Inrcmational ournal of Dcrmntolot^y.. Vol No. 1 1., November 1996 REVIEW LIPOSOMES HARRY H.S H A R A T A.M.D.. PH.D.. ANO

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1 Inrcmational ournal of Dcrmntolot^y.. Vol No. 1 1., November 1996 REVIEW LIPOSOMES HARRY H.S H A R A T A.M.D.. PH.D.. ANO KENNETH H.K A T Z, M.D. When liposomes were initially discovered more than 30 years ago, predictions were largely met with skepticism; however, recent advances have allowed the development of liposomes that are potentially medically useful. Systemic and topical drug delivery by liposomes is possible. Although liposomal amphotericin B, a systemic antifungal agent, is the only medical liposomal product commercially available in the United States, there have been considerable advances in liposomal delivery systems with important applications in dermatology. In tbis article, the basic chemistry of liposotnes will be reviewed as well as their potential uses in dermatology. The basic chemistry and a brief overview of methods of preparation will be discussed first. Then we will examine the kinetics of systemic and topical liposomal therapy, as well as hair follicle targeting. Next, the liposomal advances in skin cancer prevention, cancer therapy, and gene therapy will be discussed. Finally, specific liposoma! drugs and drug classes, including topical anesthetics, topical corticosteroids, topical interferon, liposomal amphotericin B, and artificial blood, will be examined. We will not discuss cosmetic applications of liposome preparations.^ CHEMISTRY AND PHARMACOKINETICS What is a Liposome? Alec Bangham discovered liposomes in 1963, wben he demonstrated tbat pbospbolipids in water form closed vesicles.' The liposome consists of one or more lipid bilayer membranes in whicb the fatty acid tails are embedded in the interior and the bydrophilic heads are oriented towards the external aqueous pbase. The lipid bilayers form concentric lamellae, enveloping a series of aqueous compartments (Fig. 1). Altbougb most liposomes are spherical, the lipid composition and tbe method of preparation used determine their final From the Department of Dermatology, University of Wisconsin, Madison Medical School, Madison, Wisconsin. Address for correspondence: Harry H. Sharata, M.D., Ph.D., University of Wisconsin, Dermatology Clinic, 2880 University Avenue, Madison, WI sbape, size, and tbe number of lamellations acbieved. Hydrophilic drugs are encapsulated witbin the inner aqueous compartments, whereas hydrophobic drugs are embedded in tbe pbospholipid bilayer that makes up tbe liposome. Liposomes can be classified as unilamellar or multilamellar, based on the number of concentric lipid bilayers they contain. Tbey can be furtber classified according to size and composition of the lipid bilayers. The lipid cotnposition and tbe method of liposome preparation directly affects drug absorption, distribution, metabolism, and elimination, as well as tbe toxicity profile. Several methods of liposome preparation can be employed. They include: simple mecbanical agitation, sonication, conventional bydration, debydration-rebydration, and reverse-pbase evaporation. Altbough rnost liposomes are spherical, tbe method of preparation used, along with the lipid composition, organic additives, the ph of tbe aqueous solution, and the tetnperature of preparation, all determine the size, shape, and number of lamellae in tbe liposome. Drug incorporation is accomplished by adding hydrophobic drugs to tbe lipid mixture during preparation or adding hydropbilic drugs to the aqueous salt solution during preparation. In tbis fasbion, bydrophobic drugs are incorporated into tbe lipid bilayer and bydrophilic drugs are packaged witbin the interior aqueous compartments. The simple mecbanical agitation method involves mechanical shaking of tbe component lipids and an aqueous salt solution in a flask. This metbod produces a heterogeneous mixture of large multilamellar vesicles of varying sizes. Altbougb it is tbe simplest preparation metbod, it does not produce a uniform liposome size, so tbat it is not an ideal metbod for drug preparation.' Sonication of tbese large multilamellar liposomes can be used to make small unilamellar liposomes of uniform size. Once tbe large multilamellar liposomes are made, they are exposed to prolonged ultrasound radiation that disperses tbem into small unilamellar liposomes. These small liposotnies are tben separated from the large multilamellar liposomes by gel-filtration to provide a homogeneous preparation.' Tbe "film-hydration metbod" involves dissolving the lipids in ati orgatiic solvent wbicb is then allowed to evaporate, leaving a film bebind. Tbe film is tben hydrated by addition of an aqueous salt solution at a tem- 761

2 International Journal of Dermatology Vol. 3.5, No. 11, November 1996 The "reverse-phase-evaporatioti method" is used to prepare large unilamellar liposomes. It involves mixing the lipids, aqueous salt solution, and organic solvents together and sonicating their mixture. After sonication, the solvents and a small quantity of water are removed under nitrogen at a temperature above the phase-transition temperature of the lipids, leaving the large unilamellar liposomes behind.^''' Systemic Liposomal Kinetics The liposomes originally used in medical research were referred to as conventional liposomes. These bad limited medical utility because once tbey were present in the blood stream, they were rapidly phagocytosed by the cells of the reticuloendothelial system (RES).'' Their therapeutic potential was thus confined to diseases affecting the RES (such as lymphomas or parasitic infestations). Today, liposomes can be engineered to minimize the preferential uptake by the RES. This is accomplished by incorporating glycolipids or ethylene glycol into the lipid bilayer, which forms a steric barrier of highly hydrated groups around the liposome. Tbe steric barrier decreases endocytosis by the RES by inhibiting electrostatic and hydrophobic interactions. Furthermore, incorporation of monosialogangliosides, such as GMl, confers a negative surface charge to the liposome and increases its hydrophilicity. The steric barrier and negative surface charge result in a 100-fold increase in blood circulation time.^"** This results in greater and longer lasting circulating drug levels with lower total doses administered. This, in turn, lowers directly the toxicity for drugs with a narrow toxicity index. The size of liposomes affects drug deposition and, in this manner, specific tissues may be targeted. A typical large multilamellar liposome can be as large as 20 pm in diameter, whereas a small unilamellar liposome is typically 0.1 pm to 0.15 pm in diameter.'' In comparison, the typical diameter of an erythrocyte is 7.5 [am, that of a mature melanin granule is 0.4 pm, and an intermediate filament is 0.01 pm (100 A).'" Small liposomes extravasate from capillaries more easily and accumulate in tissues, whereas larger liposomes remain in circulation longer and are taken up by reticuloendothelial cells." After endocytosis by the cells of the RES, there is fusion with intracytoplasmic lysosomes with subsequent release of the drug.'^ In this manner, drugs may be targeted to the RKS. Selective targeting of other tissues has been achieved by incorporation of monoclonal antibodies into the outer lipid membrane of small liposomes. In this manner. Heath et al. have been able specifically to target methotrexate-y-aspartate, an inhibitor of dihydrofolate reductase, to cultured fibroblasts. Although animal studies have not yet been done, one could anticipate introducing intravenous liposomes that extravasate throughout the body, where the antibodies specifically IlllHiuimwm Figure 1. A trilamellar liposome. The lipid bilayers (A) contain the component lipids, organic additives, and hydrophobic drugs. The aqueous inner compartments (B) contain an aqueous salt solution and hydrophilic drugs. The insert depicts the lipid bilayer with the various incorporation sites for drugs or additives. The bilayer consists of amphipathic lipids with the hydrophobic tails buried in the interior and the hydrophilic heads comprising the outer surface. The drugs or additives may be completely contained within the hydrophobic interior of the bilayer, associated with surface hydrophilic heads, intercalated between the lipids traversing both hydrophilic and hydrophobic regions, or free in the aqueous medium. perature above the lipid-pbase-transition temperature. Once hydrated, the film is bomogeneously dispersed using a sonicator to produce multilamellar liposomes.^''' The "dehydration-rehydration method" involves dissolving the lipids in an organic solvent. The solvent is then allowed to evaporate and the resulting film is hydrated in an aqueous salt solution and then dehydrated under a vacuum. Once the solution becomes viscous, water is added in a volume equal to that removed and the rebydrated liposomes are equalibrated at a temperature above the phase-transition temperature prior to storage.''''' 762

3 Shar.ita and Katz attach to the target tissue and cause accumulation of liposomes at the target site.' ' ''' temperature. The increased penetration may be due to a phase transition of the iipid bilayer, in which there is partial melting of the liposome. This would put the drug in direct contact with the stratum corneum, where it penetrates through to the epidermis."" The hydrogen ion content of the liposomal preparation also effects penetration. Basic solutions, with a higher ph, cause deprotonation of the lipid molecules. This increases the interbilayer repulsion and the water solubility of the lipids that, in turn, decreases the chainmelting phase transition temperature. The deprotonated lipids also increase the stability of the liposome in solutioti. There is less liposotnal aggregation and the liposotnes tnay be tnaintained with a smaller diameter; however, the increased stability results in a lower efficiency in membrane fusion and decreases the ability of the liposome to penetrate the stratutn corneutn.-' The manner in which the drug is encapsulated into the liposotne also seems to affect the positioning of the drug and alters the efficiency of drug delivery to the skin. Studies indicate that drug loading by dehydration and subsequent rehydration of the liposome creates a liposome that delivers its drug tnore efficiently than liposomes prepared by other tnethods.-^-'--^ An advantage to topical drug delivery by liposotnes is an increased uptake by the skin without a proportionate increase in systetnic absorption. Less than 0.1% of the applied dose is absorbed into the systemic citculation despite the rapid penetratioti of liposomally prepared drugs into the epidermis. This potentially litnits systemic toxicity. ^'' Topical Liposomal Kinetics The stratutn corneutn is the body's protective layer of skin that prevents the deeper layers frotn dehydrating and external chemicals and bacteria frotn entering the skin. Typically, conventional dosage forms, such as solutions, creams, and ointments, deliver drugs in a concentration-dependent manner following Fick's law of passive diffusion across the dead stratum corneum. Multilatnellar liposomes can deliver drugs within 30 minutes to the stratum corneum, epidermis, and dermis in significantly higher concentrations than conventional preparations. For example, dertnal drug levels delivered by liposomal hydrocortisone are 9 to 14 times higher than after exposure to conventional hydrocortisone preparations.''''"' Observations of penetration of radiolabeled liposomes through pig and mouse skin have showti that the ratio of radiolabeled lipids changes frotn the stratum corneum to the deeper epidermis. This suggests that the liposomal lipid assembly disaggregates in the stratum corneum and the component lipids diffuse independently into the deeper layers of the skin. Independent diffusion would be anticipated when the lipids are released frotn the liposome, because of the variable polarity of lipids.'^ The drug is delivered to the deeper epidertnal layers through dehydration of the liposomes within the stratum cortieutn. Paradoxically, wlieti larger quatitities or higher concentrations of liposomes are applied, there is a decrease in the atnount of drug that penetrates to the deeper layers of skin. A possible explanation for this is, that liposotne uptake is driven by the hydration gradient that exists across the epidermis, stratum corneum, and ambient attnosphere.'^ In this tnanner, a thinly applied film with a lower concentration of liposotnes may penetrate faster and to a greater extent than a thicker, more concentrated, layer. The less concentrated liposome film will dehydrate faster and thus be driven across the hydration gradient faster than the more concentrated preparation.-''"* In support of this explanatioti is the observation that occlusion results in less drug absorption due to abolition of the hydration gradient.'** The melting point of the lipids contained in the liposome also affects the depth of penetration. Higher concentrations of long-chain alcohols in the hydrophilic:hydrophobic interface decrease the transition temperature of the lipid chain-melting phas.e by partitioning the head group region and altering the phospholipid interdigitation.'' Liposomal formulations, using glyceryl dilaurate in the lipid bilayer, are able to deposit ten times as much drug in the deeper layers of the epidermis than the statidard topical liposomal preparations. The glyceryl dilaurate has a melting temperature of 30 C, which is just below the normal skin Hair Follicle and Pilosebaceons Targeting Many drugs are absorbed to a greater extent from areas of skin with large or great numbers of hair follicles because the drugs are shunted through the pilosebaceous unit (Fig. 2).-^^"^^ Multilatnellar liposotnes have an even greater ability to penetrate the skin through these follicular orifices.^** The lipids that form the bilayer tnetnbrane do not show any increased penetration when they are applied as a simple emulsion, but only when they are organized as latnellar assetnblies. Liposotnal preparations enhance drug delivery to the follicle five to eight times over standard aqueous preparations.-' Variations in the size and lipid cotnposition of the liposotne can affect whether absorption retnains at the upper layers of the skin or in the liposome when it petietrates to the base of the hair follicle.'" The preferential absorption of tnultilatnellar liposomes into the pilosebaceous unit can be exploited to target hair follicles and sebaceous glands. Recently, the delivery of intact DNA to the hair follicle and evidence for active getie transfer into the hair shaft atid follicles have been detnonstrated in tissue cultures of skin." Melanin can also be delivered specifically to hair follicles. When tnelanin is entrapped in a phosphatidyl763

4 International lonrnal ot Derilintoiogy Vol. 35. No. II, November 1996 ases. Tberefore, tbey are unable to excise tbe cyclobutane-pyrimidine dimers that accumulate witb ultraviolet ligbt exposure. Tbese patients develop many cutaneous, ocular, and neurologic abnormalities of a higher incidence than the rest of tbe population. One balf of tbe patients with xeroderma pigmentosum will develop a skin cancer, predominantly in sun-exposed areas, by age 10 years. This is 50 years before the remainder of tbe population will do so.'"* Endonuclease V is an enzyme produced by tbe denv gene of bacteriophage T4. The purified product, T4-endonuclease V, produces single-stranded breaks in DNA at cyclobutane dimers by cleaving the N-glycosyl bond on tbe 5'-side of the dimer. Tbe pbosphodiester bond between tbe two pyrimidines is tben cleaved and the DNA strand is returned to tbe state before ultraviolet irradiation.-'^ Tbe T4-endonuclease V can be entrapped in botb positively and negatively charged liposornes and delivered in its active form to normal persons and to keratinocytes in culture of patients witb xeroderma pigtnentosum, to buman skin explants, and to live mice."' In the recipients of liposomal T4-endonuclease V, there is an increase in DNA synthesis and increased excision and repair of cyclobutane-pyrimidine dimers. Liposomal delivery of the enzyme is far more efficient tban cell transfection or permeabilization.^'''"* The liposome applied topically penetrates tbe stratum corneum and the epidermis of murine skin. Both tbe liposome and tbe enzyme can be found in basal keratinocytes.^''' Wben it is applied to tbe skin of mice irradiated witb UV rays, there is a dose-depetidetit decrease in the number of cyclobutane-pyrimidine dimers and a subsequent 45% decrease in the incidence of skin cancer.^'* Figure 2. Many drugs, including liposomes, are preferentially shunted down hair follicles (A), where the absorption is greatest. Shunting occurs to a lesser extent through eccrine sweat glands (B). The transdermal route (C) is the least efficient for drug delivery. choline liposome, tbe liposome penetrates tbe pilosebaceous unit and deposits the melanin botb at tbe periphery of tbe follicles and within the follicle cells themselves. Microscopic examination of tbe hair sbaft of white-baired mice treated witb liposomal melanin demonstrated a band-like melanin-distribution pattern, similar to the melanin-distribution pattern that is seen in bair colored by endogenously produced melanin. Thus, in addition to deposition of the melanin witbin the hair follicle and sbaft, tbe normal pattern of melanin distribution is replicated by liposomal delivery of melanin.'^ Cancer Therapy Liposomes have bad a significant impact on research in cancer treatment. Liposomes can be used to alter tbe molecular makeup of tumor cells to make tbem tnore accessible to tbe body's own immune.system. They can be used to target tumors for systemic cbemotberapeutic agents preferentially, increasing tbeir therapeutic index. Thus, efficacy can be enhanced, wbereas toxicity is decreased by using liposomal drug preparations, such as liposomal vincristine.""' Finally, liposomes can be used to protect against common side effects of chemotberapy. Genes for human transplantation-antigens can be packaged within liposomes and injected directly into rnalignant melanoma nodules, wbere the genes are taken up and actively expressed by the local tumor cells. In a human clinical trial, five HLA-B7-negative patients witb stage IV melanoma, refractory to conventional treatment, had one to three of tbeir melanoma nodules injected with liposomes containing tbe gene encoding tbe HLA-B7 tnajor histocompatibility-cotiiplex protein. Immunochemical staining of injected nodules confirtned tbat tbe HLA-B7 protein was actively ex- SELECTED CLINICAL Al'PLICATlONS Prevention of Skin Cancer Exposure to ultraviolet (uv) ligbt has clearly been linked to tbe development of skin cancer in bumans. Ultraviolet radiation causes tbe formation of cyclobutane-pyrimidine dimers in tbe DNA. These dimers are tbe initial molecular change tbat ultimately leads to tbe carcinogenic transformation of tbe cell." Most people are able to repair most of the DNA damage witb excision-repair endonucleases and, therefore, develop only very few skin cancers. Patients with xeroderma pigmentosum and animal models have deficiencies in excision-repair endonucle764

5 Lipo.somes Sharata and Katz pressed by cells of the injected melatioma nodule. Analysis using PCR sensitive to < 2 pg per nil, failed to detect atiy uptake of the liposomal DNA into tbe systemic circulation. No anti-dna antibodies or evidence of systetnic toxicity were observed. One of tbe five patients treated, had a complete regression of the treated nodules as well as regression of several distant, untreated nodules. A possible explanation is, that tbe transplantatioti antigens expressed oti the tumor cells allow tbe patient's immune system to recognize them as foreign and to attack tbe tumor successfully. Tbe regressioti of untreated nodules suggests that the immune response triggered by the treated nodule also enhances tbe immune response to otber antigens of the tnelanoma tumor.*" Early attempts at developing tumor vaccines were largely unsuccessful, because tutnor atitigetis are processed in association with MHC class II tnolecules. Thus, tbey generate an antibody response ratber tban activate cytotoxic T lympbocytes that can attack tbe tumor tnore aggressively. Tumor specific antigens prepared in liposomes are engulfed by macropbages and processed witb MHC class I that activates cytotoxic T lymphocytes. In studies on muritie tbytnoma, injection of liposomes containing thymoma proteitis resulted in tbe regression or elimitiation of the tumors with the corresponding surface antigens.''^ Tumors tend to have ati increased vascularity cotnpared witb normal surrounding tissue and the capillaries witbin tumors tend to be "leakier" than normal capillaries. This altered vascularity of tutnors allows increased transcytosis and extravasation of small liposomes from the blood stream causing the liposomes to localize in skin tutnors as well as in the surrounding normal skin. The liposotnes are found both free in nbrmal skin, in the tumor, and in the endosotnes and lysosomes of perivascular macropbages. The localization of liposomes within tumors allows a lower administered dose to getierate an equal tberapeutic effect. Studies in transgenic mice that develop a Kaposi's sarcoma-like dertnal lesioti have cotifirmed tbat sterically stabilized liposomes localize in early and tnature Kaposi-like lesions as well as in the surrounding tissue.**' Using a microwave device, topical hyperthertnia can enhance the release of drugs encapsulated in liposomes in the skin or subcutaneous tissue.'''* Wben solid pbase pbospholipids and cholesterol constitute more than half of the liposomal membrane, the resulting liposomes release significantly more drug at 42 C than at 37 C.''' The local hyperthertnia also increases vascular permeability, allowitig for increased extravasation and deposition of the drug in tbe heated tissue.'*'' Furthermore, tutnors, especially those in skiti and muscle, tend to heat more rapidly than the surrounding nortnal tissues.''^ These characteristics of local hyperthermia and liposomes lead to an increased accutnulation of liposomes at the targeted tissue as well as an enhanced release of tbe drug at that site.'*'* Anagen effluvium is a cotnmon and unpleasant side effect of many cancer chemotherapeutic drugs. A monoclonal antibody to doxoruhicin, wben packaged iti a tnultilamellar liposome and applied to bairy areas, delivers active antibody to tbe hair follicle and the surroutiditig epidertnis. Tbe antibody acts locally to bind doxorubicin and inliibit its effect on tbe bair follicle. The presetice of tbe atitidoxorubiciti antibody, surrounding tbe bair follicle at the titne of peak systetnic doxorubicin levels, prevents drug-induced alopecia in anitnal tnodels."*** Gene Therapy Liposomes can be used for topical and systetnic gene therapy; they can be designed to transfer active, intact DNA specifically to bair follicles atid cati deliver genes to correct tbe deficiency iti respiratory epithelial chloride tratisport iti cystic fibrosis. The reticuloetidothelial systetn and hetnatopoietic cells of the bone tnarrow can also be targeted for gene therapy. Topical gene transfer to hair follicles also has been accotnplished. Lecithin-containing liposomes can be used to entrap high-molecular-weight DNA. Tbe entraptnent within the liposotne protects tbe DNA from naturally occurring DNase present in tbe skin. Tbis allows the DNA to penetrate to its target and be incorporated witbout degradation. *'' In bistocultured skin, the lecithin liposomal DNA preparations are preferentially shunted down the pilosebaceous utiit, wbere tbey actively and specifically tratisfer the geties to the hair follicles.-" "'" Topical gene transfer to respiratory epithelial cells has also been accomplished. Patients with cystic fibrosis bave a defect in camp-regulated Cl"-cbannels on tbe apical aspect of respiratory and ititestinal epithelial cells as well as in the sweat glands. Respiratory cotnplications are the tnajor cause of fatality iti tbese patietits. The gene CFTR eticodes tbe proteitis that cotnprise tbe cami>-regulated Cl"channels. The CFTR DNA cat! be incorporated into a liposotne atid be actively transferred to respiratory epithelial cells. Wben applied to the nasal epithelium of patients with cystic fibrosis, tbere is a 20% restoratioti of futictioti of the camp-regulated Cl"-channels without any toxicity; however, the effect is confitied to the area of spray application iti the airway. Further studies are needed to assess whether the entire respiratory epithelium can be treated.^' Tbe immune system can be targeted for systemic getie therapy. Liposomes containing DNA can be injected intraperitoneally. Following drainage by the lytnphatic capillaries, the liposotnes are delivered to T lytnphocytes located in lytnpb nodes and spleen that phagocytose the liposomes and incorporate the active DNA. This delivery systetn also tratisfects active DNA into the hetnatopoietic cells of the bone tnarrow. There is no systetnic toxicity associated witb this procedure. This has been accotnplished in a tnurine tnodel. Thus, 765

6 Inrcrnaticiiial joiunal of DerniiUology Vol. 35, No. 1 1, November l'j9f, liposomal DNA potentially provides an effective and safe mechanism for the delivery of genes to the reticuloendothelial system.^^ employing penetration enhancers such as urea.''''''' The increased epidermal and dermal concentrations delivered by liposomal hydrocortisone preparations have the potential advantage of lower toxicity with enhanced efficacy.'''' SELECTED THERAPEUTIC AGENTS Topical Interferon Topical Anesthesia The incidence of herpes simplex infection in the United States is 10% per year.'''' Potentially, interferon is able to prevent herpes simplex from occurring. In a randomized, double-blind, placebo-controlled study of 76 patients with severe recurrent herpes simplex infections, those treated with interferon-ai, 3 x 1 0 ' ' IU subcutaneously three times per week, had 33% fewer occurrences, milder symptoms, a 25% faster resolution of an episode, and an 8 1 % longer interval between episodes. A lower dose of 1 x 10'' lu subcutaneously, three times per week, was not significantly effective. Unfortunately, the higher, effective dose caused severe adverse effects in 35% of patients and moderately adverse effects in 48% of patients. The adverse effects included malaise, fever, myalgia, arthralgia, and fatigue, despite administration of acetaminophen, 650 mg every 4 hours. The patients also developed a mild reversible leukopenia with a 33% decrease in granulocyte counts and a 20% decrease in lymphocyte counts.'''' A second study of 69 women with recurrent herpes simplex infection confirmed the above results. The women treated with 5 x 10'' IU per kg subcutaneously for 12 doses over 14 days had a decrease in the size of their lesions, but also had a moderate but reversible neutropenia.''" The relatively severe adverse effects of subcutaneously injected interferon make it unsuitable for the general treatment of herpes simplex infections. Local anesthetics are commonly used in dermatologic surgery, but the potent anesthetic effect is preceded by the pain of injection. The eutectic mixture of lidocaine and prilocaine is the only effective transcutaneously absorbed local anesthetic currently available in the United States. It requires application with occlusion 1 hour prior to the procedure with only a mild anesthetic effect. An injection of local lidocaine through the mildly anesthetized area is usually required before the procedure. Thus, it is not very practical in an outpatient dermatologic practice. Liposomal anesthetics can provide reliable, deep anesthesia without injection by needle. Liposomal tetracaine can be applied 1 hour prior to a procedure without occlusion and will provide sufficient, local anesthesia at the site of removal of a skin lesion or for minor plastic surgery. Although the onset is slow, there is deep anesthesia that lasts for more than 4 hours.'' A second effective topical anesthetic is a lipid-detergent liposomal variation encapsulating lidocaine. This preparation provides reliable, deep, local anesthesia at the site of application within 15 minutes after application; however, the effect is not persistent and diminishes after about 30 minutes. This may be sufficiently long to perform punch and shave biopsies or for venipuncture. For longer procedures, repeated drug applications would be required.'''' The aim of topical therapy is to achieve adequate drug levels in the stratum basale of the epidermis where the active herpetic infection takes place. Topical application of standard interferon solution or emulsion does not offer any benefits in the treatment of herpes simplex due to the low extent of absorption. Interferon encapsulated in liposomes, consisting of lipids in concentrations similar to those found in the stratum corneum, is delivered in substantial quantities to the epidermis. This results in a reduction in the number of herpetic vesicles that develop in hamsters inoculated with the herpes simplex virus.^^ This may provide a safe and effective mechanism for topical treatment of herpes simplex. Topical Corticosteroids Hydrocortisone and other corticosteroids are the therapeutic workhorses of dermatology. High-potency corticosteroids are very effective in modulating inflammatory responses; however, their long-term application is limited by their local and systemic side effects such as atrophy of the skin,'-''^^ formation of striae,'^ purpura,'''*"'' glaucoma, cataracts,^" suppression of the hypothalamicpituitary-adrenal axis,'"'-''^ and even avascular necrosis of the femur.''" Although hydrocortisone is safer than fluorinated corticosteroids for long-term therapy, its low potency is often inadequate to treat moderate or severe inflammatory reactions. The penetration kinetics of hydrocortisone are greatly enhanced by encapsulating it in liposomes.''-' Liposomal hydrocortisone preparations provide drug concentrations that are 8 to 14 times higher in the epidermis and dermis than supplied by conventional topical hydrocortisone preparations.'''' This effect is even more dramatic than those of hydrocortisone creams Liposomal Amphotericin B Amphotericin B preferentially binds to ergosterol found in fungal membranes and disrupts the integrity of cells. This potent fungal cytotoxic effect makes it the drug of choice for most serious fungal infections. Its major limitations are its toxicity, including chills, fever, and nephrotoxicity that frequently necessitate early discontinuation of the drug; however, amphotericin B can be 766

7 Liposomes Sharata and Katz incorporated into stnall unilamellar liposotnes. In this fortn, it is better tolerated by patients with very few of them developing fever and chills.*'-^" Liposotnal amphotericin B provides sustained serum concentrations as tnuch as five times higher with a longer half-life than conventional amphotericin B'.''' Despite daily doses ranging from 4 to 6 mg per kg and higher serum concentrations, the toxicity to brain, kidney, and heart is significantly lower.^ '''-'^^ The liposotnal forrn remains highly effective in treating systemic fungal infections with response rates of nearly 60% in treating invasive aspergillosis and systetnic candidosis.^'* Artificial Blood A novel applicatioti of liposomes is their encapsulating hemoglobin to fortn neohemocytes. These are made large enough that they do not extravasate, but stnall enough that they can pass through nortnal and slightly constricted capillaries. In animal experiments, nearly 50% of atiitnals survived a 95% exchange transfusion replacing their blood with neohetnocytes. The neohemocytes do not cause any acute toxicity and have the obvious advantages of prolonged shelf-life and a decreased risk of viral transmission. These appear to be an ideal substitute for red blood cells in the treatment of trauma.^' CONCLUSIONS Liposomal technology is advancing rapidly and promises to deliver tnajor advances in many tnedical fieldst In dermatology, we can anticipate drugs to help prevent and treat skin cancer tnore effectively. We tnay see drugs specifically targeted to hair follicles and sebaceous glands. Gene therapy tnay be used to alter hair growth. Effective topical anesthetics have been developed, as well as corticosteroids with enhanced efficacy and reduced toxicity. We may have a safe, effective topical treatment for herpes simplex. Although liposomal atnphotericin B is the only cotntnercially available product in the United States, tbe future clearly holds many applications for liposomes in dertnatology. DRUG NAMES The eutectic mixture of lidocaine and prilocaine is EMLA cream. Liposomal Amphotericin B is Ambisone. REFERENCES 1. Baiigliatii AD. Physical structure atid behavior of lipids and lipid enzytnes. Adv Lipid Res 1963; 1: Papahdjopoulos D. Phospholipid vesicles as models for biological tnetnbranes: their properties and interactions with cholesterol and proteins. Prog Surface Sci 1973; 4: Gregoriadis G, ed. Technology for tnonitoring topically applied liposotiies. Liposome technology. 2nd Ed. London: GRG Press, 1993: Kittayanoiid D, Ratiiachandran G, Weincr N. Developtiieut of a model of the lipid constituent phase of the stratutn corneutn: 1. preparation and characterization of "skin lipid" liposotnes using synthetic lipids. J Soc Gostnct Ghetn 1992; 43: Alving GR. Immunologic aspects of liposotnes: presentation and processitig of liposotnal protein atid phospholipid antigetis. Biochim Biophys Actn 1992; 1113: Alleti TM, Ghonn A. Large unilamclhir liposotnes with low uptake into the reticulocndothclial sysretn. FEBS Lett 1987; 223: Gabizon A, Papahdjopoulos D. Liposome formulations with prolotiged circulation titne in blood and enhanced uptake by tutnors. Proc Natl Acad Sci USA 1988; 85: Lasic DD, Martin FJ, Gabizon A. Sterically stabilized liposomes: a hypothesis on the molecular origin of extended circulation titnes. Biochitn Biophys Acta 1991; 1070: Jatikncgr R, de Marie S, Bakker-Woudetiberg IA, Grotntnelin DJ. Liposomal and lipid fortnulations of atnphotericin B. Glin Phartnncokiner 1992; 23: Junqueira LG, Garneiro J, Kelley RO, eds. Basic histology. 7th Ed. Norvvalk CT: Appleton & Lange, 1992; 235: Hwang KJ, Padki MM, Ghow DD, et al. Uptake of small liposotnes by nonreticuloendothelial tissues. Biochitn Biophys Acta 1987; 901: Schafcr-Korting M, Korting HG, Braun-Falco O. Liposotne preparations: a step forward in topical drug therapy for skin disease? Am Acad Dertnatol 1989; 21: Heath TD, Fraley RT, Papahdjopoulos D. Antibody targctitig of liposotnes: cell specificity obtaitied hy conjugatioti of F(ah')2 to vesicle surface. Science 1980; 210: Heath TD, Bragman KS, Matthay KK, et al. Antibodydirected liposomes: the development of a cell-specific cytotoxic agent. Biochem Soc Traus 1984; 12: Du PIcssis J, Egbaria K, Weincr N. Influctice of fortnulation factors on the deposition of liposotnal components into the different strata of the skin, j Soc Gostnct Ghem 1992; 43: Lasch J, Laub R, Wohlrab W. How deep do intact liposotnes penetrate into human skin. J Gontrolled Release 1991; 18: Gevc G, Blutne G. Lipid vesicles penetrate into ititact skin owing to the transdertnal osmotic gradients and hydration force. Biochitn Biophys Acta 1992; 1104: Nietniec SM, Hti Z, Ratnachandran G, et al. The effect of dosing volutne on the disposition of cyclosporin A in hairless mouse skin after topical application of a nonionic liposomal fortnulation. An in vitro diffusion study. S.T.P. Phartna Science 1994; 4:

8 International Journal of Dermatology Vol..15, No. I 1, November Lobbecke L, Ccvc G. Effects of short chain alcohols on the phase behavior and interdigitation of phosphatidylcholine bilaycr membranes. Biochim Biophys Acta 1995; 1237: Dowton SM, Hii Z, Ramachandran C, et al. Influence of liposomal composition on topical delivery of encapsulated cyclosporin A. 1. An in vitro study using hairless mouse skin. S.T.P. Pharma Sciences 1993; 3: Zellmer S, Cevc G, Risse P. Temperature and ph controlled fusion between complex lipid membranes. Examples with the diacylphosphatidylcholine/fatty acid mixed liposomes. Biochim Biophys Acta 1994; 1196: Weiner N, Williams N, Birch G, et al. Topical delivery of liposomally encapsulated interferon evaluated in a cutaneous herpes guinea pig model. Antimicrob Agents Chemother 1989; 33: Weiner N, Egbaria K, Ramachandran C. Topical delivery of liposomally encapsulated interferon evaluated by in vitro diffusion studies and in a cutaneous herpes guinea pig model. In: Braun-Faico O, ed. Liposome dermatics. Berlin: Springer-Verlag, 1992: Yarosh D, Alas LG, Yee V, et al. Pyrimidine dimer removal enhanced by DNA repair liposomes reduces the incidence of uv skin cancer in mice. Cancer Res I 992; 52: Feldmann RJ, Maibach HI. Regional variation in percutaneous penetration of '''G-cortisol in man. J Invest Dermatol 1967; 48: Maibach HI, Feldmann RJ, Hilby TH, Serat WF. Regional variation in percutaneous penetration in man. Arch Environ Health 1 971; 23: Illel B, Schaefer H. Transfollicular percutaneous absorption. Acta Derm Venereol (Stockh) 1988; 68:427^30. Lieb LM, Ramachandran G, Egbaria K, Weiner N. Topical delivery enhancement with multilamellar liposomes into pilosebaceous units: 1. In vitro evaluation using fluorescent techniques with the hamster ear model. J Invest Dermatol 1992; 99: Lieb L]VI, Ramachandran G, Weiner N. Liposomally encapsulated active ingredients penetrate through the follicle. Liposome dermatics. Berlin: Springer-Verlag, 1992: Li L, Lishko V, Margolis L, Hoffman R. Product-delivering liposomes specifically target hair follicles in histocultured intact skin. In Vitro Gell Dev Biol 1992; 28A: Li L, Hoffman RM. Model of selective gene therapy of hair growth: liposome targeting of the active lac-z gene to hair follicles of histoculture skin. In Vitro Gell Dev Biol 1995;3IA:1]-13. Li L, Hoffman R, Lishko V. Liposomes can specifically target entrapped melanin to hair follicles in histocultured skin. In Vitro Gell Dev Biol 1993; 29A:I Hart RW, Setlow RB, Woodhead AD. Evidence that pyrimidine dimers in DNA can give rise to tumors. Proc Natl Acad Sci USA 1977; 74: Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Arch Dermatol 1987; 123: Dodson ML, Lloyd RS. Structure-function studies of the T4 endonuclease V repair enzyme. Mutat Res 1989; 218: Geccoli j, Rosales N, Tsimis J, Yarosh DB. Encapsula tion of the Liv-DNA repair enzyme T4 endonuclease V in liposomes and delivery to human cells. J Invest Dermatol 1989; 93: Kibitel jt, Yee V, Yarosh DB. Enhancement of ultraviolet-dna repair in denv gene transfectants and T4 endonuclease V-liposome recipients. Photochem Pbotobiol 1991; 54: Yarosh DB, Kibitel JT, Green LA, Spinowitz A. Enhanced unscheduled DNA synthesis in uv-irradiated human skin explants treated with T4N5 liposomes. J Invest Dermatol 1991; 97: Yarosh D, Bucana G, Gox P, et al. Localization of liposomes containing a DNA repair enzyme in murine skin. J Invest Dermatol 1994; 103:1-8. Boman NL, Masin D, Mayer LD, et al. Liposomal vincristine which exhibits increased drug retention and increased circulation longevity cures mice bearing P388 tumors. Gancer Res 1994; 54: Nabel Gj, Nabel EG, Yang Z, et al. Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci USA 1993; 90: Zhou F, Rouse BT, Huang L. Prolonged survival of thymoma-hearing mice after vaccination with a soluble protein antigen entrapped in liposomes: a model study. Gancer Res 1992; 52: Huang SK, Martin FJ, Jay G, et al. Extravasation and transcytosis of liposomes in Kaposi's sarcoma-like dermal lesions of transgenic mice bearing the IIIV tat gene. AmJ Pathol 1993; 143: Huang SK, Stauffer PR, Hong K, et al. Liposomes and hyperthermia in mice: increased tumor uptake and therapeutic efficacy of doxorubicin in sterically stabilized liposomes. Gancer Res 1 994; 54: Huang SK, Mayhew E, Gilani S, et al. Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing G-26 colon carcinoma. Gancer Res 1992; 52: Gope DA, Dewhirst MW, Friedman HS, et al. Enhanced delivery of a monoclonal antibody F(ab')2 fragment to subcutaneous human glioma xenografts using local hyperthermia. Gancer Res 1990; 50: Reinholt HS, Endrich B. Tumour microcirculation as a target for hyperthermia. Int J Hyperthermia 1986; 2: I I Balsari AL, Morelli D, Menard S, et al. Protection against doxorubicin-induced alopecia in rats by liposome-entrapped monoclonal antibodies. FASEB J 1994; 8: Hoffman R, Margolis L, Bergelson L. Binding and entrapment of high molecular weight DNA by lecithin liposomes. FEBS Lett 1978; 93: Li L, Hoffman RM, Lishko V. Liposome targeting of high-molecular-weight DNA to the hair follicles of histocultured skin: a model for gene therapy of the hair growth process. In Vitro Gell Dev Biol 1993; 29A: Gaplen NJ, Alton EW, Middleton PG, et al. Liposomemediated CFTK gene transfer to the nasal epithelium of patients with cystic fibrosis. Nature Medicine 1995; 1: Philip R, Liggitt D, Philip M, et al. In vivo gene delivery. J Biol Ghem 1993; 268:

9 Liposonu's Sharata and Katz 53. Gesztes A, Mezei M. Topical anesthesia of the skin by liposome-encapsulated tetracaine. Ancsth Anaig 1988; 67: Planas ME, Gotizalcz P, Rodriguez L, et nl. Noninvasive pei'cutatieous induction of topical analgesia by a new type of drug carrier, atid prolongation of local pain insensitivity by anesthetic liposotnes. Anesrh Analg 1992; 75: Lauker RM, Kaidbey K, Leyden JJ. Effects of topical ammonium lactate on cutaneous atrophy from a potent topical corticosteroid. [ Am Acad Dermntol I 992; 26: Jatnes MP, Black MM, Sparkes CG. Measurement of dertnal atrophy induced by topical steroids using a radiographic technique. BrJ Dermatol 1977; 96: Barkley WF. Striae and persistent tinea corporis related to prolonged use of betamethasone dipropionate 0.05% creatn/clotritnnzole 1% cream (lotrisone cream). ] Am Acad Dertnatol 1987; 17: Degreef H, Doonis-Goossens A. The new corticosteroids: are they safe? Dermatol Clin 1993; 11: Barnetson RS, White AD. The use of corticosteroids in dermatological practice. Med J Aust 1992; 156: McLean CJ, Lobo RD, Brazier DJ. Cataracts, glaucoma, and femoral avascular necrosis caused by topical corticosteroid ointment. Lancet 1995; 345: Katz HI, Hein NT, Prawer SE, et al. Superpotent topical steroid treattnent of psoriasis vulgaris clinical efficacy and adrenal function. J Atn Acad Dertnatol 1987; 16: Feiwel M, Jatnes VHT, Barnett ES. Effect of potent topical steroids on plasma cortisol levels in infants and children with eczetna. Lancet 1969; i: Lasch J, Wohlrab W. Liposome-bound cortisol: a new approach to cutaneous therapy. Bionied Biochim Acta 1986; 45: Wohlrab W, Lasch J. Penetration kinetics of liposo'tnal hydrocortisone in human skin. Derniatologic;i 1987; 174: Wohlrab W. The influetice of urea on the penetration kinetics of topically applied corticosteroids. Acta Denn Venereol (Stockh) 1984; 64: Munoz A, Schrager LK, Bacellar H, et al. Trends in the incidence of outcomes defining acquired immunodeficiency syndrotne in the tnulticenter AIDS cohort study. Am J Epidertniol 1993; 137: Kuhls TL, Sacher J, Pineda E, et al. Suppression of recurrent genital herpes simplex virus infection with recotnhinant alpha 2 interferon. J Infect Dis 1986; 154: Pazin GG, Harger JH, Arnistron JA, et al. Leukocyte interferon for treating first episodes of genital herpes in women. J Infect Dis 1987; 156: Gokhale PC, Barapatrc Rj, Advatii SH, et al. Phartiiacokitictics atid tolerance of liposomal amphotericin B in patients. J Antitnicroh Chetnother 1993; 32: Zoubek A, Etntninger W, Emminger-Schmidmeier W, et al. Conventional vs liposoninl atnphotericin B in imiinitiosuppressed children. Pediatr Heniatol Oncol 1992; 9: Proffitt RT, Satorius A, Chiang SM, et al. Phannacology and toxicology of a liposomal formulation of amphotericin B (ambisonie) iti rodents. Antitnicrob Agents Chemother 1989; 33: Schurmann D, de Matos MB, Grunewald T, et al. Safety and efficacy of liposotnal amphotericin B in treating AlDS-associated dissetninated cryptococcosis. J Infect Dis 1991; 164: Coker RJ, Viviani M, Gazzard BG, et al. Treattnent of cryptococcosis with liposotnal amphotericin B (anibisome) in 23 patients with AIDS. AIDS 1993; 7: Ng TT, Denning DW. Liposotnal atnphotericin B (atii- Bisotiie) therapy in itivasive fungal infections. Atch Intern Med 1995; 155: Hunt CA, Burnette RR, MacGregor RD, et al. Synthesis nnd evahiation of a prototypal artificial red cell. Science 1985; 230: No. Ht n , Hm. From the collection of the Indiana Medical History Museum, Katherine McDonnell, Director, Indianapolis, Indiana. 769

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