We recently synthesized a lipophilic prodrug of 9-(2-phosphonyl- methoxyethyl)adenine (PMEA), des... more We recently synthesized a lipophilic prodrug of 9-(2-phosphonyl- methoxyethyl)adenine (PMEA), designated PMEA-LO, and incor- porated it into reconstituted lactosylated high-density lipoprotein (LacNeoHDL). In a rat model, LacNeoHDL-associated PMEA-LO was internalized by the asialoglycoprotein receptor on parenchy- mal liver cells and converted into its active diphosphorylated me- tabolite. To further evaluate the therapeutic potential of the carrier- associated prodrug, we examined
... Remco LA de Vrueh", Erik T. Rump', Erik AL Biessen ... 2)6easley, R PI Lin, ( C , l... more ... Remco LA de Vrueh", Erik T. Rump', Erik AL Biessen ... 2)6easley, R PI Lin, ( C , l-lwang I. Y laritct 1981, [/, 1129-1133 3)Kruining, J , Heljtirtk, R A , Sclialm, S W 4)Heij(ink, It A , De Wild?, G A , Kruining, J , et dl Aiitiuirnl Ke\ 1993, 27, 141-153 5)Narsrns, L , Babaririi, J , I h Clcrcq, C ...
We recently synthesized a lipophilic prodrug of 9-(2-phosphonyl-methoxyethyl)adenine (PMEA), desi... more We recently synthesized a lipophilic prodrug of 9-(2-phosphonyl-methoxyethyl)adenine (PMEA), designated PMEA-LO, and incorporated it into reconstituted lactosylated high-density lipoprotein (LacNeoHDL). In a rat model, LacNeoHDL-associated PMEA-LO was internalized by the asialoglycoprotein receptor on parenchymal liver cells and converted into its active diphosphorylated metabolite. To further evaluate the therapeutic potential of the carrier-associated prodrug, we examined in this study the processing of (125)I-labeled PMEA-LO--loaded LacNeoHDL by HepG2 cells. Upon incubation with HepG2 cells, PMEA-LO--loaded LacNeoHDL became rapidly cell-associated. The association was saturable and of high-affinity (k(d) = 3.8 +/- 0.4 nM). Asialofetuin, an established ligand for the asialoglycoprotein receptor, inhibited the association by >75%, which confirms the role of the asialoglycoprotein receptor. Association of the prodrug-loaded particles to HepG2 cells was coupled to degradation. Rad...
9-(2-Phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of Hepatitis B virus replication, ... more 9-(2-Phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of Hepatitis B virus replication, is in vivo hardly taken up by parenchymal liver cells (the site of infection). Our aim is to examine whether lactosylated reconstituted HDL (LacNeoHDL), a lipidic particle that is specifically internalized by parenchymal liver cells, is a suitable carrier for the selective delivery of PMEA to this cell type. To incorporate PMEA into LacNeoHDL, we synthesized a lipophilic prodrug (PMEA-LO) by coupling PMEA via an acid-labile phosphonamidate bond to lithocholic acid-3alpha-oleate. The yield of the synthesis was 52% ([3H]PMEA-LO: 24%). [3H]PMEA-LO readily incorporated into LacNeoHDL (13 molecules/particle) without affecting the size and net negative charge of the carrier. Further, incubation studies at lysosomal pH showed [3H]PMEA was completely released from the carrier whereas, at neutral pH or in plasma, appreciable release was not observed. The conjugation of PMEA with lithocholic acid-...
General use of nucleoside analogues in the treatment of viral infections and cancer is often limi... more General use of nucleoside analogues in the treatment of viral infections and cancer is often limited by poor oral absorption. Valacyclovir, a water soluble amino acid ester prodrug of acyclovir has been reported to increase the oral bioavailability of acyclovir but its absorption mechanism is unknown. This study characterized the intestinal absorption mechanism of 5' -amino acid ester prodrugs of the antiviral drugs and examined the potential of amino acid esters as an effective strategy for improving oral drug absorption. Acyclovir (ACV) and Zidovudine (AZT) were selected as the different sugar-modified nucleoside antiviral agents and synthesized to L-valyl esters of ACV and AZT (L-Val-ACV and L-Val-AZT), D-valyl ester of ACV (D-Val-ACV) and glycly ester of ACV (Gly-ACV). The intestinal absorption mechanism of these 5' -amino acid ester prodrugs was characterized in three different experimental systems; in situ rat perfusion model, CHO/hPEPT1 cells and Caco-2 cells. Testing...
The hepatitis B virus (HBV) is the world's most important chronic virus infection. The immuno... more The hepatitis B virus (HBV) is the world's most important chronic virus infection. The immunomodulator interferon-alpha (IFN alpha) is the only clinically applied drug available, despite its low response rate (approximately 30%) even in highly selected chronic carriers. Antiviral nucleoside analogues have proven to be potent inhibitors of viral replication in vitro, but their significant adverse effects which are, at least partially, due to their nonspecific body distribution, have forced the cessation of their clinical development in the past. For example, vidarabine causes severe neuromuscular toxicity, and fialuridine has caused fatal cases of liver and kidney failure in a recent clinical trial. Furthermore, the potential clinical application of (modified) antisense oligodeoxynucleotides, which are very specific inhibitors of viral replication, is hampered by their nonspecific body distribution, instability in serum and poor cell penetration. As infection and replication of H...
Background: We determined whether the market exclusivity incentive of the European Orphan Drug Re... more Background: We determined whether the market exclusivity incentive of the European Orphan Drug Regulation results in a market monopoly or that absence of another Orphan Medicinal Product (OMP) for the same rare disorder, a so-called follow-on OMP, is a matter of time or market size. In the interest of rare disorder patients better understanding of the effect of the market exclusivity incentive on follow-on OMP development is warranted. Methods: First, the impact of various market-, product-and disease-related characteristics on follow-on OMP development in the EU was determined by comparing rare disorders with an approved OMP and at least one follow-on OMP (N = 26), with rare disorders with an approved OMP and no follow-on OMP (N = 18). Next, we determined whether manufacturers continued development of a follow-on OMP upon approval of the first OMP for the intended rare disorder. Since in the EU significant benefit of an OMP has to be established, we determined for each follow-on OMP for which development was continued on what grounds significant benefit was assumed by the sponsor. Data were collected from the public domain only. Results: The likelihood of a rare disorder with an approved OMP to obtain at least one follow-on OMP development was strongly associated with disease prevalence, turnover of the first OMP, disease class, diseasespecific scientific output and age of onset. Out of a total of 120 follow-on OMPs only one follow-on OMP could be identified for which development was discontinued upon approval of the first OMP for the same rare disorder. Only a substantial level of discontinuation of follow-on OMP development would have indicated the existence of a market monopoly. Moreover, sponsors that continued development of a follow-on OMP predominantly assumed that their product had an improved efficacy compared to the first approved OMP. Conclusions: This study provides evidence that absence of follow-on OMP development is a matter of time or market size, rather than that the market exclusivity incentive of the European Orphan Drug Regulation creates a market monopoly.
We studied to what extent the level of scientific knowledge on exceptionally rare metabolic inher... more We studied to what extent the level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products is associated with sponsors deciding to apply for an orphan designation at the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Methods: All metabolic diseases with a genetic cause and prevalence of less than 10 patients per 1 million of the population were selected from the 'Orphanet database of Rare diseases'. The outcome of interest was the application for an orphan designation at FDA or EMA. The level of publicly available knowledge of the disease and drug candidate before an orphan designation application was defined as whether the physiological function corresponding with the pathologic gene and initiation of the pathophysiological pathway was known, whether an appropriate animal study was identified for the disease, whether preclinical proof of concept was ascertained and the availability of data in humans. Other determinants included in the study were metabolic disease class, the prevalence of the disease, prognosis and time of first description of the disease in the literature. Univariate relative risks (RRs) and 95% confidence intervals (CIs) of an orphan designation application were calculated for each of these determinants. In addition, a multivariate Cox regression analysis was conducted (Forward LR).
Objective To encourage the development of drugs for rare diseases, orphan drug legislation has be... more Objective To encourage the development of drugs for rare diseases, orphan drug legislation has been introduced in the USA (1983) and in the EU . Recent literature discusses factors that may influence the development of new orphan medicinal products in the EU. This study aims to identify predictors for successful marketing authorisation of potential orphan drugs in the EU. Methods A comparison between randomly selected authorised and a matched sample of not-yet-authorised orphan drug designations has been performed. Determinants in the study included characteristics of the indication, of the product and of the sponsor. Data were collected from the public domain only. Results Orphan drug approval was strongly associated with previous experience of the sponsor in obtaining approval for another orphan drug (OR=17.3, 95% CI=5.6-53.1). Furthermore, existing synthetic entities compared to biotechnology products tended to have a higher likelihood of reaching approval status (OR=3.9, 95% CI=0.9-16.6).
Background: Drugs for rare diseases, so-called orphan drugs, are often intended for serious or ch... more Background: Drugs for rare diseases, so-called orphan drugs, are often intended for serious or chronically debilitating diseases. Safety information is more limited at the time of approval for orphan drugs as a result of various factors, such as the limited number of patients in clinical trials, quality of the clinical trials and special approval procedures. Several studies have been conducted on safety-related regulatory actions for drugs, but none of these have specifically focused on orphan drugs. . The main outcome measures were the nature, frequency and timing of safety-related regulatory actions, defined as (i) safety withdrawals; (ii) 'black-box' warnings; and (iii) written communications to healthcare professionals issued by the US FDA or the European Medicines Agency between January 2000 and June 2008. Results: Ninety-five orphan drugs were approved during the study period (75 in the US, 44 in the EU, and 24 in both regions). Ten products (10.5%) received a safety-related regulatory action. No safety withdrawals, four black-box warnings and 12 written communications were identified. The probability of a first safety-related regulatory action for orphan drugs was 20.3% after 8 years of follow-up. Orphan drugs approved by accelerated approval (relative risk [RR] 3.32; 95% CI 1.06, 10.42), oncological products (RR 7.83; 95% CI 0.96, 63.82) and products for gastrointestinal and metabolism indications (RR 10.44; 95% CI 1.25, 87.27) may have a higher risk for a safety-related regulatory action.
More than 25 years of orphan drug regulations have yielded several new treatments for patients wi... more More than 25 years of orphan drug regulations have yielded several new treatments for patients with rare diseases. Here, we show that successful translation of rare disease research into an orphan drug discovery and development programme is dependent on the disease class, its prevalence and the disease-specific scientific output. Our findings indicate that current orphan drug legislation alone is not sufficient to stimulate orphan drug development for diseases with a very low prevalence. Consequently, additional incentives should focus on stimulating the specific needs of rare disease research at disease class level.
The high expression level of receptors for low-density lipoprotein (LDL) on tumor cells makes LDL... more The high expression level of receptors for low-density lipoprotein (LDL) on tumor cells makes LDL an attractive carrier for selective delivery of drugs to these cells. The aim of this study is to allow incorporation of oncogene-directed antisense oligodeoxynucleotides (ODNs) into the lipid moiety of LDL. Therefore, ODNs were conjugated with oleic acid, cholesterol, and several other steroid lipids. These latter steroid lipids were synthesized starting from bile acids and were varied in lipophilicity by attaching oleic acid ester structures. The lipid structures, activated as pentafluorophenyl esters, were conjugated in solution phase to 3'-amino-tailed ODNs. The ODNs conjugated with lithocholic acid, oleic acid, and cholesterol could easily be purified by reversed phase (RP)-HPLC. However, the ODNs conjugated with the oleoyl steroid ester structures irreversibly bound to the column material. These highly lipidic ODNs were separated from the nonconjugated ODN by electrophoresis in a 1% low-melting agarose gel containing 0.1% Tween 20. This method was found to be very effective in isolating the ODNs conjugated to the oleoyl steroid ester structures. The ODNs conjugated with cholesterol and the oleoyl esters of lithocholic and cholenic acid associated readily and nearly completely with LDL. However, the less lipidic ODNs and the ODN conjugated with the dioleoyl ester of chenodeoxycholic acid did not and did incompletely associate, respectively. Lithocholic acid and oleic acid are probably not sufficiently lipophilic to induce association with LDL, whereas the dioleoyl ester structure is probably too bulky and extended to allow partitioning into the lipid moiety of LDL. We conclude that several of the lipid-ODNs can associate readily with LDL, enabling delivery of oncogene-directed antisense ODNs via the LDL receptor pathway.
We recently synthesized a lipophilic prodrug of 9-(2-phosphonyl- methoxyethyl)adenine (PMEA), des... more We recently synthesized a lipophilic prodrug of 9-(2-phosphonyl- methoxyethyl)adenine (PMEA), designated PMEA-LO, and incor- porated it into reconstituted lactosylated high-density lipoprotein (LacNeoHDL). In a rat model, LacNeoHDL-associated PMEA-LO was internalized by the asialoglycoprotein receptor on parenchy- mal liver cells and converted into its active diphosphorylated me- tabolite. To further evaluate the therapeutic potential of the carrier- associated prodrug, we examined
... Remco LA de Vrueh", Erik T. Rump', Erik AL Biessen ... 2)6easley, R PI Lin, ( C , l... more ... Remco LA de Vrueh", Erik T. Rump', Erik AL Biessen ... 2)6easley, R PI Lin, ( C , l-lwang I. Y laritct 1981, [/, 1129-1133 3)Kruining, J , Heljtirtk, R A , Sclialm, S W 4)Heij(ink, It A , De Wild?, G A , Kruining, J , et dl Aiitiuirnl Ke\ 1993, 27, 141-153 5)Narsrns, L , Babaririi, J , I h Clcrcq, C ...
We recently synthesized a lipophilic prodrug of 9-(2-phosphonyl-methoxyethyl)adenine (PMEA), desi... more We recently synthesized a lipophilic prodrug of 9-(2-phosphonyl-methoxyethyl)adenine (PMEA), designated PMEA-LO, and incorporated it into reconstituted lactosylated high-density lipoprotein (LacNeoHDL). In a rat model, LacNeoHDL-associated PMEA-LO was internalized by the asialoglycoprotein receptor on parenchymal liver cells and converted into its active diphosphorylated metabolite. To further evaluate the therapeutic potential of the carrier-associated prodrug, we examined in this study the processing of (125)I-labeled PMEA-LO--loaded LacNeoHDL by HepG2 cells. Upon incubation with HepG2 cells, PMEA-LO--loaded LacNeoHDL became rapidly cell-associated. The association was saturable and of high-affinity (k(d) = 3.8 +/- 0.4 nM). Asialofetuin, an established ligand for the asialoglycoprotein receptor, inhibited the association by >75%, which confirms the role of the asialoglycoprotein receptor. Association of the prodrug-loaded particles to HepG2 cells was coupled to degradation. Rad...
9-(2-Phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of Hepatitis B virus replication, ... more 9-(2-Phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of Hepatitis B virus replication, is in vivo hardly taken up by parenchymal liver cells (the site of infection). Our aim is to examine whether lactosylated reconstituted HDL (LacNeoHDL), a lipidic particle that is specifically internalized by parenchymal liver cells, is a suitable carrier for the selective delivery of PMEA to this cell type. To incorporate PMEA into LacNeoHDL, we synthesized a lipophilic prodrug (PMEA-LO) by coupling PMEA via an acid-labile phosphonamidate bond to lithocholic acid-3alpha-oleate. The yield of the synthesis was 52% ([3H]PMEA-LO: 24%). [3H]PMEA-LO readily incorporated into LacNeoHDL (13 molecules/particle) without affecting the size and net negative charge of the carrier. Further, incubation studies at lysosomal pH showed [3H]PMEA was completely released from the carrier whereas, at neutral pH or in plasma, appreciable release was not observed. The conjugation of PMEA with lithocholic acid-...
General use of nucleoside analogues in the treatment of viral infections and cancer is often limi... more General use of nucleoside analogues in the treatment of viral infections and cancer is often limited by poor oral absorption. Valacyclovir, a water soluble amino acid ester prodrug of acyclovir has been reported to increase the oral bioavailability of acyclovir but its absorption mechanism is unknown. This study characterized the intestinal absorption mechanism of 5' -amino acid ester prodrugs of the antiviral drugs and examined the potential of amino acid esters as an effective strategy for improving oral drug absorption. Acyclovir (ACV) and Zidovudine (AZT) were selected as the different sugar-modified nucleoside antiviral agents and synthesized to L-valyl esters of ACV and AZT (L-Val-ACV and L-Val-AZT), D-valyl ester of ACV (D-Val-ACV) and glycly ester of ACV (Gly-ACV). The intestinal absorption mechanism of these 5' -amino acid ester prodrugs was characterized in three different experimental systems; in situ rat perfusion model, CHO/hPEPT1 cells and Caco-2 cells. Testing...
The hepatitis B virus (HBV) is the world's most important chronic virus infection. The immuno... more The hepatitis B virus (HBV) is the world's most important chronic virus infection. The immunomodulator interferon-alpha (IFN alpha) is the only clinically applied drug available, despite its low response rate (approximately 30%) even in highly selected chronic carriers. Antiviral nucleoside analogues have proven to be potent inhibitors of viral replication in vitro, but their significant adverse effects which are, at least partially, due to their nonspecific body distribution, have forced the cessation of their clinical development in the past. For example, vidarabine causes severe neuromuscular toxicity, and fialuridine has caused fatal cases of liver and kidney failure in a recent clinical trial. Furthermore, the potential clinical application of (modified) antisense oligodeoxynucleotides, which are very specific inhibitors of viral replication, is hampered by their nonspecific body distribution, instability in serum and poor cell penetration. As infection and replication of H...
Background: We determined whether the market exclusivity incentive of the European Orphan Drug Re... more Background: We determined whether the market exclusivity incentive of the European Orphan Drug Regulation results in a market monopoly or that absence of another Orphan Medicinal Product (OMP) for the same rare disorder, a so-called follow-on OMP, is a matter of time or market size. In the interest of rare disorder patients better understanding of the effect of the market exclusivity incentive on follow-on OMP development is warranted. Methods: First, the impact of various market-, product-and disease-related characteristics on follow-on OMP development in the EU was determined by comparing rare disorders with an approved OMP and at least one follow-on OMP (N = 26), with rare disorders with an approved OMP and no follow-on OMP (N = 18). Next, we determined whether manufacturers continued development of a follow-on OMP upon approval of the first OMP for the intended rare disorder. Since in the EU significant benefit of an OMP has to be established, we determined for each follow-on OMP for which development was continued on what grounds significant benefit was assumed by the sponsor. Data were collected from the public domain only. Results: The likelihood of a rare disorder with an approved OMP to obtain at least one follow-on OMP development was strongly associated with disease prevalence, turnover of the first OMP, disease class, diseasespecific scientific output and age of onset. Out of a total of 120 follow-on OMPs only one follow-on OMP could be identified for which development was discontinued upon approval of the first OMP for the same rare disorder. Only a substantial level of discontinuation of follow-on OMP development would have indicated the existence of a market monopoly. Moreover, sponsors that continued development of a follow-on OMP predominantly assumed that their product had an improved efficacy compared to the first approved OMP. Conclusions: This study provides evidence that absence of follow-on OMP development is a matter of time or market size, rather than that the market exclusivity incentive of the European Orphan Drug Regulation creates a market monopoly.
We studied to what extent the level of scientific knowledge on exceptionally rare metabolic inher... more We studied to what extent the level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products is associated with sponsors deciding to apply for an orphan designation at the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Methods: All metabolic diseases with a genetic cause and prevalence of less than 10 patients per 1 million of the population were selected from the 'Orphanet database of Rare diseases'. The outcome of interest was the application for an orphan designation at FDA or EMA. The level of publicly available knowledge of the disease and drug candidate before an orphan designation application was defined as whether the physiological function corresponding with the pathologic gene and initiation of the pathophysiological pathway was known, whether an appropriate animal study was identified for the disease, whether preclinical proof of concept was ascertained and the availability of data in humans. Other determinants included in the study were metabolic disease class, the prevalence of the disease, prognosis and time of first description of the disease in the literature. Univariate relative risks (RRs) and 95% confidence intervals (CIs) of an orphan designation application were calculated for each of these determinants. In addition, a multivariate Cox regression analysis was conducted (Forward LR).
Objective To encourage the development of drugs for rare diseases, orphan drug legislation has be... more Objective To encourage the development of drugs for rare diseases, orphan drug legislation has been introduced in the USA (1983) and in the EU . Recent literature discusses factors that may influence the development of new orphan medicinal products in the EU. This study aims to identify predictors for successful marketing authorisation of potential orphan drugs in the EU. Methods A comparison between randomly selected authorised and a matched sample of not-yet-authorised orphan drug designations has been performed. Determinants in the study included characteristics of the indication, of the product and of the sponsor. Data were collected from the public domain only. Results Orphan drug approval was strongly associated with previous experience of the sponsor in obtaining approval for another orphan drug (OR=17.3, 95% CI=5.6-53.1). Furthermore, existing synthetic entities compared to biotechnology products tended to have a higher likelihood of reaching approval status (OR=3.9, 95% CI=0.9-16.6).
Background: Drugs for rare diseases, so-called orphan drugs, are often intended for serious or ch... more Background: Drugs for rare diseases, so-called orphan drugs, are often intended for serious or chronically debilitating diseases. Safety information is more limited at the time of approval for orphan drugs as a result of various factors, such as the limited number of patients in clinical trials, quality of the clinical trials and special approval procedures. Several studies have been conducted on safety-related regulatory actions for drugs, but none of these have specifically focused on orphan drugs. . The main outcome measures were the nature, frequency and timing of safety-related regulatory actions, defined as (i) safety withdrawals; (ii) 'black-box' warnings; and (iii) written communications to healthcare professionals issued by the US FDA or the European Medicines Agency between January 2000 and June 2008. Results: Ninety-five orphan drugs were approved during the study period (75 in the US, 44 in the EU, and 24 in both regions). Ten products (10.5%) received a safety-related regulatory action. No safety withdrawals, four black-box warnings and 12 written communications were identified. The probability of a first safety-related regulatory action for orphan drugs was 20.3% after 8 years of follow-up. Orphan drugs approved by accelerated approval (relative risk [RR] 3.32; 95% CI 1.06, 10.42), oncological products (RR 7.83; 95% CI 0.96, 63.82) and products for gastrointestinal and metabolism indications (RR 10.44; 95% CI 1.25, 87.27) may have a higher risk for a safety-related regulatory action.
More than 25 years of orphan drug regulations have yielded several new treatments for patients wi... more More than 25 years of orphan drug regulations have yielded several new treatments for patients with rare diseases. Here, we show that successful translation of rare disease research into an orphan drug discovery and development programme is dependent on the disease class, its prevalence and the disease-specific scientific output. Our findings indicate that current orphan drug legislation alone is not sufficient to stimulate orphan drug development for diseases with a very low prevalence. Consequently, additional incentives should focus on stimulating the specific needs of rare disease research at disease class level.
The high expression level of receptors for low-density lipoprotein (LDL) on tumor cells makes LDL... more The high expression level of receptors for low-density lipoprotein (LDL) on tumor cells makes LDL an attractive carrier for selective delivery of drugs to these cells. The aim of this study is to allow incorporation of oncogene-directed antisense oligodeoxynucleotides (ODNs) into the lipid moiety of LDL. Therefore, ODNs were conjugated with oleic acid, cholesterol, and several other steroid lipids. These latter steroid lipids were synthesized starting from bile acids and were varied in lipophilicity by attaching oleic acid ester structures. The lipid structures, activated as pentafluorophenyl esters, were conjugated in solution phase to 3'-amino-tailed ODNs. The ODNs conjugated with lithocholic acid, oleic acid, and cholesterol could easily be purified by reversed phase (RP)-HPLC. However, the ODNs conjugated with the oleoyl steroid ester structures irreversibly bound to the column material. These highly lipidic ODNs were separated from the nonconjugated ODN by electrophoresis in a 1% low-melting agarose gel containing 0.1% Tween 20. This method was found to be very effective in isolating the ODNs conjugated to the oleoyl steroid ester structures. The ODNs conjugated with cholesterol and the oleoyl esters of lithocholic and cholenic acid associated readily and nearly completely with LDL. However, the less lipidic ODNs and the ODN conjugated with the dioleoyl ester of chenodeoxycholic acid did not and did incompletely associate, respectively. Lithocholic acid and oleic acid are probably not sufficiently lipophilic to induce association with LDL, whereas the dioleoyl ester structure is probably too bulky and extended to allow partitioning into the lipid moiety of LDL. We conclude that several of the lipid-ODNs can associate readily with LDL, enabling delivery of oncogene-directed antisense ODNs via the LDL receptor pathway.
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