WO2005039558A1 - Targeted delivery of therapeutically active compounds - Google Patents

Abstract

A compound comprising: (i) A therapeutically active moiety and, (ii) A targeting moiety able to bind to a glutamine transporter.

Description

Targeted delivery of therapeutically active compounds

The present invention concerns new compounds comprising a targeting moiety able to bind to a glutamine transporter, complexes and iiposomes comprising a targeting moiety able to bind to a glutamine transporter as well as compositions comprising them. The present invention also concerns new molecules useful for preparing complexes or Iiposomes according to the invention. More particularly, the present invention concerns the use of said compounds, complexes, Iiposomes, molecules or of said compositions for transferring a substance of interest into a cell, particularly in gene transfer applications. Gene therapy has generally been conceived as principally applicable to. heritable deficiency diseases (cystic fibrosis, dystrophies, haemophilias,...) where permanent cure or improvement of the patient condition may be effected by introducing a functional gene in cells. However, a much larger group of diseases, notably acquired diseases (cancer, AIDS, multiple sclerosis,...) might be treatable by transiently engineering host cells to produce beneficial proteins. Another application of gene therapy is vaccination. In this regard, the immunogenic product encoded by the nucleic acid introduced into cells of a vertebrate may be expressed and secreted or be presented' by said cells in the context of the major histocompatibility antigens, thereby eliciting an immune response against the expressed immunogen. Functional nucleic acid can be introduced into cells by a variety of techniques resulting in either transient expression of the gene of interest, referred to as transient transfection, or permanent transformation of the host cells resulting from incorporation of the nucleic acid into the host genome. The first clinical protocol applied to man was initiated in the USA in September 1990 on a patient suffering from adenine deaminase (ADA) deficiency. This first encouraging experiment has been followed by numerous new applications, including vaccination, and promising clinical trials based on gene therapy are currently ongoing (see for example clinical trials listed at http://cnetdb.nci.nih.qov/trialsrch.shtml or http://www.wiley.co.uk/genetherapy/clinical/). Successful nucleic acid based therapy depends principally on the efficient delivery of a nucleic acid of interest, for example a gene encoding protein, to make its function or expression possible in cells of a living organism. Said genetic material can be transferred into cells using a wide variety of vectors resulting in either transient expression or permanent transformation of the host genome. During the past decade, a large number of viral, as well as non-viral, vectors has been developed for supporting said transfer (see for example Robbins et al., 1998, Tibtech 16, 35-40 ; Rolland, 1998, Therapeutic Drug Carrier Systems 15, 143-198 for reviews). This transfer is usually referred to nucleic acid delivery. Most delivery systems used to date are viral vectors, especially adeno-, pox- and retroviral vectors (see Robbins et al., 1998, Tibtech, 16, 35-40 or Walther and Stein, 2000, Drugs, 60, 249-271 for a review). Viruses have developed diverse and highly sophisticated mechanisms to achieve this goal including crossing of the cellular membrane, escape from endosomes and lysosomal degradation, and finally delivery of their genome to the nucleus followed by expression of the viral genome. In consequence, viruses have been used in many nucleic acid delivery applications, for example in vaccination or gene therapy applied to humans. However, said use of viruses suffers from a number of disadvantages: retroviral vectors cannot accommodate large-sized nucleotide sequences (e.g. the dystrophin gene which is around 13 kb), the retroviral genome is integrated into host cell DNA and may thus cause genetic changes in the recipient cell and infectious viral particles can disseminate within the organism or into the environment; adenoviral vectors can induce a strong immune response in treated patients and are lacking specificity when infecting cells (Mc Coy et al, 1995, Human Gene Therapy, 6, 1553-1560; Yang et al., 1996, Immunity, 1 , 433-442). Nevertheless, despite these drawbacks, viral vectors are currently the most useful delivery systems because of their efficiency. Besides, in order to offer safer approach for intracellular nucleic acid delivery, non-viral systems have been proposed. In 1990, Wolff et al. (Science, 247, 1465-1468) have shown that injection of naked RNA or DNA, i.e. nucleic acids without any special delivery system, directly into mouse skeletal muscle results in expression of reporter genes within the muscle cells. Nevertheless, although these results indicate that nucleic acid by itself is capable of crossing the plasma membrane of certain cells in vivo, the efficiency of the transfection actually observed remains very limited due, in particular, to the polyanionic nature of nucleic acids which limits their passage through negatively-charged cell membranes. In 1989, Feigner et al. (Nature, 337, 387-388) proposed the use of cationic lipids in order to facilitate the introduction of large anionic molecules such as nucleic acids into cells. These cationic lipids are capable of forming complexes (i.e. lipoplexes) with anionic molecules, thus tending to neutralize the negative charges of these molecules allowing them to compact into the complex, and favoring their introduction into the cell. Similarly, other non-viral delivery systems have been developed which are based for example on receptor-mediated mechanisms (Perales et al., 1994, Eur. J. Biochem. 226, 255-266; Wagner et al., 1994, Advanced Drug Delivery Reviews, 14, 113-135), on cationic polymers (forming polyplexes when complexed with anionic molecules) such as polyamidoamine (Haensler et Szoka, 1993, Bioconjugate Chem., 4, 372- 379), dendritic polymer (WO 95/24221), polyethylene imine or polypropylene imine (WO 96/02655), polylysine (US-A- 5 595 897 or FR 2 719 316), or on improved lipids (Feigner et al., 1989, Nature, 337, 387- 388) such as DOTMA (Feigner et al., 1987, PNAS, 84, 7413-7417), DOGS or Transfectam™ (Behr et al.,1989, PNAS, 86, 6982-6986), DMRIE or DORIE (Feigner et al., 1993, Methods 5, 67-75), DC-CHOL (Gao et Huang, 1991 , BBRC, 179, 280-285), DOTAP™ (McLachlan et al., 1995, Gene Therapy, 2,674-622), Lipofectamine™ or cationic glycerolipid compounds (see for example EP 901 463 and WO98/37916). These non- viral systems present potential advantages with respect to large-scale production, safety, flexibility in their chemical design, low immunogenicity and capacity to deliver large fragments of nucleic acid. However, several studies (for example, Mahato et al., 1995, J. Pharm. Sci., 84, 1267-1271 , Thierry et al., 1995, PNAS 92, 9742-9746) have shown that the transfer efficiency of the complexed anionic substances of interest into the cells, especially in the case of in vivo transfer, can greatly vary in function of the interaction between the complexes and the cell membranes, the cell type involved, the lipid composition of the cationic components, the size of the complexes formed with the anionic molecules and the ratio of the positive to negative charges of the different components of the complex. Currently, very little is known concerning the mechanisms which enable the interaction of the complexes with the cell membranes and the transfer of the complexes into the cell, and the ongoing research remains highly empirical. More particularly, it has been shown that one major pathway for said non-viral vectors intracellular delivery is intemalization into cell vesicles by endocytosis. Endocytosis is the natural process by which eukaryotic cells ingest segments of the plasma membrane in the form of small endocytosis vesicles, i.e. endosomes, entrapping extracellular fluid and molecular material, e.g. nucleic acid molecules. It is thus proposed that non-viral vectors would be internalized into cells by a non-specific process. This lack of any cell or tissue specific transfection could actually reduce the overall transfer efficiency as the administered non-viral vector can disseminate throughout the treated patient, without control, especially when administered systematically in vivo. Additionally, special applications can require that the desired transfer is perfectly controlled and specifically directed towards specific cell or tissue (e.g. in therapeutic targeting of cancer cells, of cardiac cells, of cells involved in immunity ). Such non disseminating property and/or specificity cannot be reached with the presently available vectors. Consequently, there is still a need to design non-viral, as well as viral, vectors which are capable to more specifically deliver nucleic acids to targeted or restricted type of cells and/or tissues. With this respect, one first issue is to limit the non-specific transfer of vectors by limiting non- specific interaction with cells and secondly to direct the transfer by providing targeted vectors. The use of targeted vectors, which are able to facilitate interaction with selected target cells or tissues, would limit the vector spread, thus increasing transfer efficacy in the desired target cells/tissues, and thus possible therapeutic effect of the transfered substance of interest. This approach is mainly based on the fact that most of cells and/or tissues, in their natural or diseased status, expresses unique cell/tissue surface markers. For example, endothelial cells in rapidly growing tumors express cell surface proteins not present in quiescent endothelium, i.e. Ψ integrins (Brooks et al., 1994, Science 264 , 569) and receptors for certain angiogenic growth factors (Hanahan, 1997, Science 277, 48). Thus, these cell surface markers may be used as targets to direct the vectors to specific cell type. Compounds able to target cell surface markers are disclosed in literature and may be composed of all or part of sugars, glycol, peptides (e.g. GRP, Gastrin Releasing Peptide), oligoηucleotides, lipids (especially those with C2-C22), hormones, vitamins, antigens, antibodies (or fragments thereof), specific membrane receptor ligands, ligands capable of reaction with an anti- ligand, or a combination of said compounds, e.g. galactosyl residues to target the asialoglycoprotein receptor on the surface of hepatocytes. The present invention is based on the use of a targeting moiety able to bind to a glutamine transporter to retarget therapeutically active substance to normal and abnormal (e.g. tumoral) cells. Glutamine is the most abundant free amino acid in the human body; it is essential for the growth of normal and neoplastic cells and for the culture of many cell types. Glutamine is synthesized primarily in skeletal muscle and adipose tissue and is an important amino acid for the maintenance of healthy gut function, nitrogen transport, lean tissue mass, and immune function. Important consumers of glutamine from the blood-stream include the gastrointestinal tract, the kidney, the liver and the immune system. During stress situations, the demand by these and perhaps other tissues (e.g. skeletal muscle) may exceed the ability of skeletal muscle to supply glutamine. As a result, blood and skeletal muscle glutamine concentrations fall. In such situations glutamine becomes conditionally essential (Lacey JM, Wildmore DW. Is glutamine a conditionally essential amino acid? Nutr. Rev. 1990; 48: 297). It is also a preferred energy source for many types of tumors through an altered Krebs cycle. Glutamine transport across the cell membranes of a variety of mammalian tissues is mediated by at least eight transport systems: five Na⁺ dependent glutamine transporters (i.e. System N, System A, System ASC/B°, System B° and System y⁺L transporter) and three Na⁺ independent transporters (i.e. System L, System B°^,+ and System n). Glutamine is especially an important metabolic substrate of rapidly proliferating cells. It is the major oxidizable substrate of tumor cells. Inside the mitochondrion, it is deaminated to glutamate through a phosphate- dependent glutaminase. Glutamate is then preferentially transaminated to alpha-ketoglutarate that enters the Krebs cycle. Glutamine may be completely oxidized through the abnormal Krebs cycle only if a way of forming acetyl CoA is present: cytosolic malate entering mitochondria is preferentially oxidized to pyruvate + CO₂ through an intramitochondrial NAD(P)(+)-malic enzyme, whereas intramitochondrial malate is preferentially oxidized to oxaloacetate through malate dehydrogenase, thus providing a high level of intramitochondrial substrate compartmentation. These and other regulatory aberrations in tumor cells appear to be reflections of a complex set of non-random phenotypic changes, initiated by expression of oncogenes (Baggetto LG. Deviant energetic metabolism of glycolytic cancer cells. Biochimie 1992 Nov;74(11):959-74). Cancer has been described as a nitrogen trap. The presence of a tumor produces great changes in host glutamine metabolism in such a way that host nitrogen metabolism is accommodated to the tumor-enhanced requirements of glutamine. To be used, glutamine must be transported into tumor mitochondria (for review see Medina MA. Glutamine and cancer J Nutr 2001 Sep; 131(9 Suppl):2539S-42S; discussion 2550S-1S) Cytoplasmic levels of glutamine are significantly governed by the activity of the System N transporter in the plasma membrane of parenchymal cells; in this capacity, this glutamine carrier has been shown to represent a rate-limiting step in metabolism via glutaminase. The unique properties of System N allow it to rapidly adapt in support of the dynamic demands of whole body ammonia and glucose homeostasis. In contrast to System N in normal hepatocytes, human hepatoma cells take up glutamine at rates several-fold faster through a broad-specificity higher affinity transporter with characteristics of System ASC or B° (Bode BP, Souba WW. Glutamine transport and human hepatocellular transformation. J Parenter Enteral Nutr 1999 Sep-Oct; 23(5 Suppl):S33-7). The System ASC family of transporters is involved in various solid tumors such as breast, liver and colon tumor s (Collins CL, Wasa M, Souba WW, Abcouwer SF. Determinants of glutamine dependence and utilization by normal and tumor-derived breast cell lines. J Cell Physiol 1998 Jul;176(1): 166-78 ; Wasa M, Bode BP, Abcouwer SF, Collins CL, Tanabe KK, Souba WW. Glutamine as a regulator of DNA and protein biosynthesis in human solid tumor cell lines. Ann Surg 1996 Aug; 224(2): 189-97). System L is a major nutrient transport system responsible for the transport of large neutral amino acids including several essential amino acids. A L-type amino acid transporter 1 : LAT1 subserving system L in C6 rat glioma cells requiring 4F2 heavy chain (4F2hc) for its functional expression supports provides cells with essential amino acids for cell growth and cellular responses, and in distributing amino acid-related compounds. (Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H. Biochim Biophys Acta 2001 Oct 1 ; 1514(2):291-302 Human L- type amino acid transporter 1 (LAT1 ): characterization of function and expression in tumor cell lines) Human hepatoma cells extract glutamine at rates several fold greater than normal hepatocytes through the high-affinity transporter Na(+)-dependent neutral amino acid transporter B0 (ATB0) . (Bode BP, Reuter N, Conroy JL, Souba WW. Protein kinase C regulates nutrient uptake and growth in hepatoma cells. Surgery 1998 Aug; 124(2):260-7; discussion 267-8). Hepatocellular transformation is characterized by a marked increase in glutamine transport and metabolism. Inhibition of cellular proliferation attenuates glutamine transport and metabolism, especially in fast-growing, relatively undifferentiated hepatoma cells. Because the uptake of other amino acids is similarly reduced under cytostatic conditions, plasma membrane amino acid transport activity in hepatoma cells is regulated by the proliferation state of the cells. (Bode BP, Souba WW. Modulation of cellular proliferation alters glutamine transport and metabolism in human hepatoma cells. Ann Surg 1994 Oct; 220(4):411-22; discussion 422-4). Glutamine transport rates are also strongly increased (more than sixfold) in fibrosarcomas compared to normal fibroblasts. In fibroblasts, glutamine transport was mediated by systems ASC and A. In malignant fibrosarcomas, only system ASC was identifiable, and its Vmax was 15 times higher than that observed in fibroblasts. In normal fibroblasts, the transported glutamine is used primarily for energy production via oxidation of glutamine carbons to CO₂. In fibrosarcomas, glutamine oxidation falls and glutamine is shunted into protein synthesis. Simultaneously, the malignant cell switches to a glucose oxidizer. The increased glutamine transport and glucose oxidation in fibrosarcomas appears to be related here merely to the malignant than to cell growth rates. (Fischer CP, Bode BP, Souba WW. Adaptive alterations in cellular metabolism with malignant transformation. Ann Surg 1998 May; 227(5):627-34; discussion 634-6) Human colon carcinomas are known to extract and metabolize glutamine at rates several fold greater than those of normal tissues, through the system ASC/B⁰ system (Pawlik TM, Souba WW, Sweeney TJ, Bode BP. Phorbol esters rapidly attenuate glutamine uptake and growth in human colon carcinoma cells. J Surg Res 2000 May 15;90(2):149-55). Tumor cells may express additional isoforms of amino acid transport systems which are not present in non-transformed cells (McGivan JD. Rat hepatoma cells express novel transport systems for glutamine and glutamate in addition to those present in normal rat hepatocytes. Biochem J 1998 Feb 15; 330 (Pt 1):255-60). The hepatic uptake of amino acids is increased in both sepsis and cancer. The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold. This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver (Karinch AM, Pan M, Lin CM, Strange R, Souba WW. Glutamine metabolism in sepsis and infection. J Nutr 2001 Sep; 131(9 Suppl):2535S-8S; discussion 2550S-1S) Early transient hepatic amino acid transporter stimulation may support amino acid-dependent pathways involved in the repair of bum- dependent hepatic damage (increases in the maximum velocity (Vmax) of system N and system A activities) (Lohmann R, Souba WW, Zakrzewski K, Bode BP. Stimulation of rat hepatic amino acid transport by burn injury. Metabolism 1998 May; 47(5):608-16). The metabolic response to inflammation involves an increased uptake of amino acids in the liver. The glutamine and glutamate transporters in skeletal muscle and heart appear to play a role in control of the steady-state concentration of amino acids in the intracellular space and, in the case of skeletal muscle at least, in the rate of loss of glutamine to the plasma and to other organs and tissues (Rennie MJ, Ahmed A, Khogali SE, Low SY, Hundal HS, Taylor PM. Glutamine metabolism and transport in skeletal muscle and heart and their clinical relevance. Nutr 1996 Apr; 126(4 Suppl):1142S-9S). Glutamine is transported at very high rates in skeletal muscle and heart and both the glutamate and glutamine transporter systems appear to be adaptively regulated by the availability of glutamine. Glutamine appears to be involved in the regulation of a number of important metabolic processes in heart and skeletal muscle (e.g., regulation of the glutathione reduced/oxidised ratio and regulation of protein and glycogen synthesis). Furthermore, glutamine transport appears to interact with systems for regulation of volume control and many of the metabolic features attributable to changes in glutamine concentration appear to be modulated via alteration in cytoskeletal status (Rennie MJ, Low SY, Taylor PM, Khogali SE, Yao PC, Ahmed A. Amino acid transport during muscle contraction and its relevance to exercise. Adv Exp Med Biol 1998; 441 :299-305). Glutamine deprivation causes an increase in the capacity for glutamine uptake via system N (not systems A, ASC, or L) (Tadros LB,

Willhoft NM, Taylor PM, Rennie MJ. Effects of glutamine deprivation on glutamine transport and synthesis in primary culture of rat skeletal muscle. Am J Physiol 1993 Dec; 265(6 Pt 1 ): E935-42). Blood cells such as macrophages and lymphocytes bear glutamine transport systems (Schroder MT, Schafer G, Schauder P. Characterization of glutamine transport into resting and concanavalin A-stimulated peripheral human lymphocytes. J Cell Physiol 1990 Oct; 145(1 ):155-61 ). The present invention takes advantage of the presence of glutamine transporters on many cell types and their upregulation in abnormal situation (such as on tumor cells) to drive to and/or increase transfer efficiency and/or specificity of therapeutically active substance in various cell types and in various situations. Thus, the present invention provides compound comprising: (i) A therapeutically active moiety and, (ii) A targeting moiety able to bind to a glutamine transporter, As used herein, the term "therapeutically active moiety" encompasses moiety having beneficial, prophylactic and/or therapeutic properties when administered to an animal, especially a human. Therapeutically active moieties include but are not limited to vitamins, amino acids, peptides, chemotherapeutics, antibiotics, agents affecting respiratory organs, antitussive expectorants, antitumor agents, autonomic drugs, neuropsychotropic agents, muscle relaxants, drugs affecting digestive organs, antihistamic agents, antidotes, hypnotic sedatives, antiepileptics, antipyretic analgesic antiphlogistics, cardiotonics, antiarrhythmics, hypotensive diuretics, vasodilators, hypolipidemic agents, alimentary analeptics, nucleic acid, anticoagulants, hepatics, blood sugar- lowering agents and hypotensive agents. The term "nucleic acid" or "nucleic acid molecule" as used in the scope of the present invention means a DNA or RNA or a fragment or combination thereof, which is single- or double-stranded, linear or circular, natural or synthetic, modified or not (see US 5525711 , US 4711955, US 5792608 or EP 302 175 for modification examples) without size limitation. It may, inter alia, be a genomic DNA, a cDNA, an mRNA, an antisense RNA, a ribozyme, or a DNA encoding such RNAs. The terms "polynucleotide", "nucleic acid molecule" and "nucleic acids" are synonyms with regard to the present invention. The nucleic acid may be in the form of a linear or circular polynucleotide, and preferably in the form of a plasmid. The nucleic acid can also be an oligonucleotide which is to be delivered to the cell, e.g., for antisense or ribozyme functions. According to the invention, the nucleic acid is preferably a naked polynucleotide (Wolff et al., Science 247 (1990), 1465-1468) or is formulated with at least one compound such as a polypeptide, preferably a viral polypeptide, or a cationic lipid, or a cationic polymer, or combination thereof, which can participate in the uptake of the polynucleotide into the cells (see Ledley, Human Gene Therapy 6 (1995), 1129-1144 for a review) or a protic polar compound (examples are provided below in the present application or in EP 890362). Alternatively, nucleic acid further designate a viral vector (adenoviral vector, retroviral vector, poxviral vector, etc.). The term « viral vector » as used in the present invention encompasses the vector genome, the viral particles (i.e. the viral capsid including the viral genome) as well as empty viral capsids. "Plasmid" refers to an extrachromosomic circular DNA. The choice of the plasmids is very large. Plasmids can be purchased from a variety of manufacturers. Suitable plasmids include but are not limited to those derived from pBR322 (Gibco BRL), pUC (Gibco BRL), pBluescript (Stratagene), pREP4, pCEP4 (Invitrogene), pCI (Promega) and p Poly (Lathe et al., Gene 57 (1987), 193-201 ). It is also possible to engineer such a plasmid by molecular biology techniques (Sambrook et al., Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor (1989), NY). A plasmid may also comprise a selection gene in order to select or identify the transfected cells (e.g. by complementation of a cell auxotrophy, antibiotic resistance), stabilizing elements (e.g. cer sequence; Summers and Sherrat, Cell 36 (1984), 1097-1103) or integrative elements (e.g. LTR viral sequences). One viral vector which is particularly appropriate is an adenoviral vector (for a review see for example Hitt et al. Advances in Pharmacology 40 (1997) 137-206). Preferably, it is replication-defective, especially for E1 functions by total or partial deletion of the respective region. Additionally, the adenoviral backbone of the vector may comprise additional modifications, such as deletions, insertions or mutations in one or more viral genes (see WO 94/28152, WO97/04119 EP98401722.8). In addition, adenoviral virions or empty adenoviral capsids can also be used to transfer nucleic acids (i.e. plasmidic vectors) by a virus-mediated cointemalization process as described in US 5,928,944. Adeno. associated virus (AAV) vectors can also be used which combines non pathogenicity, broad tropism and infectivity, and long term persistence. In the context of the invention, an adeno associated viral vector may derived from all the AAV serotypes. The preparation of AAV vectors is available in the art (see for example, viral vectors: basic science and gene therapy. (2000) 11-96. Cid-Arregui and Garcia-Carranca ed. Eaton Publishing.). A retroviral vector is also suitable. Retroviruses are a class of integrative viruses which replicate using a virus-encoded reverse transcriptase, to replicate the viral RNA genome into double stranded DNA which is integrated into chromosomal DNA of the infected cells. The numerous vectors described in the literature may be used within the framework of the present invention and especially those derived from murine leukemia viruses, especially Moloney (Gilboa et al., 1988, Adv. Exp.Med. Biol. 241 , 29) or Friend's FB29 strains (WO95/01447). Finally, poxviral vectors are a group of complex enveloped viruses that distinguish from the above-mentioned viruses by their large DNA genome and their cytoplasmic site of replication. Preferred poxviral vector are vaccinia viruses, such as for example the Copenhagen strain (Goebel et al., 1990, Virol. 179, 247-266 and 517-563), the Wyeth strain and the modified Ankara (MVA) strain (Antoine et al., 1998, Virol. 244, 365-396). Preferably, said nucleic acid molecule includes at least one encoding gene sequence of interest (i.e. a transcriptional unit) that can be transcribed and translated to generate a polypeptide of interest and the elements enabling its expression (i.e. an expression cassette). If the nucleic acid contains this proper genetic information when it is placed in an environment suitable for gene expression, its transcriptional unit will thus express the encoded gene product. The level and cell specificity of expression will depend to a significant extent on the strength and origin of the associated promoter and the presence and activation of an associated enhancer element. Thus in a preferred embodiment, the transcriptional control element includes the promoter/enhancer sequences such as the CMV promoter/enhancer. However, those skilled in the art will recognize that a variety of other promoter and/or enhancer sequences are known which may be obtained from any viral, prokaryotic, e.g. bacterial, or eukaryotic organism, which are constitutive or regulable, which are suitable for expression in eukaryotic cells, and particularly in target cells or tissues. More precisely, this genetic information necessary for expression by a target cell or tissue comprises all the elements required for transcription of said gene sequence (if this gene sequence is DNA) into RNA, preferably into mRNA, and, if necessary, for translation of the mRNA into a polypeptide. Promoters suitable for use in various vertebrate systems are widely described in literature. Suitable promoters include but are not limited to the adenoviral E1a, MLP, PGK (Phospho Glycero Kinase ; Adra et al. Gene 60 (1987) 65-74 ; Hitzman et al. Science 219 (1983) 620-625), RSV, MPSV, SV40, CMV or 7.5k, the vaccinia promoter, inducible promoters, MT (metallothioneine; Mc Ivor et al., Mol. Cell Biol. 7 (1987), 838-848), alpha-1 antitrypsin, CFTR, immunoglobulin, alpha-actin (Tabin et al., Mol. Cell Biol. 2 (1982), 426-436), SR (Takebe et al., Mol. Cell. Biol. 8 (1988), 466-472), early SV40 (Simian Virus), RSV (Rous Sarcoma Virus) LTR, TK-HSV-1 , SM22 (WO 97/38974), Desmin (WO 96/26284) and early CMV (Cytomegalovirus; Boshart et al. Cell 41 (1985) 521), etc. Alternatively, one may use a synthetic promoter such as those described in Chakrabarti et al. (1997, Biotechniques 23, 1094-1097), Hammond et al. (1997, J. Virological Methods 66, 135-138) or Kumar and Boyle (1990, Virology 179, 151-158) as well as chimeric promoters between early and late poxviral promoters. Alternatively, promoters can be used which are active in tumor cells. Suitable examples include but are not limited to the promoters isolated from the gene encoding a protein selected from the group consisting of MUC-1 (overexpressed in breast and prostate cancers; Chen et al., J. Clin. Invest. 96 (1995), 2775-2782), CEA (Carcinoma Embryonic Antigen; overexpressed in colon cancers; Schrewe et al., Mol. Cell. Biol. 10 (1990), 2738-2748), tyrosinase (overexpressed in melanomas; Vile et al., Cancer Res. 53 (1993), 3860-3864), ErbB-2 (overexpressed in breast and pancreas cancers; Harris et al., Gene Therapy 1 (1994), 170-175) and alpha-foetoprotein (overexpressed in liver cancers; Kanai et al., Cancer Res. 57 (1997), 461-465) or combinations thereof. The early CMV promoter is preferred in the context of the invention. The nucleic acid can also include intron sequences, targeting sequences, transport sequences, sequences involved in replication or integration. Said sequences have been reported in the literature and can readily be obtained by those skilled in the art. The nucleic acid can also be modified in order to be stabilized with specific components, for example spermine. It can also be substituted, for example by chemical modification, in order to facilitate its binding with specific polypeptides such as, for example the peptides of the present invention. According to the invention, the nucleic acid can be homologous or heterologous to the target cells into which it is introduced. In a preferred embodiment, the nucleic acid contains at least one gene sequence of interest encoding a gene product which is a therapeutic molecule (i.e. a therapeutic gene). A "therapeutic molecule" is one which has a pharmacological or protective activity when administered, or expressed, appropriately to a patient, especially patient suffering from a disease or illness condition or who should be protected against this disease or condition. Such a pharmacological or protective activity is one which is expected to be related to a beneficial effect on the course or a symptom of said disease or said condition. When the skilled man selects in the course of applying the present invention a gene encoding a therapeutic molecule, he generally relates his choice to results previously obtained and can reasonably expect, without undue experiment other than practicing the invention as claimed, to obtain such pharmacological property. According to the invention, the sequence of interest can be homologous or heterologous to the target cells into which it is introduced. Advantageously said sequence of interest encodes all or part of a polypeptide, especially a therapeutic or prophylactic polypeptide giving a therapeutic or prophylactic effect. A polypeptide is understood to be any translational product of a polynucleotide regardless of size, and whether glycosylated or not, and includes peptides and proteins. Therapeutic polypeptides include as a primary example those polypeptides that can compensate for defective or deficient proteins in an animal or human organism, or those that act through toxic effects to limit or remove harmful cells from the body. They can also be immunity conferring polypeptides which act as an endogenous antigen to provoke a humoral or cellular response, or both. The following encoding gene sequences are of particular interest. For example genes coding for a cytokine ("Sbr (interferon, interieukine (IL), in particular IL-2, IL-6, IL-10 or IL-12, a tumor necrosis factor (TNF), a colony stimulating factor (such as GM-CSF, C-CSF, M-CSF), an immunostimulatory polypeptide (such as B7.1 , B7.2, CD40, CD4, CD8, ICAM and the like), a cell or nuclear receptor, a receptor ligand (such as fas ligand), a coagulation factor (such as FVIII, FIX), a growth factor (such as Transforming Growth Factor TGF, Fibroblast Growth Factor FGF and the like), an enzyme (such as urease, renin, thrombin, metalloproteinase, nitric oxide synthase NOS, SOD, catalase), an enzyme inhibitor (such as τ-antitrypsine, antithrombine III, viral protease inhibitor, plasminogen activator inhibitor PAI-1 ), the CFTR protein, insulin, dystrophin, a MHC antigen (Major Histocompatibility Complex) of class I or II or a polypeptide that can modulate/regulate the expression of one or more cellular genes, a polypeptide capable of inhibiting a bacterial, parasitic or viral infection or its development (such as antigenic polypeptides, antigenic epitopes, transdominant variants inhibiting the action of a native protein by competition), an apoptosis inducer or inhibitor (such as Bax, Bcl2, BclX), a cytostatic agent (such as p21, p16, Rb), an apolipoprotein (such as ApoAI, ApoAIV, ApoE), an inhibitor of angiogenesis (such as angiostatin, endostatin), an angiogenic polypeptide (such as family of Vascular Endothelial Growth Factors VEGF, FGF family, CCN family including CTGF, Cyr61 and Nov), an oxygen radical scavenger, a polypeptide having an anti-tumor effect, an antibody, a toxin, an immunotoxin and a marker (such as beta-galactosidase, luciferase) or any other gene of interest that is recognized in the art as being useful for the treatment or prevention of a clinical condition. In view of treating a hereditary dysfunction, one may use a functional allele of a defective gene, for example a gene encoding factor VIII or IX in the context of haemophilia A or B, dystrophin (or minidystrophin) in the context of myopathies, insulin in the context of diabetes, CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) in the context of cystic fibrosis. Suitable anti- tumor genes include but are not limited to those encoding an antisense RNA, a ribozyme, a cytotoxic product such as thymidine kinase of herpes- 1 simplex virus (TK-HSV-1 ), ricin, a bacterial toxin, the expression product of yeast genes FCY1 and/or FUR1 having UPRTase (Uracile Phosphoribosyltransferase) and CDase (Cytosine Deaminase) activity respectively, an antibody, a polypeptide inhibiting cellular division or transduction signals, a tumor suppressor gene (p53, Rb, p73), a polypeptide activating host immune system, a tumor-associated antigen (MUC-1 , BRCA-1 , an HPV early or late antigen (E6, E7, L1 , L2), optionally in combination with a cytokine gene. The polynucleotide can also encode an antibody. In this regard, the term "antibody" encompasses whole immunoglobulihs of any class, chimeric antibodies and hybrid antibodies with dual or multiple antigen or epitope specificities, and fragments, such as F(ab)'2, Fab', Fab including hybrid fragments and anti-idiotypes (US 4,699,880). Advantageously said nucleic acid encodes all or part of a polypeptide which is an immunity conferring polypeptide and acts as endogenous immunogen to provoke a humoral or cellular response, or both, against infectious agents, including intracellular viruses, or against tumor cells. An "immunity-conferring polypeptide" means that said polypeptide when it is produced in the transfected cells will participate in an immune response in the treated patient. More specifically, said polypeptide produced in or taken up by macropinocyte cells such as APCs will be processed and the resulting fragments will be presented on the surface of these cells by MHC class I and/or II molecules in order to elicit a specific immune response. The nucleic acid may comprise one or more gene(s) of interest. In this regard, the combination of genes encoding a suicide gene product and a cytokine gene (e.g. α, $or γ interferons, interieukins, preferably selected among IL-2, IL-4, IL-6, IL-10 or IL-12, TNF factors, GM-CSF, C- CSF, M-CSF and the like), an immunostimulatory gene (e.g. B7.1 , B7.2, ICAM) or a chimiokine gene (e.g. MIP, RANTES, MCP 1 ) is advantageous. The different gene expression may be controlled by a unique promoter (polycistronic cassette) or by independent promoters. Moreover, they may be inserted in a unique site or in various sites along the nucleic acid either in the same or opposite directions. The encoding gene sequence of interest may be isolated from any organism or cell by conventional techniques of molecular biology (PCR, cloning with appropriate probes, chemical synthesis) and if needed its sequence may be modified by mutagenesis, PCR or any other protocol. Alternatively, the therapeutically active moiety is a peptide (polypeptide, protein and peptide are synonyms) including variant or modified peptides, peptide-like molecules, antibodies or fragments thereof, chimeric antibody. Within the context of the present invention, preferred proteins are those able to inhibit restenosis, hypertension, to improve heart contracting activity or heart cell survival (e.g. angiogenic factors, cellular receptors or channels involved in ion homeostasis). As used herein, "glutamine transporter" refers to the proteins involved in the transfer of glutamine through the cell membrane. Glutamine transporters comprise Na⁺ dependent glutamine transporter (e.g. System N, System A, System ASC/B°, System B° and System y⁺L transporter) and Na⁺ independent transporters (e.g. System L, System B°^,+ and System n). Glutamine transporters and gene coding glutamine transporters are described in Bode, 2001 , J. Nutr, 131 : 2475S-2485S. Targeting moiety able to bind specifically with glutamine transporters are disclosed in litterature however their application as ligand for targeting transfer of therapeutically active substance towards or into cells, or tissue, expressing them has neither been disclosed nor suggested. Applicants have now demonstrated that this latter application is perfectly workable, especially in the frame of nucleic acid transfer into cells expressing glutamine transporter, for example tumor cells, hepatoma cells, fibrosarcoma cells, skeletal muscle and heart cells, hepatic cells, macrophages and lymphocytes. As used herein, "targeting moiety able to bind to a glutamine transporter" encompasses molecules able to recognize and to bind specifically to a glutamine transporter with high affinity and preferably with high specificity but also molecules that can be transported across the plasma membrane by a glutamine transporter. According to the invention, a targeting moiety able to bind to a glutamine transporter may be for example a lipid, a glycolipid, a hormone, a sugar, a polymer, an oligonucleotide, a vitamin, an antigen, all or part of a lectin,- all or part of a polypeptide, an antibody or a fragment thereof, or a combination thereof. In a preferred embodiment, the targeting moiety able to bind to a glutamine transporter is an amino acid or one of its derivatives, more preferably a glutamine, and even more preferably L-Glutamine. When the targeting moiety able to bind to a glutamine transporter is an amino acid, said amino acid is preferably not included in a polypeptide. The term "is not included in a polypeptide" means that the amino acid used as a targeting moiety is not linked to two amino acids via its carboxyl and amino groups. Preferably, the amino acid used as a targeting moiety is not linked to an amino acid. Alternatively, the targeting moiety able to bind to a glutamine transporter can be all or part of a specific antibody which is able to bind a glutamine transporter. Such antibodies are well known to the one skilled in the art and are commercially available. Additionally, such specific antibodies can be produced according to techniques widely used in the art (see for example, Antibodies — A Laboratory Manual, Hariow and Lane, eds., Cold Spring Harbor Laboratory, New York (1988). According to a preferred embodiment of the invention, the therapeutically active moiety is coupled to the targeting moiety able to bind to a glutamine transporter, "Coupled" within the scope of the invention means that the therapeutically active moiety and the targeting moiety able to bind to a glutamine transporter are covalently or non-covalently linked. "Covalent link" refers to coupling through reactive functional groups, optionally with the intermediary use of a cross linker or other activating agent (see for example Bioconjugate techniques 1996; ed G Hermanson ; Academic Press). The therapeutically active moiety and/or the targeting moiety able to bind to a glutamine transporter may be modified in order to allow their coupling via, for example, substitution on an activated carbonyl group (including those activated in situ) or on an imidoester, via addition on an unsaturated carbonyl group, by reductive amination, nucleophilic substitution on a saturated carbon atom or on a heteroatom, by reaction on aromatic cycles,... In particular, coupling may be done using homobifunctional or heterobifunctional cross-linking reagents. Homobifunctional cross linkers including glutaraldehyde, succinic acid and bis-imidoester like DMS (dimethyl suberimidate) can be used to couple amine groups which may be present on the various moieties. Numerous examples are given in Bioconjugate techniques ((1996) 188-228; ed G Hermanson; Academic Press) which are well known by those of the art. Heterobifunctional cross linkers include those having both amine reactive and sulfhydryl-reactive groups, carbonyl-reactive and sulfhydryl-reactive groups and sulfhydryl-reactive groups and photoreactive linkers. Suitable heterobifunctional crosslinkers are, for example, described in Bioconjugate techniques (1996) 229-285; ed G Hermanson ; Academic Press) or WO99/40214. Examples are, for example, SPDP (N-succinimidyl 3-(2- pyridyldithio) propionate), SMBP (succinimidyl-4-(p-maleimidophenyl) butyrate), SMPT (succinimidyloxycarbonyl-"methyl-("2-pyridyldithio) toluene), MBS (m-maleimidobenzoyl-N-hydroxysuccinimide ester), SIAB (N-succinimidyl (4 iodoacetyl) aminobenzoate), GMBS (( maleimidobutyryloxy) succinimide ester), SIAX (succinimidyl-6- iodoacetyl amino hexonate, SIAC (succinimidyl-4-iodoacetyl amino methyl), NPIA (p- nitrophenyl iodoacetate). Other examples are useful to couple carbohydrate-containing molecules (e.g. env glycoproteins, antibodies) to sulfydryl-reactive groups. Examples include MPBH (4-(4-N maleimidophenyl) butyric acid hydrazide) and PDPH (4-(N- maleimidomethyl) cyclohexane-1-carboxyl-hydrazide (M2C2H and 3-2(2- pyridyldithio) proprionyl hydrazide). One may further cite ASIB (1-(p azidosalicylamido)-4-(iodoacetamido) butyrate), or the thiol reactive reagents described in Frisch et al. (Bioconjugate Chem. 7 (1996) 180- 186). According to a preferred embodiment, the compound of the invention further comprises a hydrophilic polymer. More preferably, said hydrophilic polymer is coupled to the therapeutically active moiety and to the targeting moiety able to bind to a glutamine transporter. As used herein, the term "hydrophilic polymer" refers to polymers which include, but are not limited to, hydroxy, amino, polyol, sugars (pyranoses or furanoses), or hydrophilic peptides related polymers. The hydrophilic polymer of the invention is preferably selected in the group consisting of polyalkylethers, ganglioside Gm1 , polyvinylpyrrolidone polyalkyloxazoline (e.g. polymethyloxazoline, polyethyloxazoline polyhydroxypropyloxazoline,...), polyalkylacrylamide (e.g polyhydroxypropylmethacrylamide, polymethacrylamide polydimethylacrylamide, ...), polyalkylacrylate (e.g polyhydroxypropylmethacrylate, polyhydroxyethylacrylate,...) polyalkylcellulose (e.g. hydroxymethylcellulose, hydroxyethylcellulose,...) polyaspartamide, tetritols, pentitols, hexitols (i.e. mannitol, sorbitol) dulcitol,... According to a more preferred embodiment, the hydrophilic polymer is a polyalkylether, such as for example polyvinylmethylether or polyethyleneglycol (PEG) and related homopolymers, such as polymethylethyleneglycol, polyhydroxypropyleneglycol, polypropyleneglycol, polymethylpropyleneglycol, and polyhydroxypropyleneoxide, or heteropolymers of small alkoxy monomers, such as a polyethetylene/polypropyleneglycol. Advantageously, these polymers have a molecular weight of at least about 120 daltons (Da), and up to about 20,000 daltons (Da). The polyalkylether, such as polyethyleneglycol or polypropyleneglycol, or the methoxy- or ethoxy- capped analogs, can be obtained commercially in a variety of polymer sizes, e.g., 120-20,000 dalton molecular weights. Alternatively, the homo- or heteropolymer can be formed by known polymer synthesis methods to achieve a desired monomeric composition and size. One preferred polyalkylether is PEG, especially those having a molecular weight ranging between about 1 ,000 and about 5,000 daltons (Da), more preferably of about 2000 Da. The compound of the invention may comprise one or more, similar or different, hydrophilic polymers. The present invention also provides complexes and Iiposomes associated with a targeting moiety able to bind to a glutamine transporter. The term "Liposome" refers to completely closed lipid bilayer membranes containing an entrapped aqueous volume. Liposomes may be unilamellar vesicles (possessing a single bilayer membrane) or multilamellar vesicles (onion-like structures characterized by multiple membrane bilayers, each separated from the next by an aqueous layer). The bilayer is composed of two lipid monolayers having a hydrophobic "tail" region and a hydrophilic "head" region. The structure of the membrane bilayer is such that the hydrophobic (nonpolar) "tails" of the lipid monolayers orient toward the center of the bilayer while the hydrophilic "head" orient towards the aqueous phase. In a preferred embodiment, the liposome according to the invention further comprises a therapeutically active compound in its entrapped aqueous volume and/or in its lipid bilayer. As used herein, "therapeutically active compound" has the same meaning than "therapeutically active moiety" previously defined. The term "complex" refers to molecular assemblages comprising at least one anionic substance of interest and at least one cationic compound (i.e. cationic lipid, cationic polymer and/or cationic peptide), for example by ionic interactions, by forming disulfide or hydrogen bonds, by hydrophobic interactions or covalent bonds. Preferably, an anionic substance of interest is capable of interacting and binding to an anionic substance of interest at least by the intermediate of ionic interactions. Such a complex may contain further elements, some of them are described in the followings. "Anionic substance of interest" designates preferably a charged molecule without limitation of the number of charges. Preferably, said molecule is selected from the group consisting of proteins and nucleic acid molecules. According to a preferred embodiment, said anionic substance of interest is a nucleic acid molecule (as previously defined). The complex of the invention comprises at least one cationic compound selected from the group consisting of cationic lipids and cationic polymers. Cationic compounds are widely described in the scientific literature (see for example the references related to non-viral delivery systems mentioned above, or WO 97/29118, WO 98/08489, WO 98/17693). Cationic lipids or mixtures of cationic lipids which may be used in the present invention include cationic lipids selected from the group consisting of Lipofectin™, DOTMA: N-[1-(2,3-dioleyloxyl)propyl]-N,N,N- trimethylammonium (Feigner, PNAS 84 (1987), 7413 7417), DOGS: dioctadecylamidoglycylspermine or Transfectam™ (Behr, PNAS 86 (1989), 6982 6986), DMRIE: 1 ,2-dimiristyloxypropyl-3-dimethyl- hydroxyethylammonium and DORIE: 1 ,2-diooleyloxypropyl-3-dimethyl- hydroxyethylammnoium (Feigner, Methods 5 (1993), 67 75), DC CHOL: 3 [N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (Gao, BBRC 179 (1991), 280 285), DOTAP (McLachlan, Gene Therapy 2 (1995), 674 622), Lipofectamine™, spermine or spermidine-cholesterol, Lipofectace™ (for a review see for example Legendre, Medecine/Science 12 (1996), 1334- 1341 or Gao, Gene Therapy 2 (1995), 710-722), cationic lipid as disclosed in patent applications WO 98/34910, WO 98/14439, WO 97/19675, WO 97/37966, WO0292554 and their isomers. Nevertheless, this list is not exhaustive and other cationic lipids well known in the art can be used in connection with the present invention as well. Cationic polymers or mixtures of cationic polymers which may be used in the present invention include cationic polymers selected from the group consisting of chitosan, poly(aminoacids) such as polylysine (US-A-5,595,897 and FR 2 719 316); polyquaternary compounds; protamine; polyimines;polyethylene imine or polypropylene imine (WO 96/02655) ; polyvinylamines; polycationic polymer derivatized with DEAE, such as pullulans, celluloses; polyvinylpyridine; polymethacrylates; polyacrylates; polyoxethanes; polythiodiethylaminomethylethylene (P(TDAE)); polyhistidine; polyomithine; poly-p-aminostyrene; polyoxethanes; co-polymethacrylates (eg copolymer of HPMA; N-(2-hydroxypropyl)-methacrylamide); the compound disclosed in US-A-3,910,862, polyvinylpyrrolid complexes of DEAE with methacrylate, dextran, acrylamide, polyimines, albumin, onedimethylaminomethylmethacrylates and polyvinylpyrrolidonemethylacrylaminopropyltrimethyl ammonium chlorides; polyamidoamines; telomeric compounds . Nevertheless, this list is not exhaustive and other cationic polymers well known in the art can be used in connection with the present invention as well. According to a particular embodiment, the complex of the invention further comprises: - at least one peptide which is capable of causing membrane disruption ; and/or - at least one colipid. In one special embodiment, the complex of the invention may comprise at least one peptide capable of causing membrane disruption. Examples of such peptides are JTS-1 , JTS-1-K13, GALA, KALA, ppTG1 and related peptides (see Mahato et al., 1999, Current Opinion in Mol. Therapeutics 1 , 226-243; WO 96/40958 ; WO 98/50078 ; Gottschalk et al., 1996, Gene Therapy, 3, 448-457 ; Haensler & Szoka, 1993, Bioconjugate Chem., 4, 372-379 ; Wyman et al., 1997, Biochemistry, 36, 3008-3017 , patent application EP 01 44 0049.3 ). Colipids may be optionally included in the complex of the invention in order to facilitate entry of the nucleic acid into the cell. According to the invention, colipids are selected from the group consisting of positively or negatively charged, neutral or zwitterionic lipids. These colipids are, for example, selected from the group consisting of phosphatidylethanolamine (PE), phosphatidylcholine, phosphocholine, dioleylphosphatidylethanolamine (DOPE), sphingomyelin, ceramide or cerebroside and one of their derivatives. The complex and the liposome according to the invention are associated with a targeting moiety able to bind to a glutamine transporter. As shown in the Experimental section, the complexes and the Iiposomes of the present invention present the advantageous property to reduce, and in preferred case to eliminate, non-specific transfer of substances of interest into cells. The targeting moiety able to bind to a glutamine transporter can be associated with any of the elements comprised in the complex or the liposome of the invention. According to a preferred embodiment, at least one compound comprised into said complex or liposome is coupled with at least one targeting moiety able to bind to a glutamine transporter. Incorporation of the targeting moiety can be performed during the synthesis of the one of the elements forming the complex or the liposome of the invention using methods familiar to skilled person (e.g. use of reactive groups, ...). Alternatively, it can also be performed on the neosynthesized compounds or on the neoformed complexes or Iiposomes. In a preferred embodiment of the invention, such targeting moiety is coupled to a carrier permitting incorporation of said targeting moiety into the complex or the liposome. The "carrier" can be any carrier which is able to be incorporated into the complex or liposome. More specifically, said carrier might be a charged, a zwitterionic or a non charged compound. It might comprise alkyl or alkenyl chains; it might for example comprise hydrophilic element such as for example those above described; it might further comprise any spacer molecule. According to special embodiment, targeting moiety able to bind to a glutamine transporter can be coupled to a cationic compound or a colipid , at the level of either the hydrophilic, hydrophobic or polar region, or combination hereof, as above described, by covalently or non-covalently links, including or not homobifunctional or heterobifunctional cross-linking reagent. The present invention also provides a molecule comprising an hydrophobic moiety, and a targeting moiety able to bind to a glutamine transporter. Such molecule may be incorporated in the complexes or in the liposome according to the invention. As used herein, the term "hydrophobic moiety" means a fatty acid, fatty alcohol, sterol, or any other hydrophobic molecule capable of distribution into a lipid phase from an aqueous medium. For example, an hydrophobic domain may be a diacylglycerol, a phospholipid, a sterol or a diacylamide derivative. According to a preferred embodiment, said hydrophobic moiety comprises at least one hydrocarbon chain, preferably two. More preferably, said hydrocarbon chain comprises at least one alkyl or alkenyl radicals having 6 to 23 carbon atoms (noted C6-C23), which are linear or branched, or radicals -C(=O)-(C6-C23) alkyl or -C(=O)-(C6-C23) alkenyl, or more particularly -C(=O)-(C12-C20) alkyl or C(=O)-(C12-C20) alkenyl, which are linear or branched, aryl radicals, cycloalkyl radicals, fluoroalkyl radicals, oxyethylene or oxymethylene groups which are optionally repeated, linear or branched, optionally substituted. Substitution can, for example, reside in cationic functions, such as for example amidinium or guanidinium groups, in C1-C5 alkyl radicals (e.g. methyl, ethyl, propyl,...) or in perfluoroalkyl radical. Alternatively, the hydrophobic moiety is provided in the form of a copolymer. Examples of such copolymer are those comprising: an hydrophobic moiety, such as Poly($Denzyl-L-aspartate), Poly(γ- caprolactone), Polystyrene or Poly(methylmethacrylate), or any of the hydrophobic moities above described. The skilled man can easily, using his general knowledge, design such copolymers. The targeting moiety able to bind to a glutamine transporter is a previously defined. According to a particular embodiment, the molecule according to the invention further comprises an hydrophilic polymer. Preferably, said hydrophilic polymer is coupled to said targeting moiety able to bind to glutamine transporter and to the hydrophobic moiety. As used herein, the term "hydrophilic polymer" refers to polymers which include, but are not limited to, hydroxy, amino, polyol, sugars (pyranoses or furanoses), or hydrophilic peptides related polymers. The hydrophilic polymer of the invention is preferably selected in the group consisting of polyalkylethers, ganglioside Gm1 , polyvinylpyrrolidone, polyalkyloxazoline (e.g. polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline,...), polyalkylacrylamide (e.g. polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, ...), polyalkylacrylate (e.g. polyhydroxypropylmethacrylate, polyhydroxyethylacrylate,...), polyalkylcellulose (e.g. hydroxymethylcellulose, hydroxyethylcellulose,...), polyaspartamide, tetritols, pentitols, hexitols (i.e. mannitol, sorbitol), dulcitol,... According to a more preferred embodiment, the hydrophilic polymer is a polyalkylether, such as for example polyvinylmethylether or polyethyleneglycol (PEG) and related homopolymers, such as polymethylethyleneglycol, . polyhydroxypropyleneglycol, polypropyleneglycol, polymethylpropyleneglycol, and polyhydroxypropyleneoxide, or heteropolymers of small alkoxy monomers, such as a polyethetylene/polypropyleneglycol. Advantageously, these polymers have a molecular weight of at least about 120 daltons (Da), and up to about 20,000 daltons (Da). The polyalkylether, such as polyethyleneglycol or polypropyleneglycol, or the methoxy- or ethoxy- capped analogs, can be obtained commercially in a variety of polymer sizes, e.g., 120-20,000 dalton molecular weights. Alternatively, the homo- or heteropolymer can be formed by known polymer synthesis methods to achieve a desired monomeric composition and size. One preferred polyalkylether is PEG, especially those having a molecular weight ranging between about 1 ,000 and about 5,000 daltons (Da), more preferably of about 2000 Da. The molecule of the invention may comprise one or more, similar or different, hydrophilic polymers. "Coupled" within the scope of the invention means that said targeting moiety able to bind to glutamine transporter and /or the hydrophobic moiety is covalently or non-covalently linked to and to the hydrophilic polymer. In a preferred embodiment, the molecule of the invention is of formula I:

in which: R1 and R2, which are identical or different, are alkyl or alkenyl radicals having 6 to 23 carbon atoms (noted C6-C23), which are linear or branched, or radicals -C(=O)-(C6-C23) alkyl or -C(=O)-(C6-C23) alkenyl, or more particularly -C(=O)-(C12-C20) alkyl or C(=O)-(C12-C20) alkenyl, which are linear or branched, aryl radicals, cycloalkyl radicals, fluoroalkyl radicals, oxyethylene or oxymethylene groups which are optionally repeated, linear or branched, optionally substituted, According to an advantageous embodiment, the compound of the invention is of formula II:

In an another preferred embodiment, the molecule of the invention is of formula III:

in which R1 , R2, are as mentioned above, n is a positive integer from 4 to 220, preferably from 22 to 110 and more preferably about 44. According to an advantageous embodiment, the compound of the invention is of formula IV:

wherein n is as mentioned above. The various elements of the complex or the liposome (e.g. anionic or cationic compounds, colipid, molecule of the invention, anionic substance of interest) may be modified or substituted by chemical or natural processes widely used by the skilled man in order to obtain compounds modified or substituted such as those disclosed above, enabling, for example, visualization of the distribution of the polypeptide expressed by the nucleic acid, of the nucleic acid, or of the complex of the invention, after in vitro or in vivo administration of the complex or of the liposome. In a specific embodiment of the invention, the size of the complex according to the invention is small (i.e. its diameter is less than 2μm, preferably less than 500 nm and, most preferably, it ranges between 20 and 100 nm). The size of the complex may be selected for optimal use in particular applications. Measurements of the complex size can be achieved by a number of techniques including, but not limited to, dynamic laser light scattering (photon correlation spectroscopy, PCS), as well as other techniques known to those skilled in the art (see, Washington, Particle Size Analysis in Pharmaceutics and other Industries, Ellis Horwood, New York, 1992, 135-169). Sizing procedure may also be applied on complexes in order to select specific complex sizes. Methods which can be used in this sizing step include, but are not limited to, extrusion, sonication and microfluidization, size exclusion chromatography, field flow fractionation, electrophoresis and ultracentrifugation. The ratios of cationic component to colipid (on a mole to mole basis), when the two compounds are co-existing in the complex, can range from 1 :0 to 1 :10. In preferred embodiments, the ratio ranges from 1 :0.5 to 1 :4, advantageously said ratio is about 1 :2. In case where the complex comprises a cationic compound and a molecule of the present invention, the ratios of said compounds can range from 1 :1 to 1 :0.1 , preferably from 1 :0.8 to 1 :0.2. The complexes of the invention may also be characterized by their theoretical charge ratio (+/-), which is the ratio of the positive charges provided by at least the cationic compound to the negative charges provided by the anionic substance of interest in the complex, assuming that all potentially cationic groups are in fact in the cationic state and all potentially anionic groups are in fact in the anionic state. To obtain such a ratio, the calculation shall take into account all negative charges in the anionic substance and shall then adjust the quantity of cationic compound, necessary to obtain the desired theoretical charge ratio indicated above.

The quantities and the concentrations of the other ingredients shall be adjusted in function of their respective molar masses and their number of positive charges. The ratio is not specifically limited: quantities are selected so that the ratio between the number of positive charges in the cationic lipid and the number of negative charges in the anionic substance is between 0.05 and 20, preferably between 2.5 and 15, and most preferably around 2.5 to 10. Furthermore, the concentration of the negatively-charged anionic substance, which may be added to the compound of the invention to form said complexes of the invention may range from 10 μg/ml to 10000 μg/ml. In a preferred embodiment of the invention, the concentration of anionic substance ranges from 100 μg/ml to

1000 μg/ml. The invention is also directed to a process for the preparation of the above described complex, comprising the following steps: - contacting at least one cationic compound with at least one anionic substance of interest and at least one molecule of the invention, - and recovering said complex, optionally after a purification or selection step. Where the complex of the invention further comprises: - at least one peptide which is capable of causing membrane disruption ; and/or - at least one colipid. said process comprises the steps of: - first mixing said cationic compound with said molecule of the invention and/or said peptide which is capable of causing membrane disruption and/or said colipid and then adding the anionic substance of interest in order to form complexes, or - first complexing said cationic compound with said anionic substance of interest compound (then mixing the formed complex with said peptide which is capable of causing membrane disruption and/or said colipid. The process can further comprise a sizing procedure. Methods which can be used in this sizing step include, but are not limited to, extrusion, sonication and microfluidization, size exclusion chromatography, field flow fractionation, electrophoresis and ultracentrifugation. The invention also encompasses a composition, preferably for transferring a therapeutically active substance into a cell and or tissue, wherein said composition comprises at least one compound, complex or liposome of the invention as previously disclosed. Said composition is particularly useful for the delivery of nucleic acids to cells or tissues of a subject in connection with nucleic acid transfer based therapy methods but are not limited to such uses. The term "gene therapy method or vaccine therapy" is preferably understood as a method for the introduction of a nucleic acid into cells either in vivo or by introduction into cells in vitro followed by re-implantation into a subject. "Gene therapy" in particular concerns the case where the gene product is expressed in a tissue as well as the case where the gene product is excreted, especially into the blood stream. The introduction or transfer process of a therapeutically active substance into a cell is by itself well known. "Introduction or transfer" means that the substance is transferred into the cell and is located, at the end of the process, inside said cell or within or on its membrane. If the substance is a nucleic acid, "introduction or transfer" is also referred to as "transfection". Transfection can be verified by any appropriate method, for example by measuring the expression of a gene encoded by said nucleic acid or by measuring the concentration of the expressed protein or its mRNA, or by measuring its biological effect. This composition of the present invention can be formulated in various forms, e.g. in solid, liquid, powder, aqueous, lyophilized form. In a preferred embodiment, this composition further comprises a pharmaceutically acceptable carrier, allowing its use in a method for the therapeutic treatment of humans or animals. In this particular case, the carrier is preferably a pharmaceutically suitable injectable carrier or diluent (for examples, see Remington's Pharmaceutical Sciences, 16th ed. 1980, Mack Publishing Co). Such a carrier or diluent is pharmaceutically acceptable, i.e. is non-toxic to a recipient at the dosage and concentration employed. It is preferably isotonic, hypotonic or weakly hypertonic and has a relatively low ionic strength, such as provided by a sucrose solution. Furthermore, it may contain any relevant solvents, aqueous or partly aqueous liquid carriers comprising sterile, pyrogen-free water, dispersion media, coatings, and equivalents, or diluents (e.g. Tris-HCI, acetate, phosphate), emulsifiers, solubilizers or adjuvants. The pH of the pharmaceutical preparation is suitably adjusted and buffered in order to be useful in in vivo applications. It may be prepared either as a liquid solution or in a solid form (e.g. lyophilized) which can be suspended in a solution prior to administration. Representative examples of carriers or diluents for an injectable composition include water, isotonic saline solutions which are preferably buffered at a physiological pH (such as phosphate buffered saline or Tris buffered saline), mannitol, dextrose, glycerol and ethanol, as well as polypeptides or proteins such as human serum albumin. For example, such composition comprise 10 mg/ml mannitol, 1 mg/ml HSA, 20 mM Tris pH 7.2 and 150 mM NaCI. The invention more particularly relates to a composition comprising at least one of the compounds, Iiposomes or complexes described above and at least one adjuvant capable of improving the transfection capacity of said compound, liposome or complex. Adjuvants may be selected from the group consisting of a chloroquine, protic polar compounds, such as propylene glycol, polyethylene glycol, glycerol, EtOH, 1 -methyl L -2- pyrrolidone or their derivatives, or aprotic polar compounds such as dimethylsulfoxide (DMSO), diethylsulfoxide, di-n-propylsulfoxide, dimethylsulfone, sulfolane, dimethylformamide, dimethylacetamide, tetramethylurea, acetonitrile or their derivatives. The composition of the present invention can be administered into a vertebrate tissue, locally and/or systematically. This administration may be carried out by an intradermal, subdermal, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary or intratumoral injection, by means of a syringe or other devices. Transdermal administration is also contemplated, such as inhalation, aerosol routes, instillation or topical application. "Vertebrate" as used herein is intended to have the same meaning as commonly understood by one of ordinary skill in the art. Particularly, "vertebrate" encompasses mammals, and more particularly humans. According to the present invention, the composition can be administered into tissues of the vertebrate body including those of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, connective tissue, blood, tumor, etc. Applied to in vivo nucleic acid transfer therapy, this invention allows repeated administration to the patient without risk of the administered preparation to induce a significant immune reaction. Additionally, the invention greatly limits the spread-off of the therapeutically active substance throughout the body, and non-specific transfer of the therapeutically active substance into non desirable cells and/or tissues. Administration may be by single or repeated dose, once or several times after a certain period of time. Repeated administration allows a reduction of the dose of active substance, in particular DNA, administered at a single time. The route of administration and the appropriate dose varies depending on several parameters, for example the individual patient, the disease being treated, or the nucleic acid being transferred. According to the invention, "cells" include prokaryotic cells and eukaryotic cells, yeast cells, plant cells, human or animal cells, in particular mammalian cells. In particular, cancer cells should be mentioned. The invention can be applied in vivo to the interstitial or luminal space of tissues in the lungs, the trachea, the skin, the muscles, the brain, the liver, the heart, the spleen, the bone marrow, the thymus, the bladder, the lymphatic system, the blood, the pancreas, the stomach, the kidneys, the ovaries, the testicles, the rectum, the peripheral or central nervous system, the eyes, the lymphoid organs, the cartilage, or the endothelium. In preferred embodiments, the cell will be a muscle cell (e.g. heart cells), as stem cell of the hematopoietic system or an airways cell, more especially a tracheal or pulmonary cell, and preferably a cell of the respiratory epithelium. The present invention also encompasses a process for transferring a nucleic acid into cells or tissues wherein said process comprises contacting said cells or said tissues with at least one compound, liposome, complex or composition according to the invention. This process may be applied by direct administration of said compound, liposome, complex or composition to cells or tissues of the animal in vivo, or by in vitro treatment of cells which were recovered from the animal and then re-introduced into the animal body (ex vivo process). In in vitro applications, cells cultivated on an appropriate medium are placed in contact with a suspension containing a compound, liposome, complex or composition of the invention. After an incubation time, the cells are washed and recovered. Introduction of the active substance can be verified (eventually after lysis of the cells) by any appropriate method. In the case of in vivo treatment according to the invention, in order to improve the transfection rate, the patient may undergo a macrophage depletion treatment prior to administration of the pharmaceutical preparation as described above. Such a technique is described in the literature (refer particularly to Van Rooijen et al., 1997, TibTech, 15, 178- 184). Finally, the present invention also provides the use of a compound, liposome, complex or molecule according to the invention for the preparation of a pharmaceutical composition for curative, preventive or vaccine treatment of mammals. Preferably, such compositions are intended for nucleic acid transfer and more preferably for the treatment of the human or animal body by gene therapy. Within the meaning of the present invention, "gene therapy" has to be understood as a method for introducing any therapeutic gene into a cell. Thus, it also includes immunotherapy that relates to the introduction of a potentially antigenic epitope into a cell to induce an immune response which can be cellular or humoral or both. "Treatment" as used herein refers to prophylaxis and therapy. It concerns both the treatment of humans and animals. A "therapeutically effective amount of a compound, complex or a composition" is a dose sufficient for the alleviation of one or more symptoms normally associated with the disease desired to be treated. A method according to the invention is preferentially intended for the treatment of the diseases listed above. The invention further concerns the use of a compound, liposome, complex or of a molecule as defined above for the preparation of a composition for curative, preventive or vaccine treatment of man or animals, preferably mammals, and more specifically for gene therapy use. The invention further concerns the use of a molecule of the invention for the preparation of a complex or of a liposome for transferring an therapeutically active substance into a cell. As previously indicated, the present invention extends to the use of ligands, or derivatives, able to recognize and react with glutamine transporter, for targeting therapeutically active compound, liposome or complex towards cells and/or tissues expressing such transporter. Said expression can be natural, for example in the case of tumoral cells (see above) or artificial when said expression is directed by genetic modification of the targeted cells. These and other embodiments are disclosed or are obvious from and encompassed by the description and examples of the present invention. Further literature concerning any one of the methods, uses and compounds to be employed in accordance with the present invention may be retrieved from public libraries, using for example electronic devices. For example the public database "Medline" may be utilized which is available on Internet, e.g. under http://www.ncbi.nlm.nih.gov/PubMed/medline.html. Further databases and addresses, such as http://www.ncbi.nlm.nih.gov, http://www.infobiogen.fr, http://www.fmi.ch/biology/research_tools.html, http://www.tigr.org, are known to the person skilled in the art and can also be obtained using, e.g., http://www.lycos.com. An overview of patent information in biotechnology and a survey of relevant sources of patent information useful for retrospective searching and for current awareness is given in Berks, TIBTECH 12 (1994), 352 364. The methods, compositions and uses of the invention can be applied in the treatment of all kinds of diseases the treatment and/or diagnostic of which is related to or dependent on the transfer of nucleic acids in cells. The compositions, and uses of the present invention may be desirably employed in humans, although animal treatment is also encompassed by the uses described herein. The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation. Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced different from what is specifically described herein. The disclosure of all patents, publications published patent applications, and database entries cited in the present application are hereby incorporated by reference in their entirety to the same extend as if each such individual patent, publication and database entry were specifically and individually indicated to be incorporated by reference and were set forth in its entirety herein. Figures Figures 1-3 illustrate pcTG260, pcTG261 and pcTG262 synthesis Figure 4 shows the expression of the luciferase gene by C2C12 cells expressing a glutamine transporter by cationic lipid/nucleic acid complexes comprising a molecule according to the invention (pcTG260) and/or a molecule equivalent to pcTG260 which does not comprise a targeting moiety able to bind to a glutamine transporter (pcTG261). The transfection procedure has been done in the presence or absence of glutamine as a competitor for glutamine transporter binding. Figure 5 shows the expression of the luciferase gene by Wldr cells expressing a glutamine transporter by cationic lipid/nucleic acid complexes comprising a molecule according to the invention (pcTG262). The transfection procedure has been done in the presence or absence of glutamine as a competitor for glutamine transporter binding. Figure 6 shows the in vivo transfection efficiency of cationic lipid/nucleic acid complexes comprising a molecule according to the invention (pcTG262) compared to cationic lipid/nucleic acid complex which does not comprise a targeting moiety able to bind to a glutamine transporter. Complexes were injected intravenously in mice.

Examples Example 1 : Synthesis of pcTG260 and pcTG261 /7-Methoxybenzyl hemisuccinate 1 A solution of -methoxylbenzyl alcohol (3.00 g, 21.71 mmol), succinic anhydride (2.61 g, 26.05 mmol), triethylamine (3.18 ml, 22.80 mmol), and DMAP

(0.13 g, 1.09 mmol) in THF (43 ml) was refluxed for 3 h. After cooling to room temperature, it was diluted with ether (50 ml) and washed with saturated aqueous sodium hydrogenocarbonate (2 x 20 ml). The aqueous layer was acidified to pH =

1 with 10%) hydrochloric acid and was extracted with ether (2 x 50 ml), dried over sodium sulfate and concentrated in vacuo to afford 4.53 g (88%) of p- methoxybenzyl hemisuccinate 1. Mp 71 °C !H-NMR (200 MHz, CDC1₃): δ 7.28 and 6.88 (2d, J= 8.7 Hz, 4H, -C₆H₄- ); 5.08 (s, 2H, -CB^Ar); 3.81 (s, 3H, -OMe); 2.67 (m, 4 H, -C(O)CH₂CH₂C(O)-). Acid 2 DCC (0.95 g, 4.62 mmol) was added to a solution of compound 1 (1.00 g,

4.20 mmol), pentafluorophenol (0.85 g, 4.62 mmol) and DMAP (0.025 g, 0.21 mmol) in acetonitrile (20 ml). After stirring for 3 h at room temperature, the precipitated dicyclohexylurea was removed by filtration and washed with acetonitrile (6 ml). The filtrate was allowed to react overnight at room temperature with a solution of J-alanine (0.56 g, 6.30 mmol) and DIE A (0.81 g,

6.30 mmol) in acetonitrile (6 ml) and water (2 ml). Ethyl acetate (50 ml) was then added and the solution was washed with 5%> hydrochloric acid (20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column (eluent: ether then ether/methanol 90/10) to give 1.13 g (87%>) of acid 2 as a white solid. ^' Mp 86 °C *H-NMR (200 MHz, CDCI3-CD3CO2D): δ 7.27 and 6.87 (2d, J- 8.6 Hz, 4H, -C₆H₄-); 6.47 (m, IH, -NHC(O)-); 5.05 (s, 2H, -CH₂Ar); 4.56 and 4.55 (2q, J = 7.2 Hz, IH, >CHMe); 3.80 (s, 3H, -OMe); 2.70 and 2.53 (2m, 4H, - C(O)CH₂CH₂C(O)-); 1.42 (d, J= 7.2 Hz, 3H, -Me). 13Q-NMR (50 MHz, CDCl₃-CD₃CO₂D): δ 177.4; 172.9; 171.8; 159.7;

130.1; 127.9; 114.0; 66.6; 55.3; 48.1; 30.8; 29.6;18.0. Diester 3 DCC (87 mg, 0.42 mmol) was added to a solution of acid 2 (118 mg, 0.38 mmol), E-glutamine tert-butyl ester hydrochloride (100 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and DIEA (54 mg, 0.42 mmol) in acetonitrile (4 ml) and

DMF (1 ml). The solution was stined overnight at room temperature. The precipitated dicyclohexylurea was removed by filtration and washed with dichloromethane (2 x 5 ml). The filtrate was diluted with additionnal dichloromethane (20 ml) and was washed with saturated aqueous sodium hydrogenocarbonate (20 ml), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column (eluent: ether/ethanol : 5/95 to 10/90) to give 132 mg (79%) of diester 3 as a white solid. Mp l l2 °C *H-NMR (200 MHz, CDCI3): δ 7.28 and 6.88 (2d, J= 8.6 Hz, 4H, -C₆H₄- ); 7.02 (d, J= 8.0 Hz, IH, -NH-); 6.50 and 6.43 (d, J= 7.3 Hz, and br s, 2H, 2 - NH-); 5.61 (br s, IH, -NH-); 5.04 (s, 2H, -CH₂Ar); 4.46 (m, 2H, >CH-); 3.81 (s, 3H, -OMe); 2.67 and 2.51 (2m, 4H, -C(O)CH₂CH₂C(O)-); 2.25 (m, 2H, - CH2C(O)NH₂); 1.93 (m, 2H, -CH₂CH₂C(O)NH₂); 1.46 (s, 9H, t-Bu-); 1.38 (d, J = 7.0 Hz, 3H, -Me). ¹³C-NMR (50 MHz, CDCI3) : δ 174.9; 173.0; 172.5; 171.6; 170.7; 160.0;

130.1; 128.0; 114.0; 82.5; 66.5; 55.4; 52.5; 49.2; 34.0; 31.6; 30.7; 29.4; 28.0; 18.0. Acid 4. Diester 3 (124 mg, 0.283 mmol) in ethyl acetate (5 ml) and methanol (2 ml) was hydrogenolysed for 2 h at room temperature in the presence of 10%> palladium on carbon (15 mg) under atmospheric pressure. After filtration on celite and concentration in vacuo, addition of ether led to the crystallisation of acid 4 as a white solid (99 mg, 94%). Mp 160 °C !H-NMR (200 MHz, D₂O): δ 4.06 (m, 2H, >CH-); 2.40 (m, 4 H, - C(O)CH₂CH₂C(O)-); 2.16 (t, J- 7.4 Hz, 2H, -CH₂C(O)NH₂); 2.05-1.65 (m, 2H, -CHgCH^fC NH^; 1.24 (s, 9H, t-Bu); 1.18 (d, J= 7.2 Hz, 3H, -Me). ¹³C-NMR (50 MHz, D₂O): δ 180.4; 177.8; 177.3; 174.6; 86.5; 55.6; 52.1;

33.7; 32.6; 32.0; 29.7; 28.7; 19.1. Amine 5 Boc-ON (62 mg, 0.25 mmol) in dichloromethane (1 ml) was added to a solution of diamino-PEG 2000* (1.50 g, 0.75 mmol) in dichloromethane (75 ml). After stirring overnight at room temperature, the medium was concentrated in vacuo and the residue was chromatographed on a silica gel column (eluent : dichloromethane/methanol 92/8 to 87/13) to give 403 mg (77%>) of compound 5. ^lB NMR (200 MHz, CDC1₃): δ 3.96 (m, 2H, -OCH2CH₂NHBoc); 3.64 (s, -OCH₂CH₂O-); 3.30 (m, 2H, -CB^NHBoc); 2.07 (br signal, 2H, -NH₂); 1.44 (s, 9H, t-Bu-). * Prepared from Polyethylene glycol 2000 (Fluka Chemie AG; Buchs, Switzerland) Diol ό DCC (333 mg, 1.62 mmol) was added to a solution of compound 1 (350 mg, 1.47 mmol), pentafluorophenol (297 mg, 1.62 mmol), and DMAP (18 mg,

0.15 mmol) in acetonitrile (15 ml). After stirring for 2 h at room temperature, the precipitated dicyclohexylurea was removed by filtration and washed with acetonitrile (5 ml). The filtrate was combined with a solution of (S)-l- aminopropane-2,3-diol (201 mg, 2.20 mmol) in acetonitrile (2 mlVwater (1 ml) and was stined for 3 h at room temperature. Water (25 ml) was then added to the reaction medium which was extracted with dichloromethane (2 x 50 ml). The combined dichloromethane layers were dried with sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column (eluent: ether then ether/methanol 90/10) to give 385 mg (84%>) of diol 6 as a white solide. Mp 78 °C !H-NMR (200 MHz, CDC1₃): δ 7.28 and 6.88 (2d, J= 8.6 Hz, 4H, -C₆H₄- ); 6.20 (br s, IH, -NH-); 5.06 (s, 2H, -CH_Ar); 3.81 (s, 3H, -OMe); 3.75 (m, IH, >CHOH); 3.53 (d, J = 4.7 Hz, 2H, -CH₂OH); 3.38 (m, 2H, -NHCH -); 2.73 and 2.49 (2m, 4H, -C(O)CH₂CH₂C(O)-). Triester 7 DCC (547 mg, 2.65 mmol) was added to a solution of diol 6 (375 mg, 1.20 mmol), oleic acid (748 mg, 2.65 mmol), and DMAP (15 mg, 0.12 mmol) in dichloromethane (12 ml). After stirring for 16 h at room temperature, the precipitated dicyclohexylurea was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel column (eluent: ether/hexane 60/40 to 80/20) to give 791 mg (78%) of triester 7. !H-NMR (300 MHz, CDCI3) : δ 7.28 and 6.88 (2d, J= 8.7 Hz, 4H, -C₆H₄-); 5.97 (t, J= 5.7 Hz, IH, -NH-); 5.34 (m, 4H, -CH-); 5.08 (m, IH, >CHO-); 5.05 (s, 2H, -CH₂-Ar); 4.24 and 4.12 (2 dd, J= 12.0, 5.7, 4.2 Hz, 2H, -CH₂O-); 3.81 (s, 3H, - OMe); 3.47 (m, 2H, -NHCH^-); 2.69 and 2.46 (2t, J = 6.7 Hz, 4H, - C(O)CH₂CH₂C(O)-; 2.32 and 2.31 (2t, J = 7.5 Hz, 4H, -OC(O)CH₂-); 2.00 (m, 8H, -CH₂CH=); 1.61 (m, 4H, -OC(O)CH₂CH₂-); 1.30 and 1.27 (2 br s, 40H, - CH₂-); 0.88 (t, J= 6.7 Hz, 6H, -Me). Acid 8 Trifluoroacetic acid (4 ml) was added to a solution of triester 7 (0.70 g, 0.83 mmol) and anisole (0.9 ml, 8.33 mmol) in dichloromethane (8 ml). After stirring for 1.5 h at room temperature, hexane (10 ml) was added and the solution was concentrated in vacuo. The residue was chromatographed on a silica gel column (eluent: ether then ether/methanol 90/10) to give 0.60 g (100%») of acid 8. *H-NMR (200 MHz, CDCl₃-CD₃CO₂D): δ 5.36 (m, 4H, -CH=); 5.09 (m, IH, >CHO-); 4.25 and 4.11 (2dd, J = 12.1, 5.9, 3.9 Hz, 2H, -CH₂O-); 3.49 (m, 2H, - NHCH2-); 2.71 and 2.48 (2t, J = 6.5 Hz, 4H, -C(O)CH₂CH₂C(O)-); 2.30 (t, J = 7.4 Hz, 4H, -OC(O)CH₂-); 1.95 (m, 8H, -CH₂CH=); 1.59 (m, 4H, - OC(O)CH₂CH₂-); 1.24 (br s, 40H, -CH₂-); 0.86 (t, J= 6.2 Hz, 6H, -Me).

Deprotection according to: Stewart, F. H. C. Aust. J. Chem. 1968, 21, 2543. . Carbamate 9 DCC (22 mg, 0.105 mmol) in dichloromethane (1 ml) was added to a solution of acid 8 (75 mg, 0.105 mmol), amine 5 (200 mg, 0.095 mmol), and HOBt (14 mg, 0.105 mmol) in THF (1 ml)/dichloromethane (1 ml). After stirring for 24 h at room temperature, the precipitated dicyclohexylurea was removed by filtration and washed with dichloromethane. The filtrate was concentrated in vacuo and chromatographed on a silica gel column (ether/methanol 85/15 then dichloromethane/methanol 89/11) to give 161 mg (60%>) of carbamate 9. ^lH NMR (300 MHz, CDC1₃): δ 6.59 and 6.39 (2m, 2H, -NH-); 5.33 (m, 4H, -CH=); 5.09 (m, IH, >CHOC(O)-); 4.24 and 4.08 (2m, 2H, -CH₂OC(O)-); 3.64 (s, -OCH₂CH₂O-); 3.50 and 3.40 (2m, 4H, -NHCH₂-); 3.29 (m, 2H, - CH2NHB0C); 2.50 (m, 4H, -C(O)CH₂CH₂C(O)-); 2.32 and 2.30 (2t, J = 6.7 Hz, 4H, -OC(O)CH₂-); 2.00 (m, 8H, -CH₂CH=); 1.59 (m, 4H, -OC(O)CH₂CH₂-); 1.44 (s, 9H, t-Bu); 1.29 and 1.26 (2 br s, 40H, -CH₂-); 0.87 (t, J = 6.7 Hz, 6H, Me-). Amine 10 Trifluoroacetic acid (1 ml) was added to a solution of carbamate 9 (251 mg, 0.09 mmol) in dichloromethane (1 nil). After stirring for 2 h at 0 °C, the medium was concentrated in vacuo. It was then diluted with dichloromethane (25 ml), washed with aqueous sodium hydrogenocarbonate, dried with sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column (eluent: dichloromethane/methanol 87/13) to give 218 mg (90%>) of amine 10. *H NMR (300 MHz, CDC1₃): δ 6.66 and 6.51 (2m, 2H, -NH-); 5.33 (m, 4H, -CH-); 5.08 (m, IH, >CHOC(O)-); 4.24 and 4.08 (2dd, J= 12.0, 5.8, 3.9 Hz, 2H, -CH₂OC(O)-); 3.63 (s, -OCH₂CH₂O-); 3.53 (m, 4H, -OCH₂CH₂NH-); 3.41 (m, 4H, -CIJ2NH-); 2.99 (m, 2H, H^CH^-); 2.50 (br s, 4H, -C(O)CH₂CH₂C(O)- ); 2.31 and 2.29 (2t, J= 7.1 Hz, 4H, -OC(O)CH₂-); 1.99 (m, 8H, -CH₂CH=); 1.60 (m, 4H,

6.5 Hz, 6H, Me-). Ester 11 A solution of DCC (27 mg, 0.132 mmol) in dichloromethane (1 ml) was added to a solution of amine 10 (237 mg, 0.088 mmol), acid 4 (49 mg, 0.132 mmol) and HOBt (27 mg, 0.132 mmol) in dichloromethane (1 ml)/DMF (1 ml). After stirring for 24 h at room temperature, the precipitated dicyclohexylurea was removed by filtration and washed with dichloromethane. The filtrate was then concentrated in vacuo and chromatographed on a silica gel column (eluent: ether/methanol 85/15 then dichloromethane/methanol 85/15) to give 172 mg (64%o) of compound 11. H NMR (300 MHz, CDCI3) : δ 7.22, 6.92, 6.68, 6.51, 5.66 (5m, 5H, - NH-); 5.33 (m, 4H, -CH=); 5.09 (m, IH, >CHOC(O)-); 4.42 (m, 2H, >CH-); 4.24 and 4.09 (2dd, J = 12.0, 5.9, 3.9 Hz, 2H, -CH₂OC(O)-); 3.63 (s, -OCH₂CH₂O-); 3.53 (m, 4H, -OCH^CH^H-); 3.41 (m, 6H, -CH₂NH-); 2.67-2.40 (m and s, 8H, - C(O)CH₂CH₂C(O)-); 2.37-2.15 (2t, J = 7.2 Hz, and m, 8H, -OC(O)CH₂- and - CH₂CH₂C(O)NH₂); 2.00 (m, 8H, -CH^CH^); 1.59 (m, 4H, -OC(O)CH₂CH₂-); 1.44 (s, 9H, t-Bu); 1.37 (d, J= 7.1 Hz, 3H, -Me); 1.28 and 1.26 (2br s, 40H, -CH₂- ); 0.87 (t, J= 6.6 Hz, 6H, Me-). pcTG260 Trifluoroacetic acid (1 ml) was added to a solution of compound 11 (116 mg, 0.038 mmol) and triethylsilane (0.1 ml) in dichloromethane (1 ml). After stirring for 1.5 h at room temperature, the medium was concentrated in vacuo and chromatographed on a silica gel column (eluent: dichloromethane/methanol 90/10 to 80/20) to give 54 mg (47%) of pcTG260. IjH NMR (300 MHz, CDC1₃): δ 5.34 (m, 4H, -CH=); 5.10 (m, IH,

>CHOC(O)-); 4.45-4.15 (m, 2H, >CH-); 4.26 and 4.09 (2dd, J= 12.0, 5.8, 4.0 Hz, 2H, -CH₂OC(O)-); 3.64 (s, -OCH₂CH₂O-); 3.55 (m, 4H, -OCH₂CH₂NH-); 3.41 (m, 6H, -Q_2NH-); 2.80-2.40 (m and s, 8H, -C(O)CH₂CH₂C(O)-); 2.40-1.90 (m, 4H, -CH^CH^C^NH^; 2.32 and 2.30 (2t, J = 7.4 Hz, 4H, -OC(O)CH₂-); 2.00 (m, 8H, -CEk-QH ); 1.60 (m, 4H, -OC^C^CH^-); 1.40 (d, J= 6.8 Hz, 3H, - Me); 1.29 and 1.26 (2 br s, 40H, -CH₂-); 0.87 (t, J- 6.3 Hz, 6H, Me-). MALDI-TOF MS. The spectrum shows two series of peaks (44 Da intervals in each series). Most abundant series: Major peak at m/z - 2824.2; calculated for [Ci3₇H₂₆ιN6θ₅₂]⁺: 2822.8 (pcTG260 + H+; n = 40). The least abundant series of peaks conesponds to the sodiated molecules. Deprotection according to: Mehta, A.; Jaouhari, R.; Benson, T. J.; Douglas, K. T. Tetrahedron Lett. 1992, 33, 5441. pcTG261 A solution of DCC (25 mg, 0.12 mmol) in dichloromethane (1 ml) was added to a solution of amine 12* (200 mg, 0.10 mmol), acid 8 (79 mg, 0.11 mmol), and HOBt (16 mg, 0.12 mmol) in dichloromethane (1 ml)/THF (1 ml).

After stirring for 16 h at room temperature, the precipitated dicyclohexylurea was removed by filtration and washed with dichloromethane (25ml). The filtrate was washed with aqueous sodium hydrogenocarbonate (20 ml), dried with sodium sulfate, concentrated in vacuo, and chromatographed on a silica gel coloumn (eluent: ether/methanol 90/10 then dichloromethane/methanol 85/15) to give 248 mg (91%) ofpcTG261. *H NMR (200 MHz, CDC1₃): δ 6.66 (m, 2H, -NH-); 5.32 (m, 4H, -CH=);

5.08 (m, IH, >CHOC(O)-); 4.24 and 4.08 (2dd, J = 12.0, 5.9, 3.9 Hz, 2H, - CH₂OC(O)-); 3.63 (s, -OCH₂CH₂O-); 3.42 (m, 4H, -NHCH₂-); 3.36 (s, 3H, - OMe); 2.49 (s, 4H, -C(O)CH₂CH₂C(O)-); 2.30 and 2.29 (2t, J = 7.4 Hz, 4H, - OC(O)CH₂-); 1.99 (m, 8H, -CH^CH^; 1.59 (m, 4H, -OC(O)CH₂CH₂-); 1.28 and 1.25 (2br s, 40H, -CH₂-); 0.86 (t, J= 6.3 Hz, 6H, -Me). * Prepared from Polyethylene glycol 2000 monomethylether (Fluka Chemie AG; Buchs, Switzerland). Abbreviations. BocON: 2-(tert-Butoxycarbonyloxyimino)-2- phenylacetonitrile; DCC: 1,3-Dicyclohexylcarbodiimide; DIEA: N- Diisopropylethylamine; DMAP: 4-(Dimethylamino)pyridine; DMF: Dimethylformamide; HOBt: 1-Hydroxybenzotriazole; PEG: Poly(ethylene glycol); PMB : -Methoxybenzyl; THF: Tetrahydrofuran. Example 2: Synthesis of pcTG262 Acid 13 DCC (115 mg, 0.56 mmol) was added to acid 8 (201 mg, 0.28 mmol), pentafluorophenol (103 mg, 0.56 mmol) and DMAP (4 mg, 0.03 mmol) in dichloromethane (3 ml) and the reaction was stined for 16 h at room temperature. Dicyclohexylurea was removed by filtration and the filtrate was concentrated in vacuum. The residue was then taken up in THF (2 ml) and was added to a stined solution of L-alanine (50 mg, 0.56 mmol) and (z-Pr) ΝEt (108 mg, 0.84 mmol) in THF/water (1/1; 4 ml). After 0.5 h at room temperature, the reaction was diluted with diethyl ether (40 ml) and was washed with 10%> aqueous HCI. The organic layer was dried over sodium sulfate, filtered, concentrated under vacuum and chromatographed on a silica gel column (eluent : diethyl ether/ethanol 100/0 to 90/10) to give 136 mg (61%) of acid 13. 1H-NMR (300 MHz, CDCl₃-CD₃CO₂D):.δ 5.33 (m, 4H, -CH=); 5.09 (m, IH, >CH-O-); 4.45 (m, IH, -C(O)-CH(Me)-NH-); 4.25 and 4.07 (2dd, J- 3.6, 6.2 and 12.0 Hz, 2H, -CH₂-O-); 3.44 (m, 2H, -NH-CH₂-); 2.55 (m, 4Η, -C(O)-CH₂- CH₂-C(O)-); 2.31 and 2.29 (2 t, J = 7.5 Ηz, 4Η, -O-C(O)-CH₂-); 1.99 (m, 8H, - CH₂-CH=); 1.59 (m, 4H, -O-C(O)-CH₂-CH₂-); 1.39 (d, J = 7.2 Ηz, -C(O)- CΗ( e)-NΗ-); 1.28 and 1.25 (2br s, 40H, -CH₂-); 0.87 (t, J- 6.7 Hz, 6H, -Me). *-Butyl ester 14 A solution of DCC (49 mg, 0.24 mmol) in THF (1 ml) was added to acid

13 (172 mg, 0.22 mmol) and 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (39 mg, 0.24 mmol) in TΗF (2 ml). After stirring for 3 h at room temperature, dicyclohexylurea was removed by filtration and washed with TΗF (3 ml). A solution of L-glutamine t-butyl ester hydrochloride (78 mg, 0.33 mmol) and (/- Pr)₂NEt (42 mg, 0.33 mol) in TΗF (2 ml) was added to the filtrate. The yellow solution was stined for 2 h at room temperature. It was then diluted with ethyl acetate (30 ml) and washed twice with a saturated aqueous solution of NaΗCO₃ (20 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was chromatographed on a silica gel column (eluent : ethyl acetate/methanol 100/0 to 94/6) to give 174 mg (81%) of t- butyl ester 14. 1H-NMR (300 MHz, CDC1₃): δ 7.06 (d, J= 8.1 Hz, IH, >CH-NH-); 6.63 (d, J= 7.3 Ηz, 1Η, >CΗ-NH-); 6.55 (br s, 1Η, -C(O)-NH₂); 6.44 (t, J= 6.0 Ηz, - NH-CΗ₂-); 5.71 (br s, IH, -C(O)-NH₂); 5.34 (m, 4Η, -CH-); 5.09 (m, IH, >CH- O-); 4.42 (m, 2H, 2 >CH-C(O)-); 4.24 and 4.10 (2dd, J= 3.7, 6.0, 12.1 Hz, 2H, - CH₂-O-); 3.44 (m, 2H, -NH-C/J -); 2.62-2.15 (m, 10H, -C(O)-CH₂-CH₂-C(O)-, - O-C(O)-CΗ₂-, -CH₂-C(O)NH₂); 2.00 (m, 8H, -CH₂-CH=); 1.95 and 1.75 (2m, 2H, -CH₂-CH₂-C(O)NH₂); 1.60 (m, 4H, -O-C(O)-CH₂-CH₂-); 1.45 (s, 9Η, t-Bu-); 1.36 (d, J= 7.0 Hz, -C(O)-CH( e)-NH-) ; 1.29 and 1.26 (2 br s, 40H, -CH₂-) ; 0.87 (t, J= 6.7 Hz, 6H, -Me). pcTG262 Trifluoroacetic acid (1 ml) was added to t-butyl ester 14 (113 mg, 0.12 mmol) in dichloromethane (1 ml). After stirring for 1.5 h at room temperature, the solution was concentrated under vacuum and chromatographed on a silica gel column (eluent : dichloromethane/methanol 95/5 to 80/20) to give 82 mg (74%) of pcTG262. 1H-NMR (500 MHz, CDCl₃-CF₃CO₂D): δ 5.34 (m, 4H, -CH=); 5.11 (m, IH, >CH-O-); 4.62 (m, IH, -CH(CO₂H)-NH-); 4.46 (m, IH, -C(O)-CH(Me)-NH- ); 4.27 and 4.19 (2dd, J = 3.4, 5.8, 12.4 Hz, 2H, -CH₂-O-); 3.43 (m, 2H, -NH- CH₂-); 2.80-2.25 (m, 6Η, -C(O)-CH₂-CH₂-C(O)-, -CH₂-C(O)NΗ₂); 2.37 (t, J= 7.6 Hz, 4H, -O-C(O)-CH₂-); 2.16 and 1.67 (2m, 2H, -CH₂-CH₂-C(O)NH₂); 2.01 (m, 8H, -CH₂-CH=); 1.61 (m, 4H, -O-C(O)-CH₂-CH₂-); 1.44 (d, J = 6.9 Ηz, -C(O)- CΗ( e)-NΗ-); 1.28 and 1.26 (2br s, 40H, -CH₂-); 0.87 (t, J= 6.9 Hz, 6H, -Me). MALDI-TOF MS. m/z = 941.3 and 963.3; calculated for [C₅₁H₉₀N₄NaOι₀]⁺: 941.65 and for [C₅₁H₈₉N₄Na₂O₁₀]⁺: 963.63. Abbreviations THF: tetrahydrofuran; DCC: 1,3-dicyclohexylcarbodiimide; DMAP: 4- (dimethylamino)pyridine Example 3: Complex preparation Lipids were mixed in chloroform and solvent removal was performed overnight at 45°C using a Rapidvap vortex evaporator (Labconco, Uniequip, Martinsried, Germany). The resulting lipid films were hydrated with a 5% glucose (w/v) solution (5-15 mg/mL cationic lipids) and sonicated (Bransonic 221 ultrasonic water bath from Branson Ultrasonics Corp., Danbury, CT, USA) until lipids were entirely resuspended. Small Iiposomes were formed by sequential extrusion through 400 and 200 nm pore diameter polycarbonate membranes (Nuclepore, Costar, Cambridge, MA, USA) using a Lipex Biorhembranes extruder (Vancouver, Canada). Preformed Iiposomes were stored at 4°C under inert atmosphere (argon) until use. Corresponding complexes were formed by mixing plasmid DNA comprising a gene coding luciferase with cationic Iiposomes. Plasmid DNA was first diluted in 5% glucose to the desired concentration and complex formation was done by rapid addition of extruded liposome suspension to the plasmid solution (volume of liposomal suspension/volume of plasmid DNA solution ~ 1/3). All complexes were prepared at a final plasmid concentration of 10Oμg/mL and kept for at least an overnight time period at 4°C before use. Example 4: Cell culture and in vitro transfection procedure C2C12 and WiDr cell lines, were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FBS and antibiotics at 37°C in a 5 % CO₂ incubator. They were normally grown in poly-styrene tissue culture flasks until they became approximately 80% confluent as assessed by light microscopy. The cells were then trypsinized with an appropriate amount of 0.05% trypsin solution for 5 mn followed by the addition of FBS-containing medium to stop the trypsin reaction. The detached cells were collected and then counted using a hemocytometer. For the transfection C2C12 or WiDr cells were seeded at a density of 1.5x10⁴ cells/well, in 96-well flat-bottomed microassay plates and incubated for 24 hr before the addition of the plasmid DNA/lipid complex. Cells were 80% confluent at the time of transfection. Each plasmid DNA lipid complex is tested in 2 conditions: medium with or without glutamine (Gin). Gin medium contains 1000x more Gin than the most concentrated Gin- lipid. 30 min before transfection, the medium from each well is replaced with one of these 2 mixtures. Complex containing 0.35 μg plasmid DNA is then added. Cells were incubated for 4 hr at 37°C in a 5% CO2 incubator. After 4 hr, medium is added so that the final FBS concentration is 10%. After 24 hr, medium is removed and replaced with DMEM containing 10%FBS and antibiotics for an additional 24 hr. The transfected cells were assayed for luciferase activity using a

Promega kit with a Berthold luminometer (LB96P). Luminescence was measured for 15 s for each assay and the luciferase activity was presented as relative light units per mg of total cells proteins. Protein assay is made according manufacturer's instructions with the BCA protein assay kit (Pierce). The results depicted in Figure 4 and 5 indicate that the use of a molecule of the invention (pcTG260 or pcTG262) enhances the transfection of cells expressing a glutamine transporter. The fact that this transfection is inhibited in the presence of glutamine indicates that the enhanced transfection of the nucleic acid is linked to the presence of the targeting moiety able to bind to a glutamine transporter. Example 5: in vitro transfection procedure Four groups of seven mice were injected intravenously with 50μg of complexes comprising pcTG90/DOPE(1 :2)-pCMV-Luciferase (N/P=5 in 250 μL of 5% glucose, 20 mM Hepes, pH=7.5) or 50μg of pcTG90/DOPE/pcTG262(1 :2:0.36)-pCMV-Luciferase, (N/P=5 in 250μL of 5% glucose, 20 mM Hepes, pH=7.5). 24 hours after injection, mice are killed, hearts and lung are removed and assessed for luciferase expression. Results are depicted in figure 6. These results indicate that complexes comprising a targeting moiety able to bind to a glutamine transporter transfect more efficiently cells expressing a glutamine transporter such as heart and lung cells.

Claims

Claims

1. A compound comprising: (i) A therapeutically active moiety and, (ii) A targeting moiety able to bind to a glutamine transporter.

2. The compound according to claim 1 wherein said therapeutically active moiety is a vitamin, an amino acid, a peptide, a chemotherapeutic, an antibiotic, an agent affecting respiratory organs, an antitussive expectorant, an antitumor agent, an autonomic drug, a neuropsychotropic agent, a muscle relaxant, a drug affecting digestive organs, an antihistamic agent, an antidote, a hypnotic sedative, an antiepileptic, an antipyretic analgesic antiphlogistic, a cardiotonic, an antiarrhythmic, an hypotensive diuretic, a vasodilator, a hypolipidemic agent, an alimentary analeptic, a nucleic acid, an anticoagulant, a hepatics a blood sugar- lowering agent or a hypotensive agent.

3. The compound according to claim 1 wherein said therapeutically active moiety is a wherein said therapeutically active moiety is a nucleic acid.

4. The compound according to claim 3 wherein said nucleic acid is selected from the group comprising genomic DNA, cDNA, mRNA, antisense RNA, ribozyme and DNA encoding RNAs.

5. The compound according to claim 3 wherein said nucleic acid is a naked polynucleotide.

6. The compound according to claim 3 wherein said nucleic acid is a viral vector.

7. The compound according to claim 6 wherein said viral vector is selected from the group comprising adenoviral vector, adeno associated viral vector, retroviral vector and poxviral vector.

8. The compound according to claims 3 to 8 wherein said nucleic acid comprises at least one encoding gene sequence of interest and the elements enabling its expression

9. The compound according to claims 1 to 8 wherein said targeting moiety able to bind to a glutamine transporter is an amino acid or one of its derivatives

10. The compound according to claim 9, wherein said amino acid is a glutamine, and more preferably L-Glutamine.

11. The compound according to claims 9 to 10 wherein said amino acid is not included in a polypeptide.

12. The compound according to claims 1 to 11 wherein said therapeutically active moiety is coupled to said targeting moiety able to bind to a glutamine transporter.

13. The compound according to claim 12 wherein said therapeutically active moiety and said targeting moiety able to bind to a glutamine transporter are covalently linked.

14. The compound according to of claims 1 to 13 further comprising a hydrophilic polymer.

15. The compound according to claim 14 wherein said hydrophilic polymer is coupled to the therapeutically active moiety and to the targeting moiety able to bind to a glutamine transporter.

16. The compound according to claims 1 to 15 wherein said hydrophilic polymer is a PEG,

17. The compound according to claim 16 wherein said PEG especially has a molecular weight ranging between about 1 ,000 and about 5,000 daltons (Da), preferably of about 2000 Da

18. A liposome associated with a targeting moiety able to bind to a glutamine transporter.

19. A complex comprising at least one anionic substance of interest and at least one cationic compound associated with a targeting moiety able to bind to a glutamine transporter.

20. The complex according to claim 20 wherein said anionic substance of interest is a nucleic acid molecule.

21. The complex according to claims 19-20 wherein said cationic compound is selected from the group consisting of cationic lipids and cationic polymers.

22. The complex according to claims 19-21 ^' futher comprising at least one peptide which is capable of causing membrane disruptionand/or at least one colipid.

23. The complex according to claims 19-22 wherein said targeting moiety able to bind to a glutamine transporter is associated is coupled with at least one compound comprised in said complex.

24. The complex according to claim 23 wherein said targeting moiety able to bind to a glutamine transporter is coupled to a charged, a zwitterionic or a non charged compound.

25. The complex according to claim 23 wherein said targeting moiety able to bind to a glutamine transporter is coupled to a carrier comprising an alkyl or alkenyl chains.

26. The complex according to claims 19-23 wherein said targeting moiety able to bind to a glutamine transporter is an amino acid or one of its derivatives

27. The complex according to claim 26 wherein said amino acid is a glutamine, and more preferably L-Glutamine.

28. The complex according to claims 26-27 wherein said amino acid is not included in a polypeptide.

29. A molecule comprising at least one hydrophobic moiety and one targeting moiety able to bind to a glutamine transporter.

30 The molecule according to claim 29 wherein said hydrophobic moiety is selected from the group comprising alkyl or alkenyl radicals having 6 to 23 carbon atoms, which are linear or branched, radicals - C(=0)-(C6-C23) alkyl, -C(=O)-(C6-C23) alkenyl, more particularly -C(=O)- (C12-C20) alkyl and C(=O)-(C12-C20) alkenyl, which are linear or branched, aryl radicals, cycloalkyl radicals, fluoroalkyl radicals, oxyethylene and oxymethylene groups which are optionally repeated, linear or branched, optionally substituted.

31. The molecule according to claims 29-30 further comprising an hydrophilic polymer.

32. The molecule according to claim 31 wherein said hydrophilic polymer is coupled to said targeting moiety able to bind to glutamine transporter and to said hydrophobic moiety.

33. The molecule according to claim 29 wherein said molecule is of formula I:

in which: R1 and R2, which are identical or different, are alkyl or alkenyl radicals having 6 to 23 carbon atoms (noted C6-C23), which are linear or branched, or radicals -C(=O)-(C6-C23) alkyl or -C(=O)-(C6-C23) alkenyl, or more particularly -C(=O)-(C12-C20) alkyl or C(=O)-(C12-C20) alkenyl, which are linear or branched, aryl radicals, cycloalkyl radicals, fluoroalkyl radicals, oxyethylene or oxymethylene groups which are optionally repeated, linear or branched, optionally substituted,

34. The molecule according to claim 29 wherein said molecule is of formula II: .

35. The molecule according to claim 32 wherein said molecule is of formula III:

in which: R1 and R2, which are identical or different, are alkyl or alkenyl radicals having 6 to 23 carbon atoms (noted C6-C23), which are linear or branched, or radicals -C(=O)-(C6-C23) alkyl or -C(=O)-(C6-C23) alkenyl, or more particularly -C(=O)-(C12-C20) alkyl or C(=O)-(C12-C20) alkenyl, which are linear or branched, aryl radicals, cycloalkyl radicals, fluoroalkyl radicals, oxyethylene or oxymethylene groups which are optionally repeated, linear or branched, optionally substituted and; n is a positive integer from 4 to 220, preferably from 22 to 110 and more preferably about 44.

36. The molecule according to claim 32 wherein said molecule is of formula IV:

wherein n is a positive integer from 4 to 220, preferably from 22 to 110 and more preferably about 44.

37. The complex according to claims 19-28 wherein said complex comprises a molecule according to claims 29-36.

38. A composition comprising comprises at least one compound according to claims 1-17, a complex according to claims 19-28, and 37 or a liposome according to claim 18.

39. A process for transferring a nucleic acid into cells or tissues wherein said process comprises contacting said cells or said tissues with a compound according to claims 1-17, a liposome according to claim 18, a complex according to claims 19-28 and 37 or a composition according to claim 38.

40. Use of a compound according to claims 1-17, a liposome according to claim 18, a complex according to claims 19-28 and 37 or a composition according to claim 38 for the preparation of a pharmaceutical composition for curative, preventive or vaccine treatment of mammals.