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1

Liposomal drug delivery, a novel approach: PLARosomes.

100%

Kozubek A., Gubernator J., Przeworska E., Stasiuk M.

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2000

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vol. 47

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issue 3

639-649

EN

Almost from the time of their rediscovery in the 60's and the demonstration of their entrapment potential, liposomal vesicles have drawn attention of researchers as potential carriers of various bioactive molecules that could be used for therapeutic applications in humans and animals. Several commercial liposome-based drugs have already been discovered, registered and introduced with great success on the pharmaceutical market. However, further studies, focusing on the elaboration of more efficient and stable amphiphile-based vesicular (or non-viral) drug carriers are still under investigation. In this review we present the achievements of our group in this field. We have discovered that natural amphiphilic dihydroxyphenols and their semisynthetic derivatives are promising additives to liposomal lipid compositions. The presence of these compounds in lipid composition enhances liposomal drug encapsulation, reduces the amount of the lipid carrier necessary for efficient entrapment of anthracycline drugs by a factor of two, stabilizes liposomal formulation of the drug (both in suspension and in a lyophilized powder), does not influence liposomal fate in the blood circulation system and benefits from other biological activities of their resorcinolic lipid modifiers.

2

Combination of combretastatin A4 phosphate and doxorubicin-containing liposomes affects growth of B16-F10 tumors

100%

Mitrus I., Sochanik A., Cichoń T., Szala S.

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issue 1

161-165

EN

The study aimed to check the effectiveness of anticancer therapy combining a vascular-disruptive drug (combretastatin phosphate, CA4P) and a liposomal formulation of a chemotherapeutic (doxorubicin). CA4P was synthesized in our laboratory according to a previously described procedure. The antivascular drug and long-circulating doxorubicin-loaded liposomes were used to treat B16-F10 murine melanoma experimental tumors. Seventy-four hours after drug administration, a decrease in the number of tumor blood vessels was apparent and necrotic areas within tumors were visible. Combination therapy consisting of alternate administrations of CA4P and liposomal doxorubicin yielded greater inhibition of tumor growth than monotherapies alone. The best therapeutic results were obtained with the antivascular drug administered intratumorally every second day at 50 mg/kg body mass. In the case of combined therapy, the best results were obtained when the vascular-disruptive agent (CA4P) and the antineoplastic agent (liposomal doxorubicin) were administered in alternation.

3

Antitumoral effect of IL-12 gene transfected via liposomes into B16F0 cells

88%

Speroni L., Gasparri J., Bustuoabad V. d. l. A., Chiaramoni N. S., Smagur A., Szala S., Taira M. C., Alonso S. d. V.

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issue 2

249-253

EN

Murine melanoma B16F0 cells were transfected with SA:DPPC:DOPE (2:1:1 molar ratio) liposomes associated with a plasmid encoding murine IL-12. Stearylamine, a cationic lipid, showed a greater transfection efficiency compared to DOTAP-containing liposomes. The lipid:DNA ratio was 2:1 (w/w). Control groups were mock transfected or transfected with an empty plasmid (pNeo). pNeo or IL-12 transfected cells and controls were inoculated intradermically into the dorsal region of the foot or the lateral flank of C57BL6 mice. Results showed that IL-12 expression had a marked effect on in vivo growth of B16 melanoma tumors developed in both anatomic sites, significantly retarding their growth and prolonging host survival.

4

Vehicles for Small Interfering RNA transfection: ExosomesversusSynthetic Nanocarriers

88%

Duechler M.

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issue 1

EN

Therapies based on RNA interference (RNAi) hold a great potential for targeted interference of the expression of specific genes. Small-interfering RNAs (siRNA) and micro-RNAs interrupt protein synthesis by inducing the degradation of messenger RNAs or by blocking their translation. RNAibased therapies can modulate the expression of otherwise undruggable target proteins. Full exploitation of RNAi for medical purposes depends on efficient and safe methods for delivery of small RNAs to the target cells. Tremendous effort has gone into the development of synthetic carriers to meet all requirements for efficient delivery of nucleic acids into particular tissues. Recently, exosomes unveiled their function as a natural communication system which can be utilized for the transport of small RNAs into target cells. In this review, the capabilities of exosomes as delivery vehicles for small RNAs are compared to synthetic carrier systems. The step by step requirements for efficient transfection are considered: production of the vehicle, RNA loading, protection against degradation, lack of immunogenicity, targeting possibilities, cellular uptake, cytotoxicity, RNA release into the cytoplasm and gene silencing efficiency. An exosomebased siRNA delivery system shows many advantages over conventional transfection agents, however, some crucial issues need further optimization before broad clinical application can be realized.

5

Facilitated diffusion of glucosamine-6-phosphate synthase inhibitors enhances their antifungal activity.

88%

Janiak A., Cybulska B., Szlinder-Richter J., Borowski E., Milewski S.

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2002

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vol. 49

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issue 1

77-86

EN

N3-(4-Methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) and 2-amino-2-deoxy-D-glucitol-6-phosphate (ADGP) are strong inhibitors of the essential fungal enzyme, glucosamine-6-phosphate synthase, but their antifungal activity is poor, due to slow penetration of these agents through the cytoplasmic membrane. In the present studies we have exploited the possibility of enhancement of ADGP and FMDP antifungal activity by improving their transport properties. It has been found that membrane-permeabilising polyene macrolides amphotericin B (AMB) and its N-methyl-N-fructosyl methyl ester derivative (MF-AME), at subinhibitory concentrations, facilitate diffusion of ADGP through the fungal cell membrane, thus allowing a decrease of its minimal inhibitory concentration (MIC). Synergistic effects have been observed for combinations of ADGP with AMB or MF-AME. Fractional inhibitory concentration (FIC) indexes, determined against a number of Candida spp., have been in the 0.18-0.81 range. Weak antifungal synergistic effects have been found for combinations of FMDP with AMB or MF-AME. ADGP can be easily encapsulated into unilamellar lipid vesicles. Liposomal preparations of ADGP demonstrated stronger antifungal activity against some fungal strains than free ADGP.

6

Liposomy – postać modyfi kująca transport substancji aktywnych przez skórę Część 2. Zastosowanie w transporcie leków o działaniu ogólnoustrojowym

75%

Sarecka-Hujar B., Jankowski A., Wysocka J.

Annales Academiae Medicae Silesiensis

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2011

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vol. 65

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issue 4

45-50

EN

The use of liposomes in pharmacy and medicine, as carriers of therapeutic substances, was postulated since the 60’s last century, when phenomenon of the closing of certain chemical compounds in lipid microvessicle was found. Recent literature data indicated that the therapeutic eff ectiveness of this method of administration of pharmaceutical substances is suitable. First liposomal forms of drugs were introduced already to the treatment. Liposomes with single compartment are composed of a single envelope, consisting of a lipid bilayer. In the liposomes with multi-compartments lipid membranes are arranged concentrically with alternating layers of water. Drug substance, depending on the solubility, is located in the water layer or the lipid layer of the liposome. The aim of this study was to assess the effi ciency of transport through the skin the liposomal forms of drugs with systemic activity compared to drugs used in standard forms. Liposomes can be used as carriers of drugs with systemic activity e.g.: cytostatics, analgetics, antihistamines, antiviral, substances of hormonal nature, 􀈕-blockers and immunosuppressive drugs. As in the case of application liposomal forms of drugs with local activity, literature data conducted on substances with systemic activity indicated that the liposomal forms are much more effi cient than standard forms of commonly used drugs. Application of liposomes as carriers of drugs allows using the lower dose of the drug, and leads to a reduction of its toxicity. The damages incurred in the unchanged cells and tissues were signifi cantly minimized when the liposomal form of cancer cytostatics was used.

PL

Stosowanie liposomów w farmacji i medycynie, jako nośników substancji leczniczych jest postulowane od lat sześćdziesiątych ubiegłego wieku, kiedy poznano zjawisko zamykania niektórych związków chemicznych w mikropęcherzykach lipidowych. Ostatnie dane literaturowe wskazują na terapeutyczną skuteczność tego sposobu podawania substancji farmaceutycznych, wprowadzono też do lecznictwa pierwsze liposomalne formy leków. Liposomy jednokompartmentowe zbudowane są z pojedynczej otoczki, złożonej z podwójnej warstwy lipidowej. W liposomach wielokompartmentowych błony lipidowe układają się koncentrycznie na przemian z warstwami wody. Substancja lecznicza, zależnie od rozpuszczalności, umiejscowiona jest w warstwie wodnej lub lipidowej liposomu. Celem pracy była ocena efektywności transportu przez skórę liposomalnych form leków o działaniu ogólnoustrojowym w porównaniu z lekami stosowanymi w standardowych postaciach. Liposomy mogą być nośnikami leków o działaniu zarówno miejscowym, jak i ogólnoustrojowym. Ogólnoustrojowo mogą być stosowane leki o działaniu: cytostatycznym, przeciwbólowym, przeciwhistaminowym, przeciwwirusowym, blokującym receptory 􀈕-adrenergiczne, immunosupresyjnym, a także leki o charakterze hormonalnym. Podobnie jak w przypadku stosowania liposomalnych form leków o działaniu miejscowym, wyniki badań przeprowadzanych na substancjach leczniczych o działaniu ogólnoustrojowym wskazują, że liposomalne postacie są znacznie efektywniejsze niż standardowe formy leków powszechnie stosowanych. Zastosowanie liposomów jako nośników substancji aktywnych daje możliwość podania mniejszej dawki leku, przyczyniając się równocześnie do obniżenia jego toksyczności. W chorobach nowotworowych liposomalne formy cytostatyków minimalizują powstałe podczas chemioterapii uszkodzenia niezmienionych komórek i tkanek.

7

Peroxidation of proteins and lipids in suspensions of liposomes, in blood serum, and in mouse myeloma cells.

75%

Gebicki J. M., Du J., Collins J., Tweeddale H.

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2000

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vol. 47

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issue 4

901-911

EN

There is growing evidence that proteins are early targets of reactive oxygen species, and that the altered proteins can in turn damage other biomolecules. In this study, we measured the effects of proteins on the oxidation of liposome phospholipid membranes, and the formation of protein hydroperoxides in serum and in cultured cells exposed to radiation-generated hydroxyl free radicals. Lysozyme, which did not affect liposome stability, gave 50% protection when present at 0.3 mg/ml, and virtually completely prevented lipid oxidation at 10 mg/ml. When human blood serum was irradiated, lipids were oxidized only after the destruction of ascorbate. In contrast, peroxidation of proteins proceeded immediately. Protein hydroperoxides were also generated without a lag period in hybrid mouse myeloma cells, while at the same time no lipid peroxides formed. These results are consistent with the theory that, under physiological conditions, lipid membranes are likely to be effectively protected from randomly-generated hydroxyl radicals by proteins, and that protein peroxyl radicals and hydroperoxides may constitute an important hazard to biological systems under oxidative stress.

8

Liposomy – postać modyfi kująca transport substancji aktywnych przez skórę Część 1. Zastosowanie w transporcie leków o działaniu miejscowym

75%

Jankowski A., Sarecka-Hujar B., Wysocka J.

Annales Academiae Medicae Silesiensis

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2011

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vol. 65

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issue 4

38-44

EN

The observation that, as a result of manual shaking of phospholipids dispersed in aqueous phase, form the structure, whose construction is very similar to naturally occurring in living organisms and the cell membrane, gave rise to intensive research into the liposomes as a form of medicine and cosmetic. In particular, the use of liposomes by the transdermal administration gave hope for larger eff ectivenees compared to traditional forms of medicine administered to the skin. The ability of liposomes to transport chemically diverse substances makes them almost ideal carriers of medicinal substances. Advantages of using liposomes apply to both improve the eff ectiveness of therapy, associated with increased bioavailability compared to the classic form of dermatological drugs, as well as the protective eff ect of this form in relation to the same active substance. The aim of the present study was to assess the effi ciency of transport of the liposomal forms through the skin, drugs with local activity compared to conventional medicines. We discussed data of recent years, comparative studies of selected drugs belonging to diff erent pharmacological groups given in the liposomal formulations compared to conventional forms of these medicines. The study focused on: local anesthetics, antifungals and antimicrobials, retinoids, corticosteroids, antihistamines, immunosuppressants, antivirals, fatty acids, prostaglandins and polysaccharides. Our review showed that the liposomal form of increased percutaneous absorption of drugs tested, of both hydrophilic and hydrophobic. This follows from the construction of the liposome binding drug substance regardless of its properties. Liposomes thus opened up new opportunities for increasing the eff ectiveness of transdermal therapy.

PL

Spostrzeżenie, że w wyniku ręcznego wytrząsania fosfolipidów w dyspersji fazy wodnej tworzą się struktury, których budowa jest bardzo zbliżona do naturalnie występującej w organizmach żywych błony komórkowej, dało początek intensywnym badaniom nad liposomami jako postacią leku i kosmetyku. W szczególności stosowanie liposomów w transdermalnej drodze podania leku dawało nadzieję na zwiększenie skuteczności w porównaniu z tradycyjnymi postaciami leku podawanymi na skórę. Zdolność liposomów do transportu zróżnicowanych chemicznie substancji czyni z nich niemal idealne przenośniki substancji leczniczych. Zalety stosowania liposomów dotyczą zarówno poprawy skuteczności terapii, związanej ze wzrostem biodostępności w porównaniu z klasycznymi postaciami leków dermatologicznych, jak i działania ochronnego tej postaci w stosunku do samej substancji aktywnej. Celem pracy była ocena efektywności transportu przez skórę form liposomalnych leków o działaniu miejscowym w porównaniu z lekami konwencjonalnymi. Przedyskutowno doniesienia z piśmiennictwa ostatnich lat, dotyczące badań porównawczych wybranych leków należących do różnych grup farmakologicznych podawanych w formie liposomów w stosunku do form konwencjonalnych tych leków. Badania dotyczyły: lokalnych anestetyków, leków przeciwgrzybiczych i przeciwbakteryjnych, retinoidów, kortykosteroidów, leków przeciwhistaminowych, immunosupresyjnych, przeciwwirusowych, kwasów tłuszczowych, prostaglandyn, a także polisacharydów. Przeprowadzone badania wykazały, że postać liposomalna zwiększa przezskórną wchłanialność testowanych leków o charakterze zarówno hydrofilowym, jak i hydrofobowym. Wynika to z budowy liposomu, wiążącego substancję leczniczą niezależnie od jej właściwości. Liposomy zatem otworzyły nowe możliwości zwiększenia skuteczności terapii transdermalnej.

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Liposomal drug delivery, a novel approach: PLARosomes.

Combination of combretastatin A4 phosphate and doxorubicin-containing liposomes affects growth of B16-F10 tumors

Antitumoral effect of IL-12 gene transfected via liposomes into B16F0 cells

Vehicles for Small Interfering RNA transfection: ExosomesversusSynthetic Nanocarriers

Facilitated diffusion of glucosamine-6-phosphate synthase inhibitors enhances their antifungal activity.

Liposomy – postać modyfi kująca transport substancji aktywnych przez skórę Część 2. Zastosowanie w transporcie leków o działaniu ogólnoustrojowym

Peroxidation of proteins and lipids in suspensions of liposomes, in blood serum, and in mouse myeloma cells.

Liposomy – postać modyfi kująca transport substancji aktywnych przez skórę Część 1. Zastosowanie w transporcie leków o działaniu miejscowym