Representation of the steric organization of a micelle (left), a liposome (center), and a lipid bilayer (right). Note: Adapted from Bitounis D, Fanciullino R, Iliadis A, Ciccolini J. Optimizing druggability through liposomal formulations: new approaches to an old concept. ISRN Pharm. 2012;2012:738432.14
Liposomes have been used to improve the therapeutic index of new or established drugs by modifying drug absorption, reducing metabolism, prolonging biological half-life or reducing toxicity. Drug distribution is then controlled primarily by properties of the carrier and no longer by physico-chemical characteristics of the drug substance only.
Despite all the hopes invested in conventional liposomes, they have presented various problems and pharmacological implications over the years. A major drawback of conventional liposomes is their quick capture by the RES. Liposomes are mainly accumulated in the liver and the spleen, due to their generous blood irroration and the abundance of tissue-resident phagocytic cells. This is extremely advantageous in the case of local infections: the high concentration of antimicrobial agents in the RES can help treat infective pathogens. However, during chemotherapy, it may lead to partial depletion of the macrophages and interfere with the important host-defense functions of this cell type. On the other hand, the marked increase in retention and accumulation of liposomal drugs in such organs as the spleen and the liver may lead to the delayed removal of lipophilic anticancer drugs from the circulation.
A number of different strategies were then tested to overcome the aforementioned limitations. The best strategy was PEGylation of the liposome surface which is able to improve the stability and circulation time of liposomes dramatically after intravenous administration, by rendering the liposomes invisible to macrophages. These “long-circulating liposomes” were then named Stealth liposomes because of their ability to evade the immune system; this results in a significant increase in blood-circulation time in vivo.
PEG is a linear or branched polyether diol with many useful properties, such as biocompatibility, solubility in aqueous and organic media, lack of toxicity, very low immunogenicity and antigenicity, and good excretion kinetics. These properties permit the employment of PEG in a variety of applications, including the biomedical field, after US Food and Drug Administration (FDA) approval for internal administration . PEG chains protect liposomes from mononuclear phagocytic system cells by building a protective, hydrophilic film on the liposomal surface. Their presence prevents the interaction of liposomes with other molecules, such as various serum components. One possible explanation for the impaired interaction is the PEG-induced “steric hindrance.” The mechanism of steric hindrance by the PEG-modified surface has been thoroughly examined. The water molecules form a structured shell through hydrogen bonding to the ether oxygen molecules of PEG. The tightly bound water forms a hydrated film around the particle and repels the protein interactions. In addition, the presence of PEG on the surface may also increase the hydrodynamic size of the particle, decreasing its clearance, a process that is dependent on molecular size as well as particle volume.
Chemical structures of distearoylphophatidylcholine (DSPC), distearoylphophatidylethanolamine after conjugation with poly-(ethylene glycol) (PEG) (DSPE-PEG) and DSPE-PEG linked with a targeting moiety. Image source: http://europepmc.org/article/PMC/2426795
PEG-bearing liposomes are not opsonized or affected by complement components, and consequently evade capture by mononuclear phagocytic system cells. Finally, the presence of PEG in liposome formulations prevents aggregation, favors the formation of small, monodisperse particles, and increases the EPR effect, due to the extended circulation time and escape from the RES. Besides, Stealth liposomes have a longer half-life (which leads to longer blood-circulation times), low systemic plasma clearance, and low volume of distribution (minimal interaction with nondiseased tissue). This results in multiple-fold greater area-under-the-curve values (drug concentration–time profile) and improved tissue distribution (targeting of target sites). Therefore, it is not surprising that the clinically approved antitumoral drug Doxil® is PEGylated in order to improve tumor-site accumulation of the drug.
Biochempeg provides a variety of PEG-liposome derivatives, including mPEG, DSPE Lipids with different molecular weight and functional PEG.
|DSPE-PEG-DSPE||1K, 2k, 3.4k, 5k, 10k, 20k||≥95%|
|mPEG-CLS||1K, 2k, 3.4k, 5k, 10k, 20k||≥95%|
|mPEG-DSPE||350, 550, 750, 1K, 2k, 3.4k, 5k, 10k, 20k, 30k, 40k||≥95%|
|mPEG-DMPE||2k, 5k, 10k, 20k||≥95%|
|mPEG-DOPE||1k, 2k, 5k||≥95%|
|DSPE-PEG-OH||200, 1K, 2k, 3.4k, 5k||≥95%|
|DSPE-PEG-SH||1K, 2k, 3.4k, 5k, 10k||≥95%|
|DSPE-PEG-CHO||1K, 2k, 3.4k, 5k, 10k, 20k||≥95%|
|DSPE-PEG-NH2||200, 400, 500, 600, 800, 1K, 2k, 3.4k, 5k, 6k, 8k, 10k, 20k||≥95%|
|DSPE-PEG-N3||600, 1K, 2k, 3.4k, 5k||≥95%|