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pegylated liposomes

pegylated liposomes

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Published by Deepti Sharma
Novel Drug delivery System
Novel Drug delivery System

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Published by: Deepti Sharma on Nov 21, 2011
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11/21/2011

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PEGylated Liposomesenhance Bioavailability
(Molecular stealth technology prolongs release and minimizes toxicity and side effects By WillBlock.)hen we go swimming in the ocean, we are, in a sense, intruders in an alien environment,one in which we are ill-equipped to survive should anything go wrong. Somewhere in the back of every swimmer’s mind must be the unsettling thought that he or she has enteredthe world of … Jaws. Without any protection. For decades, scientists have been trying, withoutnotable success, to develop effective shark repellents. But forget about repellents—wouldn’t it becool if we could apply some kind of chemical camouflage to our skin so that sharks would see usmerely as big watery blobs rather than something meaty and edible?
Conventional Liposomes Are Good . . .
 Right—dream on. As we will see below, however, that dream
has
been realized with regard to
liposomes,
which are microscopic, manmade cells used as sustained-action delivery vehicles for a wide variety of drugs, vaccines, enzymes, nonenzyme proteins, and genetic material—andnow, for some nutritional supplements as well. The molecular “payload” is encapsulated insidethe liposomes, which eventually break down through natural processes and spill their contentsinto the bloodstream or into tissues to which they have migrated by diffusion through the wallsof capillaries. Liposomes are a safe and effective way to introduce agents into our system that are problematic for some reason when taken orally, as well as agents that cannot be taken orally atall (because they’re degraded by digestive juices), such as nucleic acids and most proteins.The problem with conventional liposomes, though, is that they’re seen as alien invaders by
 phagocytes,
our own built-in version of Jaws. Phagocytes are cell-eating cells whose mission isto devour anything that doesn’t belong in our bloodstream. And when liposomes are devoured,so are their therapeutic payloads, which may thus go to waste—but not necessarily. If the payload is not broken down by enzymes inside the phagocyte, it may remain there and perhapsdo some good—provided that it was designed for that purpose. Some drugs are, in fact, designedto treat phagocyte-related diseases or to enhance phagocytic activity. Thus, allowing them to begobbled up by phagocytes is perfect.Another possible outcome in case the payload survives the onslaught of the phagocyte’sdegradative enzymes is that it may escape back into the bloodstream. This phenomenon is called
macrophage-mediated drug release
(a macrophage is one type of phagocyte).
1
It provides agradual, prolonged release, which is usually a good thing, as we will see below. Since it occurs primarily in the liver and spleen, where phagocytes are especially abundant, conventionalliposomes can be used to deliver certain drugs for treating diseases of these two organs.
. . . But PEGylated Liposomes Are Better
 
 
Generally speaking, though, phagocytes are bad news for liposomes, which they usually dispatchwithin minutes of administration.
2
Camouflaging the liposomes so as to fool phagocytes intoignoring them thus became a key objective of pharmaceutical chemists during the 1970s and beyond. (Liposomes were discovered in England in 1965.
3
) The result of their efforts was a process called
PEGylation,
in which countless molecules of a synthetic, nontoxic polymer, polyethylene glycol (PEG), are attached, at one end of the polymer chain, to the surface of theliposome.
4,5
The long, slender, highly flexible PEG molecules slosh around the liposome likespaghetti boiling in a pot. Because of their chemical affinity for water molecules, they areheavily hydrated. To phagocytes, this molecular “cloak” of water of hydration makes thePEGylated liposomes look like little watery blobs rather than something edible, so they tend toleave them alone. Mission accomplished!The two main advantages of PEGylated liposomes for delivering drugs or supplements are
increased bioavailability
and the possibility, in some cases, of 
targeted delivery
to the organs or tissues that most need them.
1
Let’s look at these two benefits in turn.
Types Of LIPOSOMES
:There are four basic kinds of liposomes, each with its own advantages and disadvantages. All of them consist of a spherical cell membrane (lipid bilayer) that encapsulates a payload of therapeutic molecules. All of them bypass the digestive tract, thus increasing the bioavailabilityof their payloads, which remain biologically inert until the cell membrane ruptures. When andwhere that occurs, and why and how it occurs, is what makes the difference. It depends on manydifferent physical and chemical properties of the liposomes and on the physiological environmentin which they find themselves.
Conventional liposomes
are “naked,” i.e., they’re ordinary liposomes made from simple phospholipids, with nothing to protect them from phagocytes. Their surfaces (both exterior andinterior) are either electrically neutral or negatively charged (depending on the specific nature of the lipid molecules used in making the bilayer. These liposomes are used mainly to deliver drugsto the phagocytes that eat them, so as to treat disorders of the phagocytes themselves or to treatdiseases of the liver or spleen, where most phagocytes are found. The latter form of treatment ismade possible by drugs that are re-released unharmed by the phagocytes.
PEGylated liposomes
are “stealth” liposomes that evade detection and destruction by phagocytes by virtue of their cloaks of hydrated PEG (polyethylene glycol) molecules. Their purpose is two-fold: (1) to increase the bioavailability of drugs or supplements by bypassing the digestive tract,and (2) to minimize any potential toxicity or side effects of these agents by remaining in thecirculation for a long time and releasing their payloads slowly. As a bonus, they’re passivelytargeted to tumors and to inflamed tissues, where they’re preferentially absorbed because of theincreased permeability of the capillaries that nourish these tissues.
Immunoliposomes
are stealth liposomes that have been specially designed for active targeting toa given type of tissue or organ that the liposome is able to recognize by its molecular fingerprint.This is accomplished by highly specific chemical modifications to the PEG molecules or the lipid
 
 bilayer of the liposomes, or both. The molecular entity responsible for cell recognition is usuallyan antibody or an antibody fragment. Antibodies are immunoglobulins, which are glycoproteins produced by the body’s immune system—hence the “immuno” part of the name. These liposomesare used primarily for cancer therapy.
Cationic liposomes
are stealth liposomes whose surfaces (both exterior and interior) are positively charged so as to increase the loading efficiency of their payload, which is recombinantDNA. These liposomes are used for gene therapy, in which certain disorders are treated byintroducing specifically engineered genetic material (DNA) into the patient’s cells through activetargeting.
PEGylated Liposomes Offer Increased Bioavailability
 Throughout the drug and supplement industries, poor bioavailability of therapeutic agents is ahuge problem, especially where older people are concerned.
6
For example, as we age, our abilityto absorb certain nutrients from the gut, such as vitamin B
12
and folic acid, declines markedly.Other nutrients, such as the antioxidants resveratrol and quercetin, have poor bioavailability to begin with, because they’re completely metabolized in the gut and liver before they ever reachthe general circulation. The metabolites of resveratrol and quercetin do enter the circulation,however, and are probably responsible for some of the beneficial effects (observed mainly inlaboratory and animal studies) attributed to the parent compounds. Yet other nutrients, such ascoenzyme Q
10
, the body’s vital “spark plug” molecule, are so costly that we need to maximizetheir bioavailability so we can take lesser amounts and still obtain the benefits.
By keeping the blood concentrationof the drug or supplement low andrelatively constant, we can avoid thepharmacological yo-yo effect (peaksand troughs) that has been the normwith traditional delivery methods.
We can address such problems with PEGylated liposomes, which can be used to deliver nutrientsto the bloodstream via a more direct and less hostile route than the digestive tract, namely, themucous membranes of the mouth (or, in some cases, the vagina or labia).* The liposomes, in theform of aqueous suspensions, can also be applied transdermally (through the skin), but thetransmucosal route seems to be more effective. Once absorbed by the mucosa, the liposomes, if they’re small enough, enter the bloodstream by diffusing through the exceedingly thin walls of capillaries, whence they travel via the venous system to the heart, and thence via the arterialsystem to all the body’s capillaries, to begin the cycle anew (one complete circuit takes about aminute).

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