Long Circulating Liposomes and Membrane Tagging

Poly(Ethylene Glycol)Lipid Conjugates

18:1 PEG350 PE
Avanti Number 880430

Polyethylene glycol (PEG)-lipid conjugates have been used extensively to improve circulation times for liposome encapsulated drugs,
including doxorubicin1,2, mitoxantrone3, and the lipophilic prodrug of 5-fluorodeoxyuridine.4 Recently, new applications have been developed
using PEGylated liposomes. PEG modified liposomes encapsulating hemoglobin provides a long circulating red cell substitute.5 Delivery
of proteins, including a sustained injectable delivery system for insulin6, streptokinase7, and superoxide dismutase8 have recently been
described. In addition to injectable applications, oral delivery of peptides has been demonstrated using insulin.9 Cationic liposomes
incorporating PEG lipid have been used as carriers for oligonucleotides resulting in enhanced uptake by cells.10

The work described above utilizing PEG lipids was performed using PEG conjugated to phosphatidylethanolamine. A neutral PEG
lipid derivative has been characterized in which the PEG moiety is linked to ceramide. By varying the acyl chain length of the ceramide, the
retention time in the liposome could be modulated which directly affected the circulation time of the liposome and the plasma concentration
of the drug.11 However, short acyl chain PEG ceramides proved to be superior for transfection because the PEG ceramide would dissociate
from the stabilized plasmid-lipid particle surface, transforming the complex from a stable particle to a transfection competent entity.12,13,14
Also, some improvement in transfection was noted when short PEG polymers (PEG 750) were incorporated into the PEG ceramide rather
than PEG 2000 or PEG 5000 polymers.13

While PEG-lipid conjugates have long been used to prolong circulation times of liposome encapsulated drugs, targeting these delivery
vehicles to specific biologic sites was not so readily achieved. Liposome research has made great strides towards achieving this goal
by the attachment of antibodies to functionalized PEG-lipid conjugates.15,16 The latest advance in the technology being the synthesis of
detachable PEG-lipid conjugates.17

Avanti now offers an extensive group of PEG-lipid conjugates incorporating both a range of acyl chain compositions and PEG polymer
species, as well as offering PEG derivatives based on the ceramide and phosphatidylethanolamine lipid anchors. PEG-lipid conjugates
incorporating functionalized PEG termini are available for the attachment of targeting agents; these include Maleimide, PDP, Biotin, Amine
and Carboxylic acid.
References
1. Working, P.K., Newman, M.S., Sullivan, T., Yarrington, J. (1999) Reduction of the cardiotoxicity of doxorubicin in rabbits and dogs by encapsulation in

longcirculating, pegylated liposomes. J Pharmacol Exp Ther, 289:11281133.
2. Gabizon, A., Goren, D., Cohen, R., Barenholz, Y. (1998) Development of liposomal anthracyclines: from basics to clinical applications. J Controlled Release 53:275279.
3. AdlakhaHutcheon, G., Bally, M.B., Shew, C.R., Madden, T.D. (1999) Controlled destabilization of a liposomal drug delivery system enhances mitoxantrone antitumor activity.

Nat Biotechnol 17:775779.
4. Koning, G.A., Morselt, H.W., Velinova, M.J., Donga, J., Gorter, A., Allen, T.M., Zalipsky, S., Kamps, J.A., Scherphof, G.L. (1999) Selective transfer of a lipophilic prodrug of

5fluorodeoxyuridine from immunoliposomes to colon cancer cells. Biochim Biophys Acta 1420:153167.
5. Phillips, W.T., Klipper, R.W., Awasthi, V.D., Rudolph, A.S., Cliff, R., Kwasiborski, V., Goins, B.A. (1999) Polyethylene glycolmodified liposomeencapsulated

hemoglobin: a long circulating red cell substitute. J Pharmacol Exp Ther 288:665670.
6. Kim, A., Yun, M.O., Oh, Y.K., Ahn, W.S., Kim, C.K. (1999) Pharmacodynamics of insulin in polyethylene glycolcoated liposomes. Int J Pharm 180:7581.
7. Kim, I.S., Choi, H.G., Choi, H.S., Kim, B.K., Kim, C.K. (1998) Prolonged systemic delivery of streptokinase using liposome. Arch Pharm Res 21:248252.
8. Corvo, M.L., Boerman, O.C., Oyen, W.J., Van Bloois, L., Cruz, M.E., Crommelin, D.J., Storm, G. (1999) Intravenous administration of superoxide dismutase entrapped in long

circulating liposomes. II. In vivo fate in a rat model of adjuvant arthritis. Biochim Biophys Acta 1419:325334.
9. Iwanaga, K., Ono, S., Narioka, K., Kakemi, M., Morimoto, K., Yamashita, S., Namba, Y., Oku, N. (1999) Application of surfacecoated liposomes for oral delivery of peptide:

effects of coating the liposomes surface on the GI transit of insulin. J Pharm Sci 88:248252.
10. Meyer, O., Kirpotin, D., Hong, K., Sternberg, B., Park, J.W., Woodle, M.C., Papahadjopoulos, D. (1998) Cationic liposomes coated with polyethylene glycol as carriers for

oligonucleotides. J Biol Chem 273:1562115627.
11. Webb, M.S., Saxon, D., Wong, F.M., Lim, H.J., Wang, Z., Bally, M.B., Choi, L.S., Cullis, P.R., Mayer, L.D. (1998) Comparison of different hydrophobic anchors conjugated to

poly(ethylene glycol): effects on the pharmacokinetics of liposomal vincristine. Biochim Biophys Acta 1372:272282.
12. Wheeler, J.J., Palmer, L., Ossanlou, M., MacLachlan, I., Graham, R.W., Zhang, Y.P., Hope, M.J., Scherrer, P., Cullis, P.R. (1999) Stabilized plasmidlipid particles: construction

and characterization. Gene Ther 6:271281.
13. Mok, K.W., Lam, A.M., Cullis, P.R. (1999) Stabilized plasmidlipid particles: factors influencing plasmid entrapment and transfection properties. Biochim Biophys Acta
1419:137150.
14. Zhang, Y., Sekirov, L., Saravolac, E., Wheeler, J., Tardi, P., Clow, K., Leng, E., Sun, R., Cullis, P., Scherrer, P. (1999) Stabilized plasmidlipid particles for regional gene therapy:

formulation and transfection properties. Gene Ther 6:14381447.
15. Allen, T.M., E. Brandeis, C.B. Hansen, G.Y. Kao, and S. Zalipsky. (1995). A new strategy for attachment of antibodies to sterically stabilized liposomes resulting in efficient

targeting to cancer cells. Biochim Biophys Acta 1237:99-108.
16. Bendas, G., A. Krause, U. Bakowsky, J. Vogel, and U. Rothe. (1999). Targetability of novel immunoliposomes prepared by a new antibody conjugation technique.

Int J Pharm 181:79-93.
17. Zalipsky, S., M. Qazen, J.A. Walker 2nd, N. Mullah, Y.P. Quinn, and S.K. Huang. (1999). New detachable poly(ethylene glycol) conjugates: cysteine-cleavable lipopolymers

regenerating natural phospholipid, diacyl phosphatidylethanolamine. Bioconjug Chem 10:703-7.

33

continued overleaf
Revised 020415

Polymers & Polymerizable Lipids

Methoxy(Polyethylene glycol) Derivatives of Phosphatidylethanolamine
Lipid
Anchor

Avanti
Number

Lipid
Anchor

Avanti
Number

Lipid
Anchor

Avanti
Number

Lipid
Anchor

Avanti
Number

mPEG 350

DMPE

880410

DPPE

880400

DSPE

880420

DOPE

880430

mPEG 550

DMPE

880510

DPPE

880500

DSPE

880520

DOPE

880530

mPEG 750

DMPE

880610

DPPE

880600

DSPE

880620

DOPE

880630

mPEG 1000

DMPE

880710

DPPE

880700

DSPE

880720

DOPE

880730

mPEG 2000

DMPE

880150

DPPE

880160

DSPE

880120

DOPE

880130

mPEG 3000

DMPE

880310

DPPE

880300

DSPE

880320

DOPE

880330

mPEG 5000

DMPE

880210

DPPE

880200

DSPE

880220

DOPE

880230

Methoxy(Polyethylene glycol) Derivatives of Ceramide*

Lipid Anchor

Avanti Number

Lipid Anchor

Avanti Number

mPEG 750

C8 Ceramide

880670

C16 Ceramide

880680

mPEG 2000

C8 Ceramide

880170

C16 Ceramide

880180

mPEG 5000

C8 Ceramide

880270

C16 Ceramide

880280

*PEG-Ceramide contains ester linkages

between the PEG and ceramide moieties which
allow the compound to be easily metabolized.
More stable linkages can be manufactured
upon request. Please contact a Product
Specialist to discuss your specific requirements.

Functionalized PEG-Lipids

Number

DSPE-PEG (2000)-DBCO

880229

DSPE-PEG (2000) Azide

880228

DSPE-PEG (2000) Succinyl

880121

DSPE-PEG (2000) Carboxylic Acid

880125

DSPE-PEG (2000) Maleimide

880126

DSPE-PEG (2000) PDP

880127

Crosslinking Lipids

Number

DSPE-PEG (2000) Cyanur

880122

23:2 Diyne PC

870016

DSPE-PEG (2000) Amine

880128

DSPE-PEG (2000) Biotin

880129

23:2 Diyne PE

790145

DSPE-PEG (2000) Folate

880124

16:0-23:2 Diyne PC

790146

DSPE-PEG (5000) Folate

880123

16:0-23:2 Diyne PE

790147

For more details: www.avantilipids.com

Phone: 800-227-0651
Email: info@avantilipids.com