Nucleic acid therapeutics (or gene therapy) has to date failed to deliver on promise but rapid improvements in the understanding and use of delivery technologies should reverse this situation. In this review of work performed in and in collaboration with the Imperial College Genetic Therapies Centre, progress towards safe nanoparticles for efficient delivery of functional nucleic acids in vivo is described. The intention is to demonstrate the fruits of a journey from the results of initial studies in animal models of disease that suggested that so much should be possible so quickly, to the realization that new technologies are rarely successful so quickly, through to developments in the present day that appear to be approaching the preclinical/clinical threshold with realism but measured confidence. New chemistry is central to the design and formulation of safe nanotechnologies. Chemistry should have a central role to play in ensuring that nucleic acid therapeutics truly live up to their potential for therapy and cure, none more so than in the derivation of newer and better therapies for cancers.
MurrayK.D., McQuillinA., StewartL., EtheridgeC.J., CooperR.G., MillerA.D., GurlingH.M.: Cationic liposome-mediated DNA transfection in organotypic explant cultures of the ventral mesencephalon.Gene Ther, 6: 190–197, 1999.
14.
AltonEWFW, MiddletonP.G., CaplenN.J., SmithS.N., SteelD.M., MunkongeF.M., JefferyP.K., GeddesD.M., HartS.L., WilliamsonR..: Non-invasive liposome-mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice.Nat Genet, 5: 135–142, 1993.
15.
TagawaT., ManvellM., BrownN., KellerM., PerouzelE., MurrayK.D., HarbottleR.P., TecleM., BooyF., Brahimi-HornM.C., CoutelleC., LemoineN.R., AltonEWFW, MillerA.D.: Characterisation of LMD virus-like nanoparticles self-assembled from cationic liposomes, adenovirus core peptide m (mu) and plasmid DNA.Gene Ther, 9: 564–576, 2002.
16.
KellerM., JorgensenM.R., PerouzelE., MillerA.D.: Thermodynamic aspects and biological profile of CDAN/DOPE and DC-Chol/DOPE lipoplexes.Biochemistry, 42: 6067–6077, 2003.
17.
CooperR.G., EtheridgeC.J., StewartL., MarshallJ., RudginskyS., ChengS.H., MillerA.D.: Polyamine analogues of 3b-[N-(N’,N’-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol) as agents for gene delivery.Chem Eur J, 4: 137–152, 1998.
18.
StewartL., ManvellM., HilleryE., EtheridgeC.J., CooperR.G., StarkH., van-HeelM., PreussM., AltonEWFW, MillerA.: Physico-chemical analysis of cationic liposome-DNA complexes (lipoplexes) with respect to in vitro and in vivo gene delivery efficiency.J Chem Soc, 2: 624–632, 2001.
19.
OliverM., JorgensenM.R., MillerA.D.: The facile solid-phase synthesis of cholesterol-based polyamine lipids.Tetrahedron Lett, 45: 3105–3108, 2004.
KellerM., TagawaT., PreussM., MillerA.D.: Biophysical characterization of the DNA binding and condensing properties of adenoviral core peptide m (mu).Biochemistry, 41: 652–659, 2002.
24.
TecleM., PreussM., MillerA.D.: Kinetic study of DNA condensation by cationic peptides used in nonviral gene therapy: analogy of DNA condensation to protein folding.Biochemistry, 42: 10343–10347, 2003.
25.
PerouzelE., JorgensenM.R., KellerM., MillerA.D.: Synthesis and formulation of neoglycolipids for the functionalization of liposomes and lipoplexes.Bioconjug Chem, 14: 884–898, 2003.
26.
FletcherS., AhmadA., PerouzelE., JorgensenM.R., MillerA.D.: A dialkanoyl analogue of DOPE improves gene transfer of lower-charged, cationic lipoplexes.Org Biomol Chem, 4: 196–199, 2006.
27.
FletcherS., AhmadA., PriceW.S., JorgensenM.R., MillerA.D.: Biophysical properties of CDAN/DOPE-analogue lipoplexes account for enhanced gene delivery.Chembiochem, 9: 455–463, 2008.
28.
FletcherS., AhmadA., PerouzelE., HeronA., MillerA.D., JorgensenM.R.: In vivo studies of dialkynoyl analogues of DOTAP demonstrate improved gene transfer efficiency of cationic liposomes in mouse lung.J Med Chem, 49: 349–357, 2006.
FletcherS., JorgensenM.R., MillerA.D.: Facile preparation of an orthogonally protected. pH-sensitive, bioconjugate linker for therapeutic applications.Organic Lett, 6: 4245–4248, 2004.
31.
PriceW.S., FletcherS., JorgensenM.R., MillerA.D.: A novel methodology for the synthesis of fumarates and maleates.SYNLETT, 1933–1937, 2006.
32.
FuregatiS., WhiteA.J.P., MillerA.D.: Observation of a 1,5-silylmigration on fructose.SYNLETT, 2385–2387, 2005.
33.
HartS.L., HarbottleR.P., CooperR., MillerA., WilliamsonR., CoutelleC.: Gene delivery and expression mediated by an integrin-binding peptide.Gene Ther, 2: 552–554, 1995.
34.
ColinM., HarbottleR.P., KnightA., KornprobstM., CooperR.G., MillerA.D., TrugnanG., CapeauJ., CoutelleC., Brahimi-HornM.C.: Liposomes enhance delivery and expression of an RGD-oligolysine gene transfer vector in human tracheal cells.Gene Ther, 5: 1488–1498, 1998.
35.
CooperR.G., HarbottleR.P., SchneiderH., CoutelleC., MillerA.D.: Peptide mini-vectors for gene delivery.Angew Chem Int Ed, 38: 1949–1952, 1999.
36.
ColinM., MauriceM., TrugnanG., KornprobstM., HarbottleR.P., KnightA., CooperR.G., MillerA.D., CapeauJ., CoutelleC., Brahimi-HornM.C.: Cell delivery, intracellular trafficking and expression of an integrin-mediated gene transfer vector in tracheal epithelial cells.Gene Ther, 7: 139–152, 2000.
37.
ColinM., MoritzS., FontangesP., KornprobstM., DelouisC., KellerM., MillerA.D., CapeauJ., CoutelleC., Brahimi-HornM.C.: The nuclear pore complex is involved in nuclear transfer of plasmid DNA condensed with an oligolysine-RGD peptide containing nuclear localisation properties.Gene Ther, 8: 1643–1653, 2001.
38.
JostP.J., HarbottleR.P., KnightA., MillerA.D., CoutelleC., SchneiderH.: A novel peptide, THALWHT, for the targeting of human airway epithelia.FEBS Lett, 489: 263–269, 2001.
39.
HarbottleR.P., CooperR.G., HartS.L., LadhoffA., McKayT., KnightA.M., WagnerE., MillerA.D., CoutelleC.: An RGD-oligolysine peptide: a prototype construct for integrin-mediated gene delivery.Hum Gene Ther, 9: 1037–1047, 1998.
40.
TuranekJ., KasnaA., KoudelaB., LedvinaM., MillerA.D.: Stimulation of innate immunity in newborn kids against Cryptosporidium parvum infection-challenge by intranasal/per-oral administration of liposomal formulation of N-L18-norAbu-GMDP adjuvant.Parasitology, 131: 601–608, 2005.
41.
DuffelsA., GreenL.G., LeyS.V., MillerA.D.: Synthesis of high-mannose type neoglycolipids: active targeting of liposomes to macrophages in gene therapy.Chem Eur J, 6: 1416–1430, 2000.
42.
WaterhouseJ.E., HarbottleR.P., KellerM., KostarelosK., CoutelleC., JorgensenM.R., MillerA.D.: Synthesis and Application of Integrin Targeting Lipopeptides in Targeted Gene Delivery.Chembiochem, 6: 1212–1223, 2005.
43.
GuisadoC., WaterhouseJ.E., PriceW.S., JorgensenM.R., MillerA.D.: The facile preparation of primary and secondary amines via an improved Fukuyama-Mitsunobu procedure. Application to the synthesis of a lung-targeted gene delivery agent.Org Biomol Chem, 3: 1049–1057, 2005.
44.
AndreuA., FairweatherN., MillerA.D.: Clostridium neurotoxin fragments as potential targeting moieties for liposomal gene delivery to the CNS.Chembiochem, 9: 219–231, 2008.
45.
WalkerW.E., MillerA.D.: Longevity of expression following liposome-mediated gene transfer.Mol Ther, 9: 184, 2004.
46.
KolbA.F., CoatesC.J., KaminskiJ.M., SummersJ.B., MillerA.D., SegalD.J.: Site-directed genome modification: nucleic acid and protein modules for targeted integration and gene correction.Trends Biotechnol, 23: 399–406, 2005.
47.
CoatesC.J., KaminskiJ.M., SummersJ.B., SegalD.J., MillerA.D., KolbA.F.: Site-directed genome modification: derivatives of DNA-modifying enzymes as targeting tools.Trends Biotechnol, 23: 407–419, 2005.
48.
DykxhoornD.M., NovinaC.D., SharpP.A.: Killing the messenger: short RNAs that silence gene expression.Nat Rev Mol Cell Biol, 4: 457–467, 2003.
KellerM., MillerA.D.: Intracellular delivery of nucleic acids: differences between transfection and siFection reflect differences between DNA and RNA, and between oligodeoxynucleotides and oligonucleotides. In: Non-viral gene therapy: gene design and delivery,TairaK., KataokaK., NiidomeT. (Eds), pp 441–455, Springer-Verlag, 2005.
54.
SpagnouS., MillerA.D., KellerM.: Lipidic Carriers of siRNA: Differences in the Formulation, Cellular Uptake, and Delivery with Plasmid DNA.Biochemistry, 43: 13348–13356, 2004.
