Self-assembled and nanostructured siRNA delivery systems

Pharmaceutical Research

Volumn 28, Issue 9, 2011, Pages 2072-2085

  Jeong, Ji Hoon ^a   Park, Tae Gwan ^b   Kim, Sun Hwa ^c  

^a Sungkyunkwan University   (South Korea)

^b Korea Advanced Institute of Science and Technology (KAIST)   (South Korea)

^c Yonsei University College of Medicine   (South Korea)

Author keywords

Non viral gene carriers; PEGylated polyplex; Self assembled nanostructures; siRNA medicines; siRNA PEG conjugates

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; DRUG CARRIER; GOLD NANOPARTICLE; LIPID; LIPOFECTAMINE; MACROGOL; MESSENGER RNA; NANOCARRIER; NANOPARTICLE; OLIGOFECTAMINE; PLASMID DNA; POLOXAMER; POLYETHYLENEIMINE; POLYLYSINE; SMALL INTERFERING RNA; UNCLASSIFIED DRUG; VASCULOTROPIN;

CANCER GENE THERAPY; CANCER INHIBITION; COMPOSITE MATERIAL; COVALENT BOND; DISULFIDE BOND; DRUG CONFORMATION; DRUG CONJUGATION; DRUG DEGRADATION; DRUG FORMULATION; DRUG PENETRATION; DRUG STABILITY; DRUG STRUCTURE; DRUG TARGETING; GENE DELIVERY SYSTEM; GENE SILENCING; GENE TARGETING; GENETIC TRANSFECTION; HUMAN; IN VITRO GENE TRANSFER; IN VIVO GENE TRANSFER; MICELLE; MOLECULAR WEIGHT; MOLECULARLY TARGETED THERAPY; NANOPHARMACEUTICS; NONHUMAN; PARTICLE SIZE; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; RNA CLEAVAGE; RNA INTERFERENCE; SOLID TUMOR;

ANIMALS; CATIONS; DRUG CARRIERS; DRUG STABILITY; GENE SILENCING; HUMANS; LIPIDS; NANOPARTICLES; OLIGONUCLEOTIDES, ANTISENSE; PARTICLE SIZE; PEPTIDES; PLASMIDS; POLYETHYLENE GLYCOLS; RNA, SMALL INTERFERING;

EID: 80054718538     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-011-0412-y     Document Type: Review

References (94)

1. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494-8. (Pubitemid 32494397)
2. Hannon GJ, Rossi JJ. Unlocking the potential of the human genome with RNA interference. Nature. 2004;431:371-8. (Pubitemid 39265678)
3. Durcan N, Murphy C, Cryan S. Inhalable siRNA: potential as a therapeutic agent in the lungs. Mol Pharm. 2008;5:566-99.
4. Kim SH, Jeong JH, Kim T, Kim SW, Bull DA. VEGF siRNA delivery system using arginine-grafted bioreducible poly (disulfide amine). Mol Pharm. 2009;6:718-26.
5. Dorsett Y, Tuschl T. siRNAs: applications in functional genomics and potential as therapeutics. Nat Rev Drug Discov. 2004;3:318-29. (Pubitemid 38499759)
6. Jeong JH, Kim SW, Park TG. Molecular design of functional polymers for gene therapy. Prog Polym Sci. 2007;32:1239-74. (Pubitemid 47513188)
7. Kim SH, Jeong JH, Ou M, Yockman JW, Kim SW, Bull DA. Cardiomyocyte- targeted siRNA delivery by prostaglandin E2-Fas siRNA polyplexes formulated with reducible poly (amido amine) for preventing cardiomyocyte apoptosis. Biomaterials. 2008;29:4439-46.
8. Smedt SCD, Demeester J, Hennink WE. Cationic polymer based gene delivery systems. Pharm Res. 2000;17:113-26. (Pubitemid 30158358)
9. Tomlinson E, Rolland AP. Controllable gene therapypharmaceutics of non-viral gene delivery systems. J Control Release. 1996;39:357-72. (Pubitemid 26194229)
10. Kwoh DT, Coffin CC, Lollo CP, Jovenal J, Banaszczyk MG, Mullen P, et al. Stabilization of poly-L-lysine/DNA polyplexes for in vivo gene delivery to the liver. Biochim Biophys Acta. 1999;1444:171-90. (Pubitemid 29104831)
11. Gao X, Kim KS, Liu D. Nonviral gene delivery: what we know and what is next. AAPS J. 2007;9:E92-104.
12. Plank C, Mechtler K, Szoka Jr FC, Wagner E. Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery. Hum Gene Ther. 1996;7:1437-46. (Pubitemid 26293564)
13. Gary DJ, Puri N, Won YY. Polymer-based siRNA delivery: perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery. J Control Release. 2007;121:64-73. (Pubitemid 47126065)
14. Shah SA, Brunger AT. A crystal structure of a statically disordered 17 base-pair RNA duplex: principles of RNA crystal packing and its effect on nucleic acid structure. J Mol Biol. 1999;285:1577-88. (Pubitemid 29060457)
15. Kebbekus P, Draper DE, Hagerman P. Persistence length of RNA. Biochemistry. 1998;34:4354-7.
16. Mok H, Lee SH, Park JW, Park TG. Multimeric small interfering ribonucleic acid for highly efficient sequence-specific gene silencing. Nat Mater. 2010;9:272-8.
17. Lee SY, Huh MS, Lee S, Lee SJ, Chung H, Park JH, et al. Stability and cellular uptake of polymerized siRNA (poly-siRNA)/polyethylenimine (PEI) complexes for efficient gene silencing. J Control Release. 2010;141:339-46.
18. Abuchowski A, McCoy JR, Palczuk NC, van Es T, Davis FF. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J Biol Chem. 1977;252:3582-6. (Pubitemid 8116088)
19. Abuchowski A, van Es T, Palczuk NC, Davis FF. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J Biol Chem. 1977;11:3578-81. (Pubitemid 8116087)
20. Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov Today. 2005;10:1451-8. (Pubitemid 41483874)
21. Veronese FM, Harris JM. Introduction and overview of peptide and protein pegylation. Adv Drug Deliv Rev. 2002;54:453-6. (Pubitemid 34615541)
22. Gursahani H, Riggs-sauthier J, Pfeiffer J, Lechuga-Ballesteros D, Fishburn CS. Absorption of polyethylene glycol (PEG) polymers: the effect of PEG size on permeability. J Pharm Sci. 2009;98:2847-56.
23. Jeong JH, Kim SW, Park TG. A new antisense oligonucleotide delivery system based on self-assembled ODNPEG hybrid conjugate micelles. J Control Release. 2003;93:183-91. (Pubitemid 37421359)
24. Jeong JH, Kim SH, Kim SW, Park TG. Intracellular delivery of poly (ethylene glycol) conjugated antisense oligonucleotide using cationic lipids by formation of self-assembled polyelectrolyte complex micelles. J Nanosci Nanotechnol. 2006;6:2790-5. (Pubitemid 44579948)
25. Osada K, Christie RJ, Kataoka K. Polymeric micelles from poly (ethylene glycol)-poly (amino acid) block copolymer for drug and gene delivery. J R Soc Interface. 2009;6:S325-39.
26. Petersen H, Fechner PM, Martin AL, Kunath K, Stolnik S, Roberts CJ, et al. Polyethylenimine-graft-poly (ethylene glycol) copolymers: influence of copolymer block structure on DNA complexation and biological activities as gene delivery system. Bioconjug Chem. 2002;13:845-54. (Pubitemid 34801128)
27. Kunath K, Harpe A, Petersen H, Fischer D, Voigt K, Kissel T, et al. The structure of PEG-modified poly (ethylene imines) influences biodistribution and pharmacokinetics of their complexes with NF-κB decoy in mice. Pharm Res. 2002;19:810-7. (Pubitemid 34686740)
28. Kataoka K, Itaka K, Nishiyama N, Yamasaki Y, Oishi M, Nagasaki Y. Smart polymeric micelles as nanocarriers for oligonucleotides and siRNA delivery. Nucleic Aicds Symp Ser. 2005;49:17-8.
29. Kim SH, Mok H, Jeong JH, Kim SW, Park TG. Comparative evaluation of target-specific GFP gene silencing efficiencies for antisense ODN, synthetic siRNA, and siRNA plasmid complexed with PEI-PEG-FOL conjugate. Bioconjug Chem. 2006;17:241-4. (Pubitemid 43157607)
30. Naeyea B, Raemdoncka K, Remauta K, Sproatb B, Demeestera J, De Smedta SC. PEGylation of biodegradable dextran nanogels for siRNA delivery. Eur J Pharm Sci. 2010;40:342-51.
31. Tamura A, Oishi M, Nagasaki Y. Efficient siRNA delivery based on PEGylated and partially quaternized polyamine nanogels: enhanced gene silencing activity by the cooperative effect of tertiary and quaternary amino groups in the core. J Control Release. 2010;146:378-87.
32. Noh SM, Park MO, Shim G, Han SE, Lee HY, Huh JH, et al. Pegylated poly-L-arginine derivatives of chitosan for effective delivery of siRNA. J Control Release. 2010;145:159-64.
33. Kim WJ, Yockmana JW, Lee M, Jeong JH, Kim Y, Kim SW. Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis. J Control Release. 2005;106:224-34. (Pubitemid 41140097)
34. Hong JW, Park JH, Huh KM, Chung H, Kwon IC, Jeong SY. PEGylated polyethylenimine for in vivo local gene delivery based on lipiodolized emulsion system. J Control Release. 2004;99:167-76. (Pubitemid 39165742)
35. Jeong JH, Lee M, Kim WJ, Yockman JW, Park TG, Kim YH, et al. Anti-GAD antibody targeted non-viral gene delivery to islet beta cells. J Control Release. 2005;107:562-70. (Pubitemid 41393362)
36. Lee H, Jeong JH, Park TG. PEG grafted polylysine with fusogenic peptide for gene delivery: high transfection efficiency with low cytotoxicity. J Control Release. 2002;79:283-91. (Pubitemid 34164180)
37. Kaul G, Amiji M. Tumor-targeted gene delivery using poly (ethyleneglycol)-modified gelatin nanoparticles: in vitro and in vivo studies. Pharm Res. 2005;22:956-65.
38. Lee H, Kim TH, Park TG. A receptor-mediated gene delivery system using streptavidin and biotin-derivatized, pegylated epidermal growth factor. J Control Release. 2002;83:109-19. (Pubitemid 35239819)
39. Meyer O, Kirpotin D, Hong K, Sternberg B, Park JW, Woodlei MC. Cationic liposomes coated with polyethylene glycol as carriers for oligonucleotides. J Biol Chem. 1998;273:15621-7. (Pubitemid 28298176)
40. Harada A, Togawa H, Kataoka K. Physicochemical properties and nuclease resistance of antisenseoligodeoxynucleotides entrapped in the core of polyion complex micelles composed of poly (ethylene glycol)-poly (L-Lysine) block copolymers. Eur J Pharm Sci. 2001;13:35-42. (Pubitemid 32259538)
41. Shi F, Wasungu L, Aomden A, Stuart MCA, Polushkin E, Engberts JBFN, et al. Interference of poly (ethylene glycol)-lipid analogues with cationic-lipid-mediated delivery of oligonucleotides; role of lipid exchangeability and non-lamellar transitions. Biochem J. 2002;366:333-41. (Pubitemid 34971834)
42. Oishi M, Nagatsugi F, Sasaki S, Nagasaki Y, Kataoka K. Smart polyion complex micelles for targeted intracellular delivery of PEGylated antisense oligonucleotides containing acid-labile linkages. Chembiochem. 2005;6:718-25. (Pubitemid 40873776)
43. Jeong JH, Kim SH, Kim SW, Park TG. In vivo tumor targeting of ODN-PEG-folic acid/PEI polyelectrolyte complex micelles. J Biomater Sci Polym Ed. 2005;16:1409-19. (Pubitemid 44069677)
44. Oishi M, Sasaki S, Nagasaki Y, Kataoka K. pH-Responsive oligodeoxynucleotide (ODN)-poly (ethylene glycol) conjugate through acid-labile β-thiopropionate linkage: preparation and polyion complex micelle formation. Biomacromolecules. 2003;4:1426-32. (Pubitemid 37184661)
45. Jeong JH, Kim SH, Kim SW, Park TG. Polyelectrolyte complex micelles composed of c-raf antisense oligodeoxynucleotide-poly (ethylene glycol) conjugate and poly (ethylenimine): effect of systemic administration on tumor growth. Bioconjug Chem. 2005;16:1034-7. (Pubitemid 41026190)
46. Kim SH, Jeong JH, Mok H, Lee SH, Kim SW, Park TG. Folate receptor targeted delivery of polyelectrolyte complex micelles prepared from ODN-PEG-folate conjugate and cationic lipids. Biotechnol Prog. 2007;23:232-7. (Pubitemid 46293509)
47. Oishi M, Nagasaki Y, Itaka K, Nishiyama N, Kataoka K. Lactosylated poly (ethylene glycol)-siRNA conjugate through acid-labile β-thiopropionate linkage to construct pH-sensitive polyion complex micelles achieving enhanced gene silencing in hepatoma cells. J Am Chem Soc. 2005;127:1624-5. (Pubitemid 40229133)
48. Zhang M, Ishii A, Nishiyama N, Matsumoto S, Ishii T, Yamasaki Y, et al. PEGylated calcium phosphate nanocomposites as smart environment-sensitive carriers for siRNA delivery. Adv Mater. 2009;21:3520-5.
49. Kim SH, Jeong JH, Lee SH, Kim SW, Park TG. LHRH receptor-mediated delivery of siRNA using polyelectrolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEI. Bioconjug Chem. 2008;19:2156-62.
50. Kim SH, Jeong JH, Lee SH, Kim SW, Park TG. PEG conjugated VEGF siRNA for anti-angiogenic gene therapy. J Control Release. 2006;116:123-9. (Pubitemid 44854271)
51. Kim SH, Jeong JH, Lee SH, Kim SW, Park TG. PEG Local and systemic delivery of VEGF siRNA using polyelectrolyte complex micelles for effective treatment of cancer. J Control Release. 2008;129:107-16.
52. Lee SH, Kim SH, Park TG. Intracellular siRNA delivery system using polyelectrolyte complex micelles prepared from VEGF siRNA-PEG conjugate and cationic fusogenic peptide. Biochem Biophys Res Commun. 2007;357:511-6. (Pubitemid 46603160)
53. Mok H, Park TG. Self-crosslinked and reducible fusogenic peptides for intracellular delivery of siRNA. Biopolymers. 2008;89:881-8.
54. Lee SH, Bae KH, Kim SH, Lee KR, Park TG. Aminefunctionalized gold nanoparticles as non-cytotoxic and efficient intracellular siRNA delivery carriers. Int J Pharm. 2008;364:94-101.
55. Kim HR, Kim IK, Bae KH, Lee SH, Lee Y, Park TG. Cationic solid lipid nanoparticles reconstituted from low density lipoprotein components for delivery of siRNA. Mol Pharm. 2008;5:622-31.
56. Jeong JH, Mok HJ, Oh Y, Park TG. siRNA conjugate delivery systems. Bioconjug Chem. 2009;20:5-14.
57. Jeong JH, Kim SW, Park TG. Novel intracellular delivery system of antisense oligonucleotide by self-assembled hybrid micelles composed of DNA/PEG conjugate and cationic fusogenic peptide. Bioconjug Chem. 2003;14:473-9. (Pubitemid 36348672)
58. Scanlon KJ. Anti-genes: siRNA, ribozymes and antisense. Curr Pharm Biotechnol. 2004;5:415-20. (Pubitemid 39317609)
59. de Martimprey H, Vauthier C, Malvy C, Couvreur P. Polymer nanocarriers for the delivery of small fragments of nucleic acids: oligonucleotides and siRNA. Eur J Pharm Biopharm. 2009;71:490-504.
60. Brown KM, Chu C, Rana TM. Target accessibility dictates the potency of human RISC. Nat Struct Mol Biol. 2005;12:469-70. (Pubitemid 43085910)
61. Jung S, Lee SH, Mok H, Chung HJ, Park TG. Gene silencing efficiency of siRNA-PEG conjugates: effect of PEGylation site and PEG molecular weight. J Control Release. 2010;144:306-13.
62. Oishi M, Nagasaki Y, Nishiyama N, Itaka K, Takagi M, Shimamoto A, et al. Enhanced growth inhibition of hepatic multicellular tumor spheroids by lactosylated poly (ethylene glycol)-siRNA conjugate formulated in PEGylated polyplexes. ChemMedChem. 2007;2:1290-7.
63. Braasch DA, Jensen S, Liu Y, Kaur K, Arar K, White MA, et al. RNA interference in mammalian cells by chemically-modified RNA. Biochemistry. 2003;42:7967-75. (Pubitemid 36807714)
64. Prakash TP, Allerson CR, Dande P, Vickers TA, Sioufi N, Jarres R, et al. Positional effect of chemical modifications on short interference RNA activity in mammalian cells. J Med Chem. 2005;48:4247-53. (Pubitemid 40884928)
65. Shah S, Friedman SH. Tolerance of RNA interference toward modifications of the 5' antisense phosphate of small interfering RNA. Oligonucleotides. 2007;17:35-43. (Pubitemid 46651426)
66. Amarzguioui M, Holen T, Babaie E, Prydz H. Tolerance for mutations and chemical modifications in a siRNA. Nucleic Acids Res. 2003;31:589-95. (Pubitemid 36175948)
67. Moschos SA, Jones SW, Perry MM, Williams AE, Erjefalt JS, Turner JJ, et al. Lung delivery studies using siRNA conjugated to TAT (48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug Chem. 2007;18:1450-9. (Pubitemid 47464052)
68. Muratovska A, Eccles MR. Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells. FEBS Lett. 2004;558:63-8. (Pubitemid 38167411)
69. Akerman ME, Chan WC, Laakkonen P, Bhatia SN, Ruoslahti E. Nanocrystal targeting in vivo. Proc Natl Acad Sci USA. 2002;99:12617-21.
70. Meong F, Hennink WE, Zhong Z. Reduction-sensitive polymers and bioconjugates for biomedical applications. Biomaterials. 2009;30:2180-98.
71. Werth S, Urban-Klein B, Dai L, Hobel S, Grzelinski M, Bakowsky U, et al. A low molecular weight fraction of polyethylenimine (PEI) displays increased transfection efficiency of DNA and siRNA in fresh or lyophilized complexes. J Control Release. 2006;112:257-70.
72. Urban-Klein B, Werth S, Abuharbeid S, Czubayko F, Aigner A. RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther. 2005;12:461-6. (Pubitemid 40394299)
73. Mok H, Park TG. Functional polymers for targeted delivery of nucleic acid drugs. Macromol Biosci. 2009;9:731-43.
74. Wagner E. Application of membrane-active peptides for nonviral gene delivery. Adv Drug Deliv Rev. 1999;38:279-89. (Pubitemid 29376578)
75. Wyman TB, Nicol F, Zelphati O, Scaria PV, Plank C, Szoka FC. Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers. Biochemistry. 1997;36:3008-17. (Pubitemid 27138586)
76. Choi SH, Lee SH, Park TG. Temperature-sensitive pluronic/poly (ethylenimine) nanocapsules for thermally triggered disruption of intracellular endosomal compartment. Biomacromolecules. 2006;7:1864-70. (Pubitemid 43985108)
77. Choi SH, Lee J, Choi S, Park TG. Thermally reversible pluronic/heparin nanocapsules exhibiting 1000-fold volume transition. Langmuir. 2006;22:1758-62.
78. Lee K, Bae KH, Lee Y, Lee SH, Ahn C, Park TG. Pluronic/polyethylenimine shell crosslinked nanocapsules with embedded magnetite nanocrystals for magnetically triggered delivery of siRNA. Macromol Biosci. 2010;10:239-45.
79. Storhoff JJ, Elghanian R, Mucic RC, Mirkin CA, Letsinger RL. One-pot colorimetric differentiation of polynucleotides with single base imperfections using gold nanoparticle probes. J Am Chem Soc. 1998;120:1959-64. (Pubitemid 28179167)
80. Otsuka H, Akiyama Y, Nagasaki Y, Kataoka K. Quantitative and reversible lectin-induced association of gold nanoparticles modified with a-lactosyl-?-mercapto-poly (ethylene glycol). J Am Chem Soc. 2001;123:8226-30. (Pubitemid 32916399)
81. Gannon CJ, Patra CR, Bhattacharya R, Mukherjee P, Curley SA. Intracellular gold nanoparticles enhance non-invasive radiofrequency thermal destruction of human gastrointestinal cancer cells. J Nanobiotech. 2008;6:2.
82. Rosi NL, Giljohann DA, Thaxton CS, Lytton-Jean AK, Han MS, Mirkin CA. Oligonucleotide-modified gold nanoparticles for intracellular gene regulation. Science. 2006;312:1027-30.
83. Sandhu KK, McIntosh CM, Simard JM, Smith SW, Rotello VM. Gold nanoparticle-mediated transfection of mammalian cells. Bioconjug Chem. 2002;13:3-6. (Pubitemid 34119628)
84. Niidome T, Nakashima K, Takahashi H, Niidome Y. Preparation of primary amine-modified gold nanoparticles and their transfection ability into cultivated cells. Chem Commun. 2004;10:1978-9. (Pubitemid 39336030)
85. Behlke MA. Progress towards in vivo use of siRNAs. Mol Ther. 2006;13:644-70.
86. Zimmermann TS, Lee ACH, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN, et al. RNAi-mediated gene silencing in non-human primates. Nature. 2006;441:111-4.
87. Pal A, Ahmad A, Khan S, Sakabe I, Zhang C, Kasid UN, et al. Systemic delivery of RafsiRNA using cationic cardiolipin liposomes silences Raf-1 expression and inhibits tumor growth in xenograft model of human prostate cancer. Int J Oncol. 2005;26:1087-91.
88. Coleman RE, Biganzoli L, Canney P, Dirix L, Mauriac L, Chollet P, et al. A randomized phase II study of two different schedules of pegylated liposomal doxorubicin in metastatic breast cancer (EORTC-10993). Eur J Cancer. 2006;42:882-7.
89. Zhu C, Jung S, Luo S, Meng F, Zhu X, Park TG, et al. Codelivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers. Biomaterials. 2010;31:2408-16.
90. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65:271-84. (Pubitemid 30122932)
91. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79:185-8. (Pubitemid 24324908)
92. Al-Abd AM, Lee SH, Kim SH, Cha J, Park TG, Lee SJ. Penetration and efficacy of VEGF siRNA using polyelectrolyte complex micelles in a human solid tumor model in-vitro. J Control Release. 2009;137:130-5.
93. Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev. 2007;59:748-58. (Pubitemid 47320813)
94. Merdan T, Callahan J, Petersen H, Kunath K, Bakowsky U, Kopeckova P, et al. Pegylated polyethylenimine-Fab' antibody fragment conjugate for targeted gene delivery to human ovarian carcinoma cells. Bioconjug Chem. 2003;14:989-96. (Pubitemid 37152959)