Cholesterol as a bilayer anchor for PEGylation and targeting ligand in folate‐receptor‐targeted liposomes

Zhao, Xiaobin; Muthusamy, Natarajan; Byrd, John C.; Lee, Robert J.

doi:10.1002/jps.20885

Cited by 70 publications

(42 citation statements)

References 63 publications

(75 reference statements)

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“…FRtargeted liposomal DOX containing F-PEG-CHEMS was cleared more rapidly compared to non-targeted liposomal DOX. This is consistently with findings on F-PEG-DSPE and F-PEGChol-containing liposomes reported previously (Gabizon et al, 2003;Zhao et al, 2007).…”

Section: Pharmacokinetic Properties Of Dox-loaded Liposomessupporting

confidence: 93%

Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes

Xiang

et al. 2008

International Journal of Pharmaceutics

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113

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Folate receptors (FRs) have been identified as cellular surface markers for cancer and leukemia. Liposomes containing lipophilic derivatives of folate have been shown to effectively target FRexpressing cells. Here, we report the synthesis of a novel lipophilic folate derivative, folatepolyethylene glycol-cholesterol hemisuccinate (F-PEG-CHEMS), and its evaluation as a targeting ligand for liposomal doxorubicin (L-DOX) in FR-expressing cells. Liposomes containing F-PEG-CHEMS, with a mean diameter of 120±20nm, were synthesized by polycarbonate membrane extrusion and were shown to have excellent colloidal stability. The liposomes were taken up selectively by KB cells, which overexpress FR-α. Compared to folate-PEG-cholesterol (F-PEGChol), which contains a carbamate linkage, F-PEG-CHEMS better retained its FR-targeting activity during prolonged storage. In addition, F-PEG-CHEMS containing liposomes loaded with DOX (F-L-DOX) showed greater cytotoxicity (IC 50 =10.0μM) than non-targeted control L-DOX (IC 50 = 57.5μM) in KB cells. In ICR mice, both targeted and non-targeted liposomes exhibited long circulation properties, although F-L-DOX (t 1/2 = 12.34 hr) showed more rapid plasma clearance than L-DOX (t 1/2 = 17.10 hr). These results suggest that F-PEG-CHEMS is effective as a novel ligand for the synthesis of FR-targeted liposomes. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , 2001; Momot et al., 2003;Papahadjopoulos et al., 1991) and is facilitated by plasma protein opsonization. Incorporation of polyethylene glycol (PEG) coating on liposomes has been shown to reduce the rate of RES clearance of liposomes Fritze et al., 2006; Momot et al., 2003;Papahadjopoulos et al., 1991). Liposomal delivery has been shown to reduce cardiac toxicity of doxorubicin (Perez et al., 2002). Targeted liposomes can be synthesized by incorporating a tumor cell-selective ligand, such as antibodies, transferrin and folic acid (Gabizon et al., 2004;Lukyanov et al., 2004;Pan et al. 2007;Wu et al., 2006a;Xiong et al., 2005), via a lipophilic anchor, typically consisting of a derivative of distearoylphosphatidylethanolamine (DSPE). NIH Public AccessMembrane folate receptors (FRs), including FR-α and FR-β, are glycosylphosphatidylinositol (GPI)-anchored glycoproteins. FR-α expression is amplified in over 90% of ovarian carcinomas and at varying frequencies in other epithelial cancers. Meanwhile, FR-β is expressed in a non-functional form in neutrophils and in a functional form in activated macrophages and in myeloid leukemias (Elwood et al., 1989;McHugh et al., 1979). In contrast, most normal...

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Section: Pharmacokinetic Properties Of Dox-loaded Liposomessupporting

confidence: 93%

Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes

Xiang

et al. 2008

International Journal of Pharmaceutics

Self Cite

113

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“…The coculture model has been widely employed in many brain-targeted studies and the culture process of BCECs and ACs has been described previously. 22,23 After a series of purification, the morphologies of the ACs and BCECs were characterized by inverted fluorescence microscopy. BCECs and ACs were cocultured in a "contact through feet" model.…”

Section: Establishment Of the Bbb Model In Vitromentioning

confidence: 99%

“…Triplicate samples were performed, and the results were expressed as cumulative cleared volume to indicate the transendothelial ability of coumarin 6-loaded liposomes. 22 …”

Section: The Fluorescein Sodium Leakage Test Of the Bbb Model In Vitromentioning

confidence: 99%

Investigation of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers for brain targeting

Xie

Yao²,

Qin³

et al. 2012

IJN

113

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Background An intimidating challenge to transporting drugs into the brain parenchyma is the presence of the blood–brain barrier (BBB). Glucose is an essential nutritional substance for brain function sustenance, which cannot be synthesized by the brain. Its transport primarily depends on the glucose transporters on the brain capillary endothelial cells. In this paper, the brain-targeted properties of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers were compared and evaluated to establish an optimized drug-delivery system. Methods Coumarin 6-loaded liposomes (GLU200-LIP, GLU400-LIP, GLU1000-LIP, and GLU2000-LIP) composed of phospholipids and glucose-derived cholesterols were prepared by thin-film dispersion-ultrasound method. The BBB model in vitro was developed to evaluate the transendothelial ability of the different liposomes crossing the BBB. The biodistribution of liposomes in the mice brains was identified by in vivo and ex vivo nearinfrared fluorescence imaging and confocal laser scanning microscopy and further analyzed quantitatively by high-performance liquid chromatography. Results Glucose-derived cholesterols were synthesized and identified, and coumarin 6-loaded liposomes were prepared successfully. The particle sizes of the four types of glucose-modified liposomes were around or smaller than 100 nm with a polydispersity index less than 0.300. GLU400-LIP, GLU1000-LIP, and GLU2000-LIP achieved higher cumulative cleared volumes on BBB model in vitro after 6 hours compared with GLU200-LIP ( P < 0.05) and were significantly higher than that of the conventional liposome ( P < 0.001). The qualitative and quantitative biodistribution results in the mice showed that the accumulation of GLU1000-LIP in the brain was the highest among all the groups ( P < 0.01 versus LIP). Conclusion The data indicated that GLU400-LIP, GLU1000-LIP, and GLU2000-LIP all possess the potential of brain targeting, among which GLU1000-LIP, as a promising drug-delivery system, exhibited the strongest brain delivery capacity.

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“…Recently, some peptides that readily penetrate through the cell membrane have been isolated. 120 The mechanism used to enable penetration of these peptides through the membrane has not been fully elucidated. It has been suggested that, because of their structural peculiarities, the peptides are able to "crawl" through the cell membrane.…”

Section: Liposomesmentioning

confidence: 99%

Nanoscale drug delivery systems and the blood–brain barrier

Alyautdin¹,

Khalin²,

Nafeeza³

et al. 2014

IJN

120

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The protective properties of the blood–brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain’s vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual’s age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.

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Cholesterol as a bilayer anchor for PEGylation and targeting ligand in folate‐receptor‐targeted liposomes

Cited by 70 publications

References 63 publications

Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes

Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes

Investigation of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers for brain targeting

Nanoscale drug delivery systems and the blood–brain barrier

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Cholesterol as a bilayer anchor for PEGylation and targeting ligand in folate‐receptor‐targeted liposomes

Cited by 70 publications

References 63 publications

Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes

Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes

Investigation of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers for brain targeting

Nanoscale drug delivery systems and the blood&ndash;brain barrier

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Nanoscale drug delivery systems and the blood–brain barrier