Tuesday, April 24, 2012

DELIVERY - Liposomes | Improve the Targeting Ability of Liposomes

Maybelle Cowan-Lincoln
Improve the Targeting Ability of Liposomes

‘Stealth’ and stimuli methods explored as ways to bolster delivery

Liposomes are spherical phospholipid vesicles, typically ranging in size from 50 to 1,000 nanometers (nm), that serve as delivery systems for a wide variety of drugs. Liposomes are made of one or more concentric lipid bilayers surrounding an aqueous inner compartment with aqueous phases also occurring between the lipid bilayers. Hydrophilic, or water-soluble, drugs can be loaded into the aqueous compartments, while hydrophobic, or water-insoluble, drugs can be loaded into the lipid bilayers.1
Liposomes are classified in various ways, including size (small, intermediate, or large) and lamellarity (unilamellar, oligolamellar, and multilamellar). Unilamellar vesicles are generally 50 to 250 nm, with one lipid bilayer around an aqueous core that can encapsulate water-soluble drugs. Multilamellar vesicles measure one to five µm and contain several concentric lipid bilayers. Their high lipid content facilitates encapsulating lipid-soluble drugs.2

A Neat Package

First developed around 1980, the potential of liposomes as a drug delivery system has been recognized for more than 20 years. In addition to the fact that they can incorporate both hydrophilic and hydrophobic compounds, liposomes display good biocompatibility and low toxicity. They tend not to activate the immune system and can deliver a drug directly to the site of action.3
Liposomes are especially useful in the delivery of protein and peptide drugs. These categories include potent and life-saving therapeutics, including enzymes and insulin. The use of proteins and peptides is limited by their instability at physiological pH and temperature. Incorporating these compounds into liposome delivery systems improves their pharmacological properties by delivering:
  • Increased stability;
  • Prolonged activity;
  • Decreased total amount of active ingredient needed;
  • Possibility of a single dose administration; and
  • Decreased immune system activation.
Liposomes are especially useful in the delivery of protein and peptide drugs. These categories include potent and life-saving therapeutics, including enzymes and insulin.
On the other hand, there are definite drawbacks to the use of liposomes. They cannot achieve sustained drug delivery over a long period of time, and liposomes with a positive charge carry the risk of toxicity. Also, as a result of their rapid opsonization (the process by which phagocytes eliminate pathogens from the system), liposomes are quickly eliminated from the blood by the reticuloendothelial system, particularly the liver. These factors have limited the use of liposomes in pharmaceuticals.

Sneak Up on Target Tissue

One of the most widely used methods to overcome the downsides of liposome drug delivery is stealth liposomes. This technology involves altering the surface of the liposome by coating it with either a natural or synthetic polymer conjugate. The most commonly used polymer is polyethylene glycol (PEG), a linear polyether diol with a number of beneficial properties:
  • Biocompatibility;
  • Lack of toxicity.
  • Low immunogenicity;
  • Solubility in aqueous or organic vehicles; and
  • Good excretion profile.
Adding PEG to liposomes has been demonstrated to inhibit the elimination of liposomes by the reticuloendothelial system, resulting in longer drug half-lives. In addition, PEG stabilizes liposomes by slowing the rate at which the drug seeps into the blood.4
But does the addition of PEG have any other effect on the drug payload? To answer this question, researchers at Seoul National University’s College of Pharmacy evaluated the circulation longevity of methotrexate, a chemotherapy compound, when delivered in a PEG-coated liposome. They discovered that plasma levels of methotrexate increased as the concentration of PEG increased, up to 5%. From these results, investigators concluded that PEG-coated liposomes show promise for targeted delivery of anti-cancer drugs.
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Case Study: Liposome-Hydrogel Hybrid Nanoparticles

Among the disadvantages of liposomes as a drug delivery system is their instability in the blood stream and their tendency to rupture easily if the environment changes.1,2 One vehicle that addresses these issues combines the biocompatibility and targeting dexterity of liposomes with the strength of a hydrogel—a network of polymer chains filled with water.
Researchers at the University of Maryland and the National Institute of Standards and Technology have developed a method to manufacture these hybrid vesicles, or rather, to help them self-assemble. The technique is called COMMAND: controlled microfluidic mixing and nanoparticle determination.
The process uses a microscopic fluidic device made by etching “channels” into a silicon wafer. Phospholipid molecules and cholesterol are dissolved in isopropyl alcohol. This solution is forced through the miniscule center channel (21 micrometers, approximately three times the size of a yeast cell). On either side of this channel are two channels in which a water-based solution containing hydrogel particles flows. The water-based solution “focuses” the central stream, housing the lipids as they all flow into a “mixer” channel. At the point of intersection, the lipids encapsulate the hydrogen particles, forming hybrid vesicles.3,4
The size of the vesicles can be controlled by varying the volumetric flow rate ratio between the central stream and the focusing streams. If the lipid-alcohol stream is tightly focused and slow flowing, small vesicles form. A fast flowing, highly focused stream produces larger vesicles. The dimensions of the microfluidic device and the geometry of the channels also affect vesicle size.
Researchers believe that this process, which facilitates mass production of uniform vesicles, will pave the way for the use of liposome-hydrogel hybrid nanoparticles in a wide variety of future clinical applications.


  1. Mufamadi MS, Pillay V, Choonara YE, et al. A review on composite liposomal technologies for specialized drug delivery. J Drug Deliv. 2011;2011:939851.
  2. National Institute of Standards and Technology. Liposome-hydrogel hybrids: no toil, no trouble for stronger bubbles. NIST website. June 9, 2010. Available at: www.nist.gov/pml/div683/bubbles_060910.cfm. Accessed Jan. 24, 2012.
  3. Hong JS, Stavis SM, DePaoli Lacerda SH, Locascio LE, Raghavan SR, Gaitan M. Microfluidic directed self-assembly of liposome-hydrogel hybrid nanoparticles. Langmuir. 2010;26(13):11581-11588.
  4. National Institute of Standards and Technology. NIST, Maryland researchers COMMAND a better class of liposomes. NIST website. April 27, 2010. Available at: www.nist.gov/pml/div683/command_042710.cfm. Accessed Jan. 24, 2012.

The Cancer Challenge

The use of conventional chemotherapy drugs is often limited by their inability to target diseased tissue and the severe toxic effects on healthy organs and tissues that result. The “holy grail” is, therefore, a drug that targets tumors exclusively. Stealth liposomes have made great strides in this direction.
PEG-coated stealth liposomes have a passive targeting effect not yet fully understood. They collect in the interstitial spaces in the tumor cells, but in order for the drug to be effective, it must be released from the liposome into the tumor extracellular fluid and then diffuse into the tumor cells. Current research has concentrated on achieving this action with the use of pH-sensitive liposomes. These vesicles are designed to release their drug payload in an acidic environment. In general, tumor tissue has a lower pH than healthy tissue, triggering drug release.
Among the arenas in which PEG-coated liposomes have achieved clinical success is the treatment of Kaposi’s sarcoma and recurrent ovarian cancer with PEGylated liposomal doxorubicin (PLD). Taking the drug in this format, patients experience significantly less myelosuppression, alopecia, and nausea compared with an equally effective dose of conventional doxorubicin.
Another new technology to increase the accumulation of liposomes at the target site is immunoliposomes. Immunoglobulins, especially those of the IgG class, are attached to the surface of the liposomes. They act as ligands—molecules that connect to a site on a receptor protein—capable of recognizing and binding to tissue at sites of interest. However, most immunoliposomes are still eliminated by the liver before they can deliver significant results. One way to meet this challenge is to use stealth liposome technology: Coat the immunoliposomes with PEG to create long-circulating liposomes. Currently, one immunoliposome formulation is in clinical trials, a PEGylated DXR formulated to recognize gastric, colon, and breast cancer cells.

Triggering Release

Recent developments in liposomal drug delivery include stimuli-type liposomes. This technology employs various environmental factors to trigger drug delivery. The stimuli can include light, temperature, magnetism, and ultrasound waves. Once exposed to the proper stimulus, the liposome delivers its drug to the cytoplasm of the targeted cell through cell membrane pores.
An example of this technology is superparamagnetic iron oxide particles embedded in the shells of liposomes, making the shell leaky when exposed to an alternating current electromagnetic field. The drug is then released through the shell into the site of action. The rate of release can be controlled by altering the magnetic field strength and adjusting how the nanoparticles are loaded.5
Nanoparticles made of gold can deliver efficient, targeted delivery of multiple drug compounds. When exposed to infrared light, gold nanoparticles melt and release their payload. Different shaped nanoparticles melt at different wavelengths. Therefore, to release multiple compounds, each drug can be encased in a unique nanoparticle shape. As the wavelength of the external light source varies, each drug is released into the patient’s system.6

Polymer Vesicles

Over the years, the terms “liposome” and “vesicle” have been used almost interchangeably. However, vesicle formation occurs in many materials other than conventional lipids.7
Vesicles made of polymers offer exciting possibilities for drug delivery. Polymer bilayers are thicker than lipids, so permeation is slower. Also, the release rate can be tailored by altering the thickness of the bilayers during preparation. Additionally, by using polymers that respond to various environmental stimuli, including pH and temperature, drug release can be further controlled.


  1. Torchilin VP. Lipid-based parenteral drug delivery systems: biological implications. In: Wasan KM, ed. Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples. Hoboken, N.J.: John Wiley & Sons; 2007:48-87.
  2. Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rarionale, and clinical applications, existing and potential. Int J Nanomedicine. 2006:1(3):297-315.
  3. Mufamadi MS, Pillay V, Choonara YE, et al. A review on composite liposomal technologies for specialized drug delivery. J Drug Deliv. 2011;2011:939851.
  4. Hong MS, Lim SJ, Oh YK, Kim CK. pH-sensitive, serum-stable and long-circulating liposomes as a new drug delivery system. J Pharm Pharmacol. 2002;54(1):51-58.
  5. Chin Y, Bose A, Bothun GD. Controlled release from bilayer-decorated magnetoliposomes via electromagnetic heating. ACS Nano. 2010;4(6):3215-3221.
  6. Trafton A. Gold particles for controlled drug delivery. Massachusetts Institute of Technology website. Dec. 30, 2008. Available at: http://web.mit.edu/newsoffice/2008/nanorods-1230.html. Accessed Jan. 24, 2012.
  7. Antonietti M, Förster S. Vesicles and liposomes: a self-assembly principle beyond lipids. Adv Mater. 2003;15(16):1323-1333.
Maybelle Cowan-Lincoln is a pharmaceutical writer based in New Jersey. Her work has been featured in numerous scientific publications.

Editor's Choice

  1. Drummond DC, Noble CO, Hayes ME, Park JW, Kirpotin DB. Pharmacokinetics and in vivo drug release rates in liposomal nanocarrier development. J Pharm Sci. 2008;97(11):4696-4740.
  2. Kan P, Tsao CW, Wang AJ, Su WC, Liang HF. A liposomal formulation able to incorporate a high content of Paclitaxel and exert promising anticancer effect. J Drug Deliv. Available at: www.hindawi.com/journals/jdd/2011/629234/ref. Accessed Jan. 24, 2012.
  3. Jesorka A, Orwar O. Liposomes: technologies and analytical applications. Annu Rev Anal Chem. 2008;1:801-832.

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