4170 Nucleic Acids Research, 2008, Vol. 36, No. 12 conjugated to a disulﬁde-bridged D-peptide analogue of insulin- like growth factor 1. Bioconjug. Chem., 18, 1831–1840. 113. Rozema,D.B., Lewis,D.L., Wakeﬁeld,D.H., Wong,S.C., Klein,J.J., Roesch,P.L., Bertin,S.L., Reppen,T.W., Chu,Q., Blokhin,A.V. et al. (2007) Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes. Proc. Natl Acad. Sci. USA, 104, 12982–12987. 114. Kumar,P., Wu,H., McBride,J.L., Jung,K.E., Kim,M.H., Davidson,B.L., Lee,S.K., Shankar,P. and Manjunath,N. (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature, 448, 39–43. 115. Drummond,D.C., Meyer,O., Hong,K., Kirpotin,D.B. and Papahadjopoulos,D. (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol. Rev., 51, 691–743. 116. Tiera,M.J., Winnik,F.O. and Fernandes,J.C. (2006) Synthetic and natural polycations for gene therapy: state of the art and new perspectives. Curr. Gene Ther., 6, 59–71. 117. Pridgen,E.M., Langer,R. and Farokhzad,O.C. (2007) Biodegradable, polymeric nanoparticle delivery systems for cancer therapy. Nanomed., 2, 669–680. 118. Gilmore,I.R., Fox,S.P., Hollins,A.J. and Akhtar,S. (2006) Delivery strategies for siRNA-mediated gene silencing. Curr. Drug Deliv., 3, 147–145. 119. Li,W. and Szoka,F.C. Jr. (2007) Lipid-based nanoparticles for nucleic acid delivery. Pharm. Res., 24, 438–449. 120. Fattal,E., Couvreur,P. and Dubernet,C. (2004) ‘‘Smart’’ delivery of antisense oligonucleotides by anionic pH-sensitive liposomes. Adv. Drug Deliv. Rev., 56, 931–946. 121. Vinogradov,S.V., Batrakova,E.V. and Kabanov,A.V. (2004) Nanogels for oligonucleotide delivery to the brain. Bioconjug. Chem., 15, 50–60. 122. Meyer,M. and Wagner,E. (2006) Recent developments in the application of plasmid DNA-based vectors and small interfering RNA therapeutics for cancer. Hum. Gene Ther., 17, 1062–1076. 123. Meyer,M., Philipp,A., Oskuee,R., Schmidt,C. and Wagner,E. (2008) Breathing life into polycations: functionalization with ph- responsive endosomolytic peptides and polyethylene glycol enables siRNA delivery. J. Am. Chem. Soc., 130, 3272–3273. 124. Grzelinski,M., Urban-Klein,B., Martens,T., Lamszus,K., Bakowsky,U., Hobel,S., Czubayko,F. and Aigner,A. (2006) RNA interference-mediated gene silencing of pleiotrophin through polyethylenimine-complexed small interfering RNAs in vivo exerts antitumoral eﬀects in glioblastoma xenografts. Hum. Gene Ther., 17, 751–766. 125. Schiﬀelers,R.M., Ansari,A., Xu,J., Zhou,Q., Tang,Q., Storm,G., Molema,G., Lu,P.Y., Scaria,P.V. and Woodle,M.C. (2004) Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res., 32, e149. 126. DeRouchey,J., Schmidt,C., Walker,G.F., Koch,C., Plank,C., Wagner,E. and Radler,J.O. (2008) Monomolecular assembly of siRNA and poly(ethylene glycol)-peptide copolymers. Biomacromolecules, 9, 724–732. 127. Kang,H., DeLong,R., Fisher,M.H. and Juliano,R.L. (2005) Tat- conjugated PAMAM dendrimers as delivery agents for antisense and siRNA oligonucleotides. Pharm. Res., 22, 2099–2106. 128. Tsutsumi,T., Hirayama,F., Uekama,K. and Arima,H. (2007) Evaluation of polyamidoamine dendrimer/alpha-cyclodextrin con- jugate (generation 3, G3) as a novel carrier for small interfering RNA (siRNA). J. Control Release, 119, 349–359. 129. Yoo,H. and Juliano,R.L. (2000) Enhanced delivery of antisense oligonucleotides with ﬂuorophore-conjugated PAMAM dendri- mers. Nucleic Acids Res., 28, 4225–4231. 130. Zhou,J., Wu,J., Hafdi,N., Behr,J.P., Erbacher,P. and Peng,L. (2006) PAMAM dendrimers for eﬃcient siRNA delivery and potent gene silencing. Chem. Commun., 2362–2364. 131. Boussif,O., Lezoualc’h,F., Zanta,M.A., Mergny,M.D., Scherman,D., Demeneix,B. and Behr,J.P. (1995) A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc. Natl Acad. Sci. USA, 92, 7297–7301. 132. Toub,N., Bertrand,J.R., Tamaddon,A., Elhamess,H., Hillaireau,H., Maksimenko,A., Maccario,J., Malvy,C., Fattal,E. and Couvreur,P. (2006) Eﬃcacy of siRNA nanocapsules targeted against the EWS-Fli1 oncogene in Ewing sarcoma. Pharm. Res., 23, 892–900. 133. Kataoka,K., Itaka,K., Nishiyama,N., Yamasaki,Y., Oishi,M. and Nagasaki,Y. (2005) Smart polymeric micelles as nanocarriers for oligonucleotides and siRNA delivery. Nucleic Acids Symp. Ser., 49, 17–18. 134. Derfus,A.M., Chen,A.A., Min,D.H., Ruoslahti,E. and Bhatia,S.N. (2007) Targeted quantum dot conjugates for siRNA delivery. Bioconjug. Chem., 18, 1391–1396. 135. Tan,W.B., Jiang,S. and Zhang,Y. (2007) Quantum-dot based nanoparticles for targeted silencing of HER2/neu gene via RNA interference. Biomaterials, 28, 1565–1571. 136. Santel,A., Aleku,M., Keil,O., Endruschat,J., Esche,V., Durieux,B., Loﬄer,K., Fechtner,M., Rohl,T., Fisch,G. et al. (2006) RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy. Gene Ther., 13, 1360–1370. 137. Santel,A., Aleku,M., Keil,O., Endruschat,J., Esche,V., Fisch,G., Dames,S., Loﬄer,K., Fechtner,M., Arnold,W. et al. (2006) A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endothelium. Gene Ther., 13, 1222–1234. 138. Zelphati,O. and Szoka,F.C. Jr. (1996) Mechanism of oligonucleo- tide release from cationic liposomes. Proc. Natl Acad. Sci. USA, 93, 11493–11498. 139. Oishi,M., Nagasaki,Y., Itaka,K., Nishiyama,N. and Kataoka,K. (2005) Lactosylated poly(ethylene glycol)-siRNA conjugate through acid-labile beta-thiopropionate linkage to construct pH- sensitive polyion complex micelles achieving enhanced gene silencing in hepatoma cells. J. Am. Chem. Soc., 127, 1624–1625. 140. Kabanov,A.V. (2006) Polymer genomics: an insight into pharma- cology and toxicology of nanomedicines. Adv. Drug Deliv. Rev., 58, 1597–1621. 141. Nelson,C.M. and Bissell,M.J. (2006) Of extracellular matrix, scaﬀolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol., 22, 287–309. 142. Juliano,R.L. (2007) Biological Barriers to Nanocarrier-Mediated Delivery of Therapeutic and Imaging Agents. In Niemeyer,C.M. and Mirkin,C.A. (eds), Nanobiotechnology II., Wiley-VCH, Weinheim, Germany, pp. 263–278. 143. Brenner,B.M., Deen,W.M. and Robertson,C.R. (1976) Determinants of glomerular ﬁltration rate. Annu. Rev. Physiol., 38, 11–19. 144. Geary,R.S., Watanabe,T.A., Truong,L., Freier,S., Lesnik,E.A., Siouﬁ,N.B., Sasmor,H., Manoharan,M. and Levin,A.A. (2001) Pharmacokinetic properties of 20-O-(2-methoxyethyl)-modiﬁed oligonucleotide analogs in rats. J. Pharmacol. Exp. Ther., 296, 890–897. 145. Rippe,B., Rosengren,B.I., Carlsson,O. and Venturoli,D. (2002) Transendothelial transport: the vesicle controversy. J. Vasc. Res., 39, 375–390. 146. Lee,C.C., MacKay,J.A., Frechet,J.M. and Szoka,F.C. (2005) Designing dendrimers for biological applications. Nat. Biotechnol., 23, 1517–1526. 147. Uzgiris,E. (2004) The role of molecular conformation on tumor uptake of polymeric contrast agents. Invest. Radiol., 39, 131–137. 148. Scherphof,G.L. (1991) In vivo behavior of liposomes: interaction with themononuclear phagocyte system and implications for drug targeting. In Juliano,R.L. (ed.), Targeted Drug Delivery, Springer, Berlin, pp. 285–313. 149. Greish,K. (2007) Enhanced permeability and retention of macro- molecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J. Drug Target, 15, 457–464. 150. Jain,R.K. (1999) Transport of molecules, particles, and cells in solid tumors. Annu. Rev. Biomed. Eng., 1, 241–263. 151. Kobayashi,H., Boelte,K.C. and Lin,P.C. (2007) Endothelial cell adhesion molecules and cancer progression. Curr. Med. Chem., 14, 377–386. 152. Serini,G., Napione,L. and Bussolino,F. (2008) Integrins team up with tyrosine kinase receptors and plexins to control angiogenesis. Curr. Opin. Hematol., 15, 235–242. 153. Cai,W., Shin,D.W., Chen,K., Gheysens,O., Cao,Q., Wang,S.X., Gambhir,S.S. and Chen,X. (2006) Peptide-labeled near-infrared quantum dots for imaging tumor vasculature in living subjects. Nano Lett., 6, 669–676.