Solving Drug Delivery Problems with Liposomal Carriers - American

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Solving Drug Delivery Problems with Liposomal Carriers Theresa M . Allen

Downloaded by UNIV OF MINNESOTA on July 11, 2013 | http://pubs.acs.org Publication Date: May 15, 2000 | doi: 10.1021/bk-2000-0752.ch011

Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

Liposomes are beginning to achieve widespread acceptance as drug carriers, with several products in the clinic and many more in clinical development. Particularly useful is the ability of liposomes to solublize drugs and protect them from degradation. Furthermore, liposomal association of drugs can result in substantial changes in drug clearance, volume of distribution and biodistribution which can help to solve delivery problems associated with unfavorable drug pharmacokinetics. This can lead to increased drug efficacy and decreased drug-associated toxicities. In addition to their use as carriers for chemotherapeutic drugs, liposomes are receiving attention for their use as non-viral delivery systems for gene therapy and as carriers in vaccines.

There is no such thing as a perfect drug. A 'perfect' drug would cure or prevent disease in a highly selective manner by homing only to specific target tissue(s) with no side effects, i.e. it would function as a "magic bullet". It would, arguably, be water soluble and orally active, with pharmacokinetics permitting a once per day administration schedule. We can also fantasize about other properties which we would impart to our perfect drug. In the real world, however, we have to deal with problems like poor solubilities, rapid degradation, unfavorable pharmacokinetics, and poor selective toxicities with attendant side effects. Many novel drug entities fail clinical trials because of these considerations. Other drugs have made it into the clinic, but still have significant problems associated with their administration and/or selectivity.

Liposomal Drug Delivery Systems in Clinical Development Several drug delivery systems are being researched as a means of solving problems associated with drug delivery, including: liposomes, polymer drug carriers, microspheres, antibody-drug conjugates and immunotoxins. Amongst the drug carriers, liposomes (phospholipid bilayer spheres) are the most developed*. There

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In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.


101 are currently four liposome-based products in the clinic: a liposomal formulation of the antifungal drug amphoterecin Β (AmBisome®, NeXstar Pharmaceuticals), and two liposomal anticancer anthracycline formulations, Stealth liposomal doxorubicin (Caelyx® or Doxil®, SEQUUS Pharmaceuticals), liposomal daunorubicin (DaunoXome®, NeXstar Pharmaceuticals) and a liposome-based photosensitizer porfimer sodium (Photofrin®, QLT Phototherapeutics). Approval for another liposomal doxorubicin formulation (Evacet®, The Liposome Company) is currently being sought from the FDA. Several more liposomal drugs are currently in clinical development including several additional anticancer drugs (vincristine, annamycin, cis-platin, camptothecins, taxanes, tretinoin) antibiotics (amikacin, gentamicin), immune modulators (IL-2, muramyl tripeptide) and photosensitizers (benzophorphrin derivatives in age-related macular degeneration). Furthermore, liposomes are being developed for delivery of antigens for vaccines and as non-viral vectors for gene therapy. The high level of commercial activity surrounding liposomal drug delivery is a result, in part, of the low toxicity of liposomal compenents, their biodegradability, their excellent storage stability, and relative ease of manufacure. This paper will provide a brief review of the current state of liposomal drug delivery and suggest some future directions for the field.

Choice of Drugs for Liposomal Delivery How can it be decided whether or not a drug is a candidate for liposomal delivery? A variety of drugs can achieve stable association with liposomes, but not all (Figure 1). Hydrophilic drugs, i.e. those with low octanol:water partition coefficients, can be readily accommodated within the aqueous interior of liposomes^. Drugs in the liposome interior are protected from enzymatic degradation and will be slowly released over a period of hours to days, depending on liposome composition and osmotic strength of the drug solution. On the other hand, the entrapment efficiency of hydrophilic drugs may be low which could be a problem for expensive compounds such as proteins and peptides. In addition, the rate of drug release is non-linear. Hydrophobic drugs may also be associated with liposomes^. These drugs, having high octanohwater partition coefficients, can be accommodated within the hydrophobic acyl chain region of the phospholipid bilayer. The association can be very rapid and efficient, allowing the liposomes to function as solubilizers for drugs having low solubilities. Following in vivo administration, hydrophobic drugs appear to rapidly transfer to lipoproteins or other biological membranes^. Association with liposomes of drugs of intermediate solubility can be problematic. Drugs is this category often transfer rapidly between the liposome aqueous interior, the liposome membrane and the external medium (Figure 1). However, clever manipulation of the conditions of entrapment may allow even some of these drugs to be efficiently entrapped. Weak acids and bases can be entrapped with high efficiency by liposomes exhibiting a pH gradient across the liposome bilayer, or drugs can be complexed with substances in the liposome interior which render them more stable and less soluble^. For example, very efficient loading of


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doxorubicin can occur through the formation of a doxorubicin sulfate precipitate in the liposome interior and these liposomes show high stability and low leakage rates^.

Figure 1. Interactions of drugs with liposomes. (A) Hydrophilic drugs are encapsulated in the aqueous compartment(s). (B) Hydrophobic molecules can b accommodated in bilayer interior. (C) Charged molecules, e.g. DNA, associate w the bilayer surface through Van der Waal's interactions. (D) Molecules with intermediate solubilities will be in equilibrium between the membrane interior a exterior and will not easily form a stable association with liposomes

Pharmacokinetics of Liposomal Drugs One of the most compelling reasons for the use of liposomal drugs is the often dramatic changes in drug pharmacokinetics which result from liposome encapsulation^. Because liposomes are large (on the scale of a drug molecule), and particulate in nature, they have difficulty in extravasating through normal vasculature. This results in volumes of distribution (V ) which are similar to plasma volumes in vivo, i.e. approximately 4 L in humans^. Since many free, i.e. non-encapsulated, drugs have large V , often over 100-200 L in humans, this represents a substantial change. Thus liposomal delivery can result in decreased drug concentrations in normal tissues, e.g. heart, GI tract or kidney, and consequently decreased drug toxicities. Decreased drug toxicities accompanying liposome encapsulation of drugs may be particularly relevant for anticancer drugs or antiviral drugs. On the other hand, liposomal delivery may impede the delivery of drug from liposomes to some D

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103 tissues because of poor extravasation of the liposomes. Fortunately, some diseased tissues have increased vasculature permeability which can lead to increased uptake of liposomal drugs into those tissues (see below)°. While liposome composition will have little influence on the volume of distribution of liposomal carriers per se, the volume of distribution for liposomeentrapped drugs may appear to change with drug release rate, which is itself dependent on liposome composition. For example, the anticancer drug doxorubicin has a V in humans of 254 L humans^. When entrapped in liposomes with very low release rates, the V decreases to 4.1 L. However, for a formulation with higher drug release rates, the V is a combination of the V for the liposomal carrier and the V for the released (now free) drug and could be anywhere between 4.1 L and 254 L depending on the release rate of drug^. Liposome composition can also have significant effects on the clearance rate of liposomal drugs. Size, surface charge, phospholipid composition, the presence or absence of cholesterol, and the presence or absence of surface hydrophilic polymers can all affect the clearance of liposomes and their associated d r u g s C l e a r a n c e half-lives as low as a few minutes have been described for some "classical" liposome formulations. Liposomes are cleared from blood primarily by uptake into the mononuclear phagocyte system (MPS, i.e., reticuloendothelial system) and are found principally in Kupffer cells in liver and in fixed macrophages in spleen because these organs receive the largest blood flows *. Particularly if one is delivering cytotoxic drugs, this has implications for impairment of MPS function. Classical liposomes are cleared into liver with Michaelis-Menten (saturable) pharmacokinetics^. More recent research has resulted in the description of long-circulating (Stealth) liposomes which have a reduced rate and extent of uptake into MPS tissues. These liposomes have hydrophilic polymers such as polyethylene glycol (PEG) grafted at the liposome surface (reviewed in ^»^). The polymers repel opsonins involved in the MPS uptake of liposomes and significantly reduce the clearance rate of liposomes. These liposomes are cleared with log-linear (non-saturable) pharmacokinetics^. Clearance half-lives for PEG-grafted liposomes of up to 2 days in humans have been described^. Decreased clearance rates for liposomal drugs and reduced volumes of distribution, lead to increased areas under the plasma concentration versus time curve (AUC). When the clearance rate of liposomal drugs in reduced, i.e. if the liposomes can circulate long enough, they can begin to extravasate through leaky vasculature, which is characteristic of several diseased tissues, in a process called passive targeting^. Examples of tissues with increased vascular permeability include solid tumours undergoing angiogenesis (recruitment of new blood vessels) and tissues exposed to various cytokines as might occur during the process of bacterial infections. The concentration of liposomal drugs in tumours, relative to free drug tumour concentrations, can be increased up to 10-fold or higher through the passive targeting mechanism. This increased localization of drugs to diseased tissues can lead to increases in the efficacy of the drugs. For example, the efficacy of Stealth liposomal doxorubicin (Caelyx/Doxil®) in the treatment of Kaposi's sarcoma approximately doubled with a complete plus partial response rate (PR/CR) of 46.2 % for the liposomal drug compared to 25.6% for a free drug schedule consisting of adriamycin (doxorubicin), bleomycin, vincristine (ABV)*^. D

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Potential Uses for Liposomal Drugs Liposomes cannot solve all drug delivery problems, but, based on the physical and pharmacokinetic properties of liposomes, many possible applications for liposomal drugs can be suggested. In general, liposomes are very versatile drug carriers^. They can be given by a number of routes of administration, although administration via the oral route has, until now, been less successful than other routes^. Non-toxic, non-immunogenic and biodegradable liposomes are easy to formulate and can be manufactured with relative ease. Storage stabilities of up to two years have been achieved. When a currently approved drug is placed in a liposome it is considered to be a new drug and must go through the approval process again, with the attendant cost in time and money, but, on the positive side, the liposomal drug can then receive patent protection even after this protection has expired on the conventional form of the drug. Because liposomes can readily solubilize hydrophobic drugs within the fatty acyl chain region of their bilayers, their use to formulate such drugs would be an obvious application^*. Lipid components can be chosen which are non-toxic and biodegradable and such systems may have advantages over traditional excipients such as dimethyl sulfoxide (DMSO), Cremphor EL or surfactants. Hydrophobic compounds, like photosensitizers, have been reported to transfer rapidly from liposomes to lipoproteins upon in vivo administration-^. More research is needed into the factors which govern the pharmacokinetics and biodistribution of drugs 'solubilized' in liposomal membranes. Liposomes have many actual and potential applications for hydrophilic drugs which are entrapped in the aqueous interior of liposomes. Many examples exist of applications in which liposomes function as sustained release systems for drugs (see also below)^^. The rate of drug release can be manipulated over a wide range, depending on how the liposomal drugs are formulated. However, more research is needed into the relationship between drug release rate and therapeutic efficacy^. Is a faster drug release rate or a slower one more efficacious is treating, for example, a solid tumour? Are there factors, such as tumour doubling times, which can be used to predict optimum drug release rates? Are there simple, inexpensive ways of formulating liposomes which demonstrate triggered release of drugs once they reach the site of drug action? Would this lead to improved therapeutic effects? When drugs are sequestered in the liposome aqueous interior they are protected from enzymatic and other process of degradation, thus the half-life of the drugs can be prolonged. Consequently, another application for liposomes is in the 'protection' of drugs which are degraded rapidly. For example, the half-life of cytosine arabinoside, an anticancer drug, is increased from a few minutes to several hours upon liposome encapsulation as the drug is sequestered away from the degrading enzyme cytosine deaminase^ . This effect can lead to a decrease in the maximum tolerated dose of the drug because drug is available over significantly longer periods of time. Because liposome can maintain a pH gradient across their membranes, drugs which are sensitive to pH-mediated breakdown, such as the camptothecins, can be protected from degradation within liposomes^. Similarly, 4


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liposomes should be considered in applications involving proteins and peptides, many of which have short half-lives in vivo. Smaller peptides can be easily accomodated within the aqueous space of liposomes, although it is difficult to entrap larger proteins within the small liposomes required for many therapeutic applications. More work on how to increase the entrappment efficiency of proteins and peptides needs to be done. The ability of liposomal carriers to alter the biodistribution of drugs leads to other possible applications. Since liposomes do not readily exit through normal, tight, vascular endothelium, they can be used to reduce the exposure of sensitive normal tissues to damaging drugs. For example, liposomal encapsulation of doxorubicin results in a decrease in cardiac toxicities and liposomal association of amphotericin leads to a reduction in dose-limiting kidney toxicities 16,26 The pharmacokinetic profile of liposomes suggests that they would be particularly well suited for applications involving drug delivery within the vasculature. Applications of liposomal drugs which take advantage of the 'passive targeting' abilities should also be considered. Liposomal drugs can localize to tissues which have increased vascular permeabilities accompanying the disease process and this is the basis of the clinical approval of two liposomal formulations of anthracyclines and the pending approval of a further liposomal anthracycline for use in the treatment of solid tumours (see above) ^ . In at least one instance however, liposomes may extravasate into normal tissues. The tendency of small liposomes to be 'squeezed ' out into skin in regions experiencing pressure or rubbing, has been reported to cause 'hand and foot' syndrome in patients being treated with Stealth liposomal doxorubicin^. Liposomes have received considerable attention for their potential as nonviral delivery vehicles for plasmid DNA or antisense oligonucleotides (asODNs) for gene therapy27>28 Liposomal vectors are considered to be safer than viral vectors, but, on the whole, they lack the transfection efficiency of the viral vectors. More than one clinical trial is currently underway for intrapulmonary and intratumoral administration of liposomal vectors29,30 AsODNs are small enough to be treated like other hydrophilic drugs and they can be passively entrapped in the aqueous interior of liposomes-^. Plasmid DNA presents more difficulties because of its large size. In some applications plasmid DNA has been associated with cationic liposomes, forming large heterogeneous complexes. Although these cationic lipid-DNA complexes can be very efficient as transfecting cells in vitro, their size and charge guarantees their rapid removal into the MPS in vivo following intravenous administration^?. In addition, cationic lipids, which are not normal components of cell membranes, have considerable toxicity compared to neutral or negative phospholipids. Techniques for condensing DNA and associating it with lipid particles have been described which should improve the outlook for non-viral liposomal vectors, and investigators are exploring alternatives to cationic lipids^. However, considerable work remains to be done to develop liposomal vectors which are non-toxic, and have good in vivo transfection efficiency. Even though non-immunogenic liposomes can be readily formulated, liposomes can also be good antigen carriers for stimulating immune responses for the purposes of vaccines-^2,33 liposome membrane can effectively mimic natural membranes which present proteins, peptides and carbohydrates to the immune system. Many studies have demonstrated that antigens incorporated into liposomal


106 Mayers or sequestered into the liposome interior can generate vigorous immune responses-* ^ Sometimes an immune-stimulating substance or adjuvant is incorporated into the liposome to facilitate the generation of an immune response, e.g. muramyl tripeptide or lipid A. 4


Improving on the Current Generation of Liposomes There are several ways in which liposomal carriers might be improved. The next generation of liposomal carriers is likely to be specifically targeted to diseased cells via target-specific ligands attached at the liposome surface^ *\ A number of the steps toward this goal have already been achieved. Methods for attaching antibodies and other ligands to both classical and Stealth liposomes have been described-*?. Although antibody-targeted classical liposomes are removed very rapidly from circulation into the MPS, it has been shown that antibody-targeted Stealth liposomes retain long circulation times. When the antibodies are coupled to the terminus of PEG in Stealth liposomes they are also able to retain binding affinities for their respective antigens. Liposomes are also to restore multivalent binding to antibody fragments, which may help improve the binding avidity of fragments. The therapeutic efficacy of targeted liposomes has been examined in several experimental models of haematological and solid tumours-*8>39 Some tentative conclusions can be drawn from these experiments. The best therapeutic results in the treatment of cancers appear to come from liposomes with modest, rather than high, antibody densities where the targeting moiety has good affinity for its antigen and is targeted against an internalizing receptor on the target cell. In this case, binding of the liposomal ligand to its receptor triggers the internalization of the liposome package into the lysosomal apparatus **. However, more effective techniques to promote release of the drug or genetic material from endosomes need to be found. The antigen (receptor) should preferably be expressed uniquely in high concentrations by the target cell and not be down-regulated or sloughed into circulation. Targets which are readily accessible from the vasculature or peritoneal cavity appear to result in better therapeutic effects. Large solid tumours generally do not respond as well to ligand-targeted liposomes as they do to passively targeted liposomes, perhaps because of the 'binding site barrier' which traps the ligandtargeted liposomes at the tumour exterior, preventing them from penetrating into the tumour interior 1. Targeted liposomal anticancer drugs have resulted in significant improvements over non-targeted therapy in haematological malignancies such as Β cell lymphoma, and in 'adjuvant' models of solid tumours where individual metastatic cells are destroyed by the targeted therapy during migration or just after settling down to form new colonies in sites of metastases'' ^. It appears that targeted liposomal therapy will be most successful when the liposomes have ready access to their target cells. Other improvements in liposome therapy will undoubtedly follow improvements in our understanding of how liposomal drugs are trafficked in cells after different routes of presentation, i.e., free drug versus non-targeted liposomal drug versus targeted liposomal drug (no endocytosis) versus targeted liposomal drug 4

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internalized by receptor-mediated endocytosis ^. An understanding of how different routes of trafficking of liposomal drugs within cells would affect drug resistance mechanisms would, for example, allow a better choice of a liposomal anticancer drug formulation which might overcome drug resistance. Further improvements in the ability of liposomal delivery systems to overcome problems of drug delivery will come with a better understanding of how to optimize the rate of drug release from liposomes for each particular application. For example, for a schedule-dependent anticancer drug being used in the treatment of a cancer with a rapid doubling time (like leukemias), liposomes with very slow rates of drug release are less effective than liposomes with more rapid drug release^. On the other hand, for treating slow-growing solid tumours, the drug should be retained in the liposomes until the liposomes can localize in the tumour by the passive targeting mechanism mentioned above, in order to reduce the distribution of any released drug to normal tissues. Once the liposomal drug localizes to the solid tumour we really don't understand whether it would be better to trigger a rapid burst of drug release within the tumour, or to have a slower sustained release of drug over a period or several weeks, or to have a release rate somewhere in between. In the area of gene delivery using non-viral, liposomal vectors, significant improvements in the transfection ability, stability and pharmacokinetics of the vectors are needed. Currently, other than via injection directly into the target site, there is no way to target gene delivery to selective in vivo targets. Nor do we have a good understanding of how plasmid DNA and asODNs are trafficked within cells once they reach the target cell. If they are delivered to specific cells via receptor-mediated endocytosis, can we find better ways of releasing the material from endosomes before extensive degradation takes place?

Summary Many significant developments have taken place over the last three decades in the field of liposomal drug delivery and several products have reached the clinic in recent years. Liposomes are proving themselves capable of solving a variety of drug delivery problems and their use will continue to grow in the future as many exciting new drugs and genes are being found from the human genome project, combinatorial chemistry, high throughput screening, etc. Many of these drugs will have problems of pharmacokinetics, solubility, toxicity, etc., some of which can be solved by liposomal delivery. The decision of whether to go to a liposomal drug delivery system for a particular drug requires an excellent understanding of the physical properties of the drug to be delivered as well as those of the liposomal carrier and how the two will interact. The effect of liposome association on the pharmacokinetics and biodistribution of the chosen drug must also be well understood. Finally, in order to make the best decisions about drug formulation, we should have a clear appreciation of the biology and physiology of the disease to be treated. Only in the light of this background knowledge can sensible, rational decisions be made about liposomal drug delivery systems which will lead to new clinical products.


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Solving Drug Delivery Problems with Liposomal Carriers - American

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