Antitumour activity of cytotoxic liposomes equipped with selectin ligand SiaLeX, in a mouse mammary adenocarcinoma model

Водовозова, Е. Л.; Моисеева, Е. В.; Grechko, G.K.; Gayenko, Galina P.; Nifant'ev, Nikolay E.; Bovin, Nicolai V.; Molotkovsky, Jul.G.

doi:10.1016/s0959-8049(00)00029-0

Cited by 74 publications

(39 citation statements)

References 23 publications

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“…Then, the lipid suspension was extruded through polycarbonate membranes (Nucleopore) with 100 nm pores 20 times using the mini-extruder (Avanti Polar Lipids). The resulting vesicles, as shown previously (22), are unilamellar with mean diameters of ?120 nm.…”

Section: Vesicle Preparationsupporting

confidence: 75%

New BODIPY lipid probes for fluorescence studies of membranes

Болдырев

Zhai

Momsen

et al. 2007

Journal of Lipid Research

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Many fluorescent lipid probes tend to loop back to the membrane interface when attached to a lipid acyl chain rather than embedding deeply into the bilayer. To achieve maximum embedding of BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) fluorophore into the bilayer apolar region, a series of sn-2 acyl-labeled phosphatidylcholines was synthesized bearing 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-8-yl (Me 4 -BODIPY-8) at the end of C 3 -, C 5 -, C 7 -, or C 9 -acyl. A strategy was used of symmetrically dispersing the methyl groups at BODIPY ring positions 1, 3, 5, and 7 to decrease fluorophore polarity. Iodide quenching of the phosphatidylcholine probes in bilayer vesicles confirmed that the Me 4 -BODIPY-8 fluorophore was embedded in the bilayer. Parallax analysis of Me 4 -BODIPY-8 fluorescence quenching by phosphatidylcholines containing iodide at different positions along the sn-2 acyl chain indicated that the penetration depth of Me 4 -BODIPY-8 into the bilayer was determined by the length of the linking acyl chain. Evaluation using monolayers showed minimal perturbation of ,10 mol% probe in fluid-phase and cholesterol-enriched phosphatidylcholine. Spectral characterization in monolayers and bilayers confirmed the retention of many features of other BODIPY derivatives (i.e., absorption and emission wavelength maxima near 498 nm and ?506-515 nm) but also showed the absence of the 620-630 nm peak associated with BODIPY dimer fluorescence and the presence of a 570 nm emission shoulder at high Me 4 -BODIPY-8 surface concentrations. We conclude that the new probes should have versatile utility in membrane studies, especially when precise location of the reporter group is needed. Fluorescent lipid probes have proven to be valuable tools in membrane studies (see Ref. 1 for review). Because the determination of depth-dependent parameters of bilayers can benefit the understanding of membranous structures (2), sets of probes bearing the same fluorophore at different distances from the bilayer surface are potentially quite useful. Ideally, such fluorophores should be apolar enough to localize at the membrane depth that reflects the apolar nature of the surrounding acyl chain region without being strongly influenced by the transbilayer polarity gradient (3). The first probe set designed to achieve this goal was a series of n-(9-anthroyloxy) fatty acids synthesized by Thulborn and Sawyer (4), who showed that the fluorophore resided in the bilayer at a graded series of depths that coincided with the attachment point of the anthroyloxy fluorophore along the acyl chain. Other widely used fluorophores, such as N-dansyl (5) or N-NBD (6, 7), have been shown to have polar characteristics that interfere with localization deep inside the bilayer even when attached to the end of the acyl chain.During the past decade, BODIPY (4,4-difluoro-4-bora3a,4a-diaza-s-indacene) fluorophore probes have found a wide range of applications in cell biology and biophysics, even though this zwitterionic fluorophore wa...

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Section: Vesicle Preparationsupporting

confidence: 75%

New BODIPY lipid probes for fluorescence studies of membranes

Болдырев

Zhai

Momsen

et al. 2007

Journal of Lipid Research

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“…For larger tumor nodules, individual mean tumor diameter (TD, mm) as an average of 3 perpendicular TDs was used as a measure of tumor size. 23 The mice were monitored daily for health control and survival: animals at the end point of leukemic lymphoma (weight loss .20% and/or food rejection independently of tumor size) were immediately euthanatized. 21 The significance of differences in averages was determined by using the Student's t-test, and the results were presented as mean ± standard deviation.…”

Section: Antitumor Effect Of Mtx-dg Liposomes Versus Intact Mtx In Vivomentioning

confidence: 99%

Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

Алексеева¹,

Моисеева²,

Onishchenko³

et al. 2017

IJN

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In a previous study, a formulation of methotrexate (MTX) incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug) was developed. In this study, first, the interactions of MTX-DG liposomes with various human and mouse tumor cell lines were studied using fluorescence techniques. The liposomes composed of egg phosphatidylcholine (PC)/yeast phosphatidylinositol/MTX-DG, 8:1:1 by mol, were labeled with fluorescent analogs of PC and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies on inhibitors of liposome uptake and processing by cells demonstrated that the formulation used multiple mechanisms to deliver the prodrug inside the cell. According to the data from the present study, undamaged liposomes fuse with the cell membrane only 1.5–2 hours after binding to the cell surface, and then, the components of liposomal bilayer enter the cell separately. The study on the time course of plasma concentration in mice showed that the area under the curve of MTX generated upon intravenous injection of MTX-DG liposomes exceeded that of intact MTX 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, the administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen resulted in lower toxicity and retarded lymphoma growth rate as compared with MTX.

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“…Схематически конструкция липосомы изображена на рисунке 1. Контакт с рецептором на поверхности клетки-мишени обеспечивается за счёт экспонирования углеводных групп SiaLe X на достаточном расстоянии от мембраны с помощью полярных гибких вставок ПЭГ(степень полимеризации [8][9][10][11][12][13][14].…”

Section: результаты и обсуждениеunclassified

“…В то же время, в составе липосом пролекарства оказались устойчивы к преждевременному гидролизу эстеразами плазмы крови человека [9]. Противоопухолевое действие липосомальных препаратов мелфалана продемонстрировано на моделях лимфолейкоза [10] и рака молочных желез мышей [11].…”

unclassified

“…1), в виде конъюгата с олигоэтиленгликольоктадецилом противоопухолевый эффект значительно усиливается [11]. Селектины (углеводсвязывающие адгезионные белки) повышенно экспрессированы на активированных эндотелиальных клетках, лейкоцитах и тромбоцитах.…”

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Liposome formulations of combretastatin a4 and 4-arylcoumarin analog prodrugs: antitumor effect in the mouse model of breast cancer

et al. 2012

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Антимитотический агент комбретастатин А4 (СА-4) сравнительно недавно предложен в качестве антиваскулярного средства для противоопухолевой терапии. С целью уменьшения системной токсичности за счет применения в виде липосомальных препаратов, в данной работе синтезированы новые липофильные пролекарства -олеоильные производные СА-4 и его 4-арилкумаринового аналога (ArC): СА4-Ole и ArC-Ole, соответственно. Показано, что липосомы среднего диаметра 100 нм, полученные на основе яичного фосфатидилхолина и фосфатидилинозита из пекарских дрожжей, количественно включают до 15 моль-% СА4-Ole или 7 моль-% ArC-Ole. Также получены липосомы с пролекарствами, оснащённые тетрасахаридным лигандом селектинов, а именно сиалил-Lewis X (SiaLe X ), с целью адресной доставки к эндотелию формирующейся de novo сосудистой системы. Противоопухолевые свойства in vivo изучали на модели медленно растущего рака молочных желез (РМЖ) мышей. В используемых дозировке (22 мг/кг) и протоколе введения (4 раза с интервалом в одну неделю, начиная с появления пальпируемых опухолей) цитостатик СА-4 не оказал противоопухолевого действия, более того, даже стимулировал рост РМЖ. Липосомальные формы CA4-Ole не оказывали стимулирующего действия на рост опухолей. Однако, для получения выраженного противоопухолевого эффекта, очевидно, необходимо увеличить кратность введения препаратов липосом. Новый антимитотический агент ArC показал меньший на порядок уровень цитотоксичности in vitro в культуре клеток карциномы молочной железы человека. Тем не менее, при испытаниях на мышиной модели РМЖ полученный аналог показал противоопухолевый эффект в двухкратной эквивалентной дозе по СА-4. Результаты показывают перспективность применения ArC-Ole в липосомах, оснащённых SiaLe X : препарат частично подавлял рост опухоли уже после второго введения. Необходим дальнейший подбор доз и режимов введения ArC и препаратов липосом с ArC-Ole.Ключевые слова: комбретастатин А4, 4-арилкумарины, липофильные пролекарства, липосомы, сиалил-Lewis X, рак молочной железы. 326 * -адресат для переписки

show abstract

Antitumour activity of cytotoxic liposomes equipped with selectin ligand SiaLeX, in a mouse mammary adenocarcinoma model

Cited by 74 publications

References 23 publications

New BODIPY lipid probes for fluorescence studies of membranes

New BODIPY lipid probes for fluorescence studies of membranes

Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

Liposome formulations of combretastatin a4 and 4-arylcoumarin analog prodrugs: antitumor effect in the mouse model of breast cancer

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