res.2006,39,925–934.
[193] Crespo, L.; Sanclimens, G.; Pons, M. et al. Peptide and amide bond-containingdendrimers. Chem. Rev.2005,105,1663–1681.
[194] Chow, H.-F.; Mak, C. C. Synthesis and chiroptical properties of layer-blockdendrimers. Pure Appl. Chem.1997,69,483–488.
[195] Chow, H.-F.; Mak, C. C. Synthesis and structure-optical rotation relationshipsof homochiral, monodisperse, tartaric acid-based dendrimers. J. Chem. Soc., PerkinTrans.11994,2223–2228.
[196] Chow, H.-F.; Mak, C. C. Facile preparation of optically active dendriticfragments containing multiple tartrate-derived chiral units. Tetrahedron Lett.1996,37,5935–5938.
[197] Chow, H.-F.; Mak, C. C. Preparation and structure-chiroptical relationships oftartaric acid-based layer-block chiral dendrimers. J. Chem. Soc., Perkin Trans.11997,91–95.
[198] Buschhaus, B.; Bauer, W.; Hirsch, A. Synthesis and chiroptical properties of anew type of chiral depsipeptide dendrons. Tetrahedron2003,59,3899–3915.
[199] Maurer, K.; Hager, K.; Hirsch, A. Self-assembly and chiroptical properties ofchiral dendrimers consisting of a Hamilton receptor substituted porphyrin anddepsipeptide cyanurates. Eur. J. Org. Chem.2006,3338–3347.
[200] Ghosh, S.; Banthia, A. K. Toward chiral polyamidoamine (PAMAM) dendriticarchitecture with tartaric acid core. J. Indian Chem. Soc.2002,79,442–443.
[201] Singh, G.; Triadafilopoulos, G. Epidemiology of NSAID induced gastro-intestinal complications. J. Rheumatol. Suppl.1999,56,18–24.
[202] Cena, C.; Lolli, M. L.; Lazzarato, L. et al. Antiinflammatory, gastrosparing, andantiplatelet properties of new NO-donor esters of aspirin. J. Med. Chem.2003,46,747–754.
[203] Yumiko, N.; Kozo, T.; Kimio, H. Promoting effect of o-ethylmenthol on thepercutaneous absorption of ketoprofen. Int. J. Pharm.1996,145,29–36.
[204] Makiko, F.; Naohide, H.; Kumi, S. Effect of fatty acid esters on permeation ofketoprofen through hairless rat skin. Int. J. Pharm.2000,205,117–125.
[205] Vergote, G. J.; Vervaet, C.; Driessche, I. V. An oral controlled release matrixpellet formulation containing nanocrystalline ketoprofen. Int. J. Pharm.2001,219,81–87.
[206] Sloan, K.B.; Wasdo, S. Designing for topical delivery: Prodrugs can make thedifference. Med. Res. Rev.2003,23,763–793.
[207] Ahuja, M.; Dhake, A. S.; Sharma, S. K. et al. Topical ocular delivery ofNSAIDs. AAPS J.2008,10,229–241.
[208] MacNaughton, W. K.; Cirino, G.; Wallace, J. L. Endothelium-derived relaxingfactor (nitric oxide) has protective actions in the stomach. Life Sci.1989,45,1869–1876.
[209] Kitagawa, H., Takeda, F., Kohei, H. Effect of endothelium-derived relaxingfactor on the gastric lesion induced by HCl in rats. J. Pharmacol. Exp. Ther.1990,253,1133–1137.
[210] Wallace, J. L.; Granger, D. N. The cellular and molecular basis of gastricmucosal defence. FASEB J.1996,10,731–740.
[211] Fiorucci, S.; Santucci, L.; Gresele, P. et al. Gastrointestinal safety of NO-aspirin(NCX-4016) in healthy human volunteers: A proof of concept endoscopic study.Gastroenterology2003,124,600–607.
[212] Davies, N. M.; Roseth, A. G.; Appleyard, C. B. et al. NO-naproxen vs. naproxen:Ulcerogenic, analgesic and anti-inflammatory effects. Aliment. Pharmacol. Ther.1997,11,69–79.
[213] Lanas, A.; Bajador, E.; Serrano, P. et al. Nitrovasodilators, low-dose aspirin,nonsteroidal anti-inflammatory drugs, and the risk of upper gastrointestinal bleeding.New Engl. J. Med.2000,343,834–839.
[214] Lanas, A.; García-Rodríguez, L. A.; Arroyo, M. T. et al. Effect of antisecretorydrugs and nitrates on the risk of ulcer bleeding associated with nonsteroidalanti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am. J. Gastroenterol.2007,102,507–515.
[215] Schoenfeld, P.; Kimmey, M. B.; Scheiman, J. et al. Review article: Nonsteroidalanti-inflammatory drug-associated gastrointestinal complications—Guidelines forprevention and treatment. Aliment. Pharmacol. Ther.1999,13,1273–1285.
[216] Ranatunge, R. R.; Augustyniak, M. E.; Dhawan, V. et al. Synthesis andanti-inflammatory activity of a series of N-substituted naproxen glycolamides: Nitricoxide-donor naproxen prodrugs. Bioorg. Med. Chem.2006,14,2589–2599.
[217] Ongini, E.; Bolla, M. Nitric-oxide based nonsteroidal anti-inflammatory agents.Drug Discov. Today: Ther. Strat.2006,3,395–400.
[218] Cena, C.; Lolli, M. L.; Lazzarato, L. et al. Antiinflammatory, gastrosparing, andantiplatelet properties of new NO-donor esters of aspirin. J. Med. Chem.2003,46,747–754.
[219] Chiroli, V.; Benedini, F.; Ongini, E. et al. Nitric oxide-donating non-steroidalanti-inflammatory drugs: The case of nitroderivatives of aspirin. Eur. J. Med. Chem.2003,38,441–446.
[220] Fiorucci, S.; Santucci, L.; Distrutti, E. NSAIDs, coxibs, CINOD andH2S-releasing NSAIDs: What lies beyond the horizon. Digest. Liver Dis.2007,39,1043–1051.
[221] Velázquez, C. A.; Praveen Rao, P. N.; Citro, M. L. et al. O2-Acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs): Synthesis, nitric oxiderelease, and biological evaluation studies. Bioorg. Med. Chem.2007,15,4767–4774.
[222] Abadi, A. H.; Hegazy, G. H.; El-Zaher, A. A. Synthesis of novel4-substituted-7-trifluoromethylquinoline derivatives with nitric oxide releasing properties and theirevaluation as analgesic and anti-inflammatory agents. Bioorg. Med. Chem.2005,13,5759–5765.
[223] Ziakas, G. N.; Rekka, E. A.; Gavalas, A. M. et al. Nitric oxide releasingderivatives of tolfenamic acid with anti-inflammatory activity and safegastrointestinal profile. Bioorg. Med. Chem.2005,13,6485–6492.
[224] Hulsman, N.; Medema, J. P.; Bos, C. et al. Chemical insights in the concept ofhybrid drugs: The antitumor effect of nitric oxide-donating aspirin involves a quinonemethide but not nitric oxide nor aspirin. J. Med. Chem.2007,50,2424–2431.
[225] Kashfi, K.; Rigas, B. The mechanism of action of nitric oxide-donating aspirin.Biochem. Biophys. Res. Commun.2007,358,1096–1101.
[226] Rigas, B.; Williams, J. L. NO-donating NSAIDs and cancer: An overview witha note on whether NO is required for their action. Nitric Oxide Biol. Chem.2008,19,199–204.
[227] Dunlap, T.; Abdul-Hay, S. O.; Chandrasena, R. E. P. et al. Nitrates and NO-NSAIDs in cancer chemoprevention and therapy: In vitro evidence querying the NOdonor functionality. Nitric Oxide Biol. Chem.2008,19,115–124.
[228] Stasko, N. A.; Schoenfisch, M. H. Dendrimers as a scaffold for nitric oxiderelease. J. Am. Chem. Soc.2006,128,8265–8271.
[229] Taite, L. J.; West, J. L. Poly(ethylene glycol)-lysine dendrimers for targeteddelivery of nitric oxide. J. Biomater. Sci., Polym. Ed.2006,17,1159–1172.
[230] Stasko, N. A.; Fischer, T. H.; Schoenfisch, M. H. S-Nitrosothiol-modifieddendrimers as nitric oxide delivery vehicles. Biomacromolecules2008,9,834–841.
[231] ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P. et al. Removal of benzyl-typeprotecting groups from peptides by catalytic transfer hydrogenation with formic acid.J. Org. Chem.1979,44,3442–3444.
[232] Smith, H. L.; Brown, E. S.; Smith, J. D. et al. Hydrogenolysis of benzyl esterswith palladiumon-carbon catalysts. J. Pharm. Sci.1965,54,1269–1273.
[233] Zagorevskii1, V. A.; Tsvetkova1, I. D.; Orlova1, é. K. et al. Pyran, its analogs,and related compounds. Chem. Heterocycl. Compd.1971,7,14–18.
[234] Rainsford, K. D. Anti-inflammatory drugs in the21st century. Sub-cell.biochem.2007,42,3–27.
[235] Rephaeli, A.; Zhuk, R.; Nudelman, A. Prodrugs of butyric acid from bench tobedside: Synthetic design, mechanisms of action, and clinical applications. Drug Dev.Res.2000,50,379–391.
[236] Muramatsu, I.; Murakami, M.; Takahiro Yoneda, T. et al. The formylation ofamino acids with acetic formic anhydride. Bull. Chem. Soc. Jpn.1965,38,244–246.