11 results on '"Lee, Robert J."'
Search Results
2. Folate Receptor-Mediated Liposomal Delivery of a Lipophilic Boron Agent to Tumor Cells in Vitro for Neutron Capture Therapy
- Author
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Sudimack, Jennifer J., Adams, Dianne, Rotaru, Joan, Shukla, Supriya, Yan, Junhua, Sekido, Masaru, Barth, Rolf F., Tjarks, Werner, and Lee, Robert J.
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- 2002
- Full Text
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3. Tumor-selective targeted delivery of genes and antisense oligodeoxyribonucleotides via the folate receptor
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Zhao, Xiaobin B. and Lee, Robert J.
- Subjects
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CANCER treatment , *GENE therapy , *LIPOSOMES , *POLYMERS - Abstract
Gene therapy is a promising approach for the treatment of cancer. The main obstacle for the clinical application of cancer gene therapy is the lack of gene transfer vectors that are safe, efficacious, and tumor-selective. In recent years, targeted gene delivery through cellular receptors, using either viral or nonviral vectors, is emerging as a novel approach to enhance the efficacy of tumor-selective gene delivery. The folate receptor (FR), which is absent in most normal tissues and elevated in over 90% of ovarian carcinomas and at a high frequency in other human malignancies, is an attractive tumor-selective target. FR-targeted vectors include folate-derivatized adenoviruses, cationic polymers, cationic liposomes, and pH-sensitive liposomes. In addition, FR-targeted liposomes have been evaluated for the targeted delivery of antisense oligodeoxyribonucleotides (ODNs). These vectors have invariably shown impressive FR-selectivity in cell culture assays and, in addition, shown promising tumor-specific gene transfer activity in several in vivo models. There are important theoretical advantages for FR-targeted vectors over traditional non-targeted vectors in therapeutic gene and oligodeoxyribonucleotides delivery in vivo to cancer cells. Further preclinical characterization of these vectors is, therefore, warranted to determine their potential utility in cancer gene therapy. [Copyright &y& Elsevier]
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- 2004
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4. A folate receptor-targeted liposomal formulation for paclitaxel
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Wu, Jun, Liu, Qing, and Lee, Robert J.
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PACLITAXEL , *CYTOPLASM , *CANCER cells , *ANTINEOPLASTIC agents - Abstract
Abstract: A novel liposomal formulation of paclitaxel targeting the folate receptor (FR) was synthesized and characterized. This formulation was designed to overcome vehicle toxicity associated with the traditional Cremophor EL-based formulation and to provide the added advantages of prolonged systemic circulation time and selective targeting of the FR, which is frequently overexpressed on epithelial cancer cells. The formulation had the composition of dipalmitoyl phosphatidylcholine/dimyristoyl phosphatidylglycerol/monomethoxy-polyethylene glycol (PEG)2000-distearoyl phosphatidylethanolamine/folate-PEG3350-distearoyl phosphatidylethanolamine (DPPC/DMPG/mPEG-DSPE/folate-PEG-DSPE) at molar ratios of (85.5:9.5:4.5:0.5) and a drug-to-lipid molar ratio of 1:33. The liposomes were prepared by polycarbonate membrane extrusion. The mean particle size of the liposomes was 97.1nm and remained stable for at least 72h at 4°C. FR-targeted liposomes of the same lipid composition entrapping calcein were shown to be efficiently taken up by KB oral carcinoma cells, which are highly FR+. FR-targeted liposomes containing paclitaxel showed 3.8-fold greater cytotoxicity compared to non-targeted control liposomes in KB cells. Plasma clearance profiles of paclitaxel in the liposomal formulations were then compared to paclitaxel in Cremophor EL formulation. The liposomal formulations showed much longer terminal half-lives (12.33 and 14.23h for FR-targeted and non-targeted liposomes, respectively) than paclitaxel in Cremophor EL (1.78h). In conclusion, the paclitaxel formulation described in this study has substantial stability and favorable pharmacokinetic properties. The FR-targeted paclitaxel formulation is potentially useful for treatment of FR+ tumors and warrants further investigation. [Copyright &y& Elsevier]
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- 2006
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5. Preparation, therapeutic efficacy and intratumoral localization of targeted daunorubicin liposomes conjugating folate-PEG-CHEMS
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Xiong, Subin, Yu, Bo, Wu, Jun, Li, Hong, and Lee, Robert J.
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LIPOSOMES , *BIOCONJUGATES , *TREATMENT effectiveness , *ANTINEOPLASTIC agents , *TARGETED drug delivery , *POLYETHYLENE glycol , *FOLIC acid - Abstract
Abstract: Folate polyethylene glycol-cholesterol hemisuccinate (folate-PEG-CHEMS) is a novel folate ligand firstly synthesized by our group and demonstrated good stability and potential targeting results on KB cells in vitro. The current study further explored endocytosis mechanisms of liposomes via folate receptor on L1210JF cells and assessed targeted therapeutic efficacy of folate-PEG-CHEMS anchored liposomes loading daunorubicin (F-L-DNR) in vivo. Folate-PEG-CHEMS was synthesized by a modified method. The liposome properties, cell cytotoxicity, intracellular and intratumoral localization, and therapeutic efficacy on a murine tumor model bearing L1210JF cells were evaluated. High encapsulation efficiency (95.1%±1.5%) and appropriate particle size (76.0±35.5nm) and zeta potential (−12.83±1.36mV) were achieved for F-L-DNR. IC50 of F-L-DNR on L1210JF cells was 2–3-folds lower than that of non-targeted liposomal daunorubicin (L-DNR). Anticancer efficacy on L1210JF tumor model indicated that mice survival time of F-L-DNR group at doses of 5mg/kg and 10mg/kg was significantly longer than that of L-DNR or free DNR. Confocal fluorescence photographs of F-L-DNR indicated enhanced endocytosis of liposomes via folate receptor on L1210JF cells, prolonged retaining time in tumors and improved drug release in the tumor site at 24h post intravenous injection of F-L-DNR. In conclusion, folate-PEG-CHEMS is an effective ligand for folate-targeted daunorubicin liposomes to achieve increased drug release in tumor and therapeutic efficacy. [Copyright &y& Elsevier]
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- 2011
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6. Targeting human clonogenic acute myelogenous leukemia cells via folate conjugated liposomes combined with receptor modulation by all-trans retinoic acid
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Li, Hong, Lu, Yanhui, Piao, Longzhu, Wu, Jun, Liu, Shujun, Marcucci, Guido, Ratnam, Manohar, and Lee, Robert J.
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ACUTE myeloid leukemia , *ANTIBODY-drug conjugates , *LIPOSOMES , *DRUG receptors , *TRETINOIN , *DOXORUBICIN , *ANTIBODY-dependent cell cytotoxicity , *PHARMACOKINETICS - Abstract
Abstract: Our previous data demonstrated that folate receptor β (FR-β) targeted liposomal doxorubicin (FT-L-DOX) showed enhanced cytotoxicity relative to non-targeted liposomal doxorubicin (CON-L-DOX), and the effect was enhanced by selective FR-β upregulation by all-trans retinoic acid (ATRA) in AML blast cells. In this study, the enhanced cytotoxicity was investigated in the proliferating human AML clonogenic cells by combining FT-L-DOX with ATRA. Also, pharmacokinetic properties by pretreatment of ATRA were evaluated using FR-targeted liposomal calcein (FT-L-Calcein). Pharmacokinetic study showed that the area under the concentration curve (AUC) of FT-L-Calcein was decreased and total clearance was increased by pretreatment with ATRA. Meanwhile, the volume of distribution was significantly increased by pretreatment of ATRA. Moreover, calcein level in the liver, spleen and kidney was increased following intravenous administration of FT-L-Calcein by pretreatment of ATRA. In vitro cytotoxicity of FT-L-DOX was higher than that of CON-L-DOX and was increased by pretreatment with ATRA. Colony formation in AML cells was lower due to treatment with FT-L-DOX compared with CON-L-DOX and colony formation further decreased upon pretreatment with ATRA. Moreover, FT-L-DOX was more toxic to AML clonogenic cells than to AML blast cells. The results demonstrate that the efficiency of FR-mediated targeting of FT-L-DOX was preferentially enhanced by ATRA induced FR-β upregulation in AML clonogenic cells. [ABSTRACT FROM AUTHOR]
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- 2010
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7. Triggering liposomal drug release with a lysosomotropic agent.
- Author
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Subin Xiong, Hong Li, Bo Yu, Jun Wu, and Lee, Robert J.
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LIPOSOMES , *ENDOSOMES , *ORGANELLES , *CANCER treatment , *TUMORS , *CHLOROQUINE - Abstract
Drug release from liposomes in the endosome-lysosomal organelles into cytoplasm is critical to cytotoxicity and anticancer effects. Chloroquine is a lysosomotropic agent that has been reported to enhance in vitro cytotoxicity of basic anticancer drugs. To investigate the mechanism of chloroquine triggering basic anticancer drugs release from liposomes and the potential to treat solid tumors in clinic, daunorubicin was loaded into folate-targeted liposomes by ammonium sulfate remote loading method. In vitro triggered release profiles showed that chloroquine can instantly expel about 11% daunorubicin out of liposomes. In vitro cytotoxicity of folate-targeted liposomal daunorubicin on L1210JF(FR+) was enhanced by chloroquine, which was further confirmed by confocal micrographs. Intraliposomal pH was increased by adding chloroquine into 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) liposomes with ammonium sulfate gradient, but was not higher than 5.5. Ion exchange and pH rising are the most plausible mechanisms of chloroquine triggering daunorubicin release from liposomes. In vivo anticancer effects on a murine solid tumor model with L1210JF indicated that chloroquine induced daunorubicin release from liposomes as well. Overall, these results support the potential application of chloroquine to trigger the release of liposomal drugs and ultimately to improve the therapeutic efficacy. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:5011-5018, 2010 [ABSTRACT FROM AUTHOR]
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- 2010
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8. Synthesis and evaluation of a novel ligand for folate-mediated targeting liposomes
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Xiang, Guangya, Wu, Jun, Lu, Yanhui, Liu, Zhilan, and Lee, Robert J.
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VITAMIN B complex , *CANCER , *LEUKEMIA , *LIPOSOMES - Abstract
Abstract: 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 FR-expressing cells. Here, we report the synthesis of a novel lipophilic folate derivative, folate-polyethylene 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-PEG-Chol), 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 (IC50 =10.0μM) than non-targeted control L-DOX (IC50 =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 =12.34h) showed more rapid plasma clearance than L-DOX (t 1/2 =17.10h). These results suggest that F-PEG-CHEMS is effective as a novel ligand for the synthesis of FR-targeted liposomes. [Copyright &y& Elsevier]
- Published
- 2008
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9. Cholesterol as a bilayer anchor for PEGylation and targeting ligand in folate-receptor-targeted liposomes.
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Zhao, Xiaobin B., Muthusamy, Natarajan, Byrd, John C., and Lee, Robert J.
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BILAYER lipid membranes , *ISOPENTENOIDS , *STEROLS , *PHOSPHOLIPIDS , *DOXORUBICIN , *LIPOSOMES - Abstract
Phospholipids have been extensively evaluated as an anchor for both PEGylation and receptor-targeting in liposomal formulations. However, cholesterol, another important component in biomembranes, has not been fully investigated as an alternative anchor. In this study, the potential role of cholesterol for anchoring PEG and folate was investigated. Cholesterol derivatives were synthesized for PEGylation (mPEG-cholesterol) and folate receptor (FR) targeting (folate-PEG-cholesterol) and incorporated into the bilayer of FR-targeted liposomal doxorubicin. The colloidal stability of these cholesterol derivative-containing liposomes was superior to non-PEGylated liposomes, indicating that steric barrier provided by mPEG-cholesterol can efficiently inhibit aggregation of liposomes. FR-targeting activity of these liposomes was demonstrated by in vitro cell-binding studies on FR-overexpressing KB cells. In addition, in vivo circulation of cholesterol-anchored liposomes was prolonged compared to non-PEGylated liposomes. These studies suggest that cholesterol is a viable bilayer anchor for synthesis of PEGylated and FR-targeted liposomes. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2424–2435, 2007 [ABSTRACT FROM AUTHOR]
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- 2007
- Full Text
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10. A novel pH-sensitive liposome formulation containing oleyl alcohol
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Sudimack, Jennifer J., Guo, Wenjin, Tjarks, Werner, and Lee, Robert J.
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LIPOSOMES , *PALLADIUM - Abstract
pH-sensitive liposomes are designed to undergo acid-triggered destabilization. First generation pH-sensitive liposomes, based on the cone-shaped lipid dioleoylphosphatidylethanolamine (DOPE), have been shown to lose fusogenicity in the presence of serum. Here, we report the design and evaluation of novel serum-resistant pH-sensitive liposome formulations that are based on the composition of egg phosphatidylcholine (PC), cholesteryl hemisuccinate (CHEMS), oleyl alcohol (OAlc), and Tween-80 (T-80). When loaded with the fluorescent probe calcein, these liposomes exhibited excellent stability at pH 7.4 and underwent rapid destabilization upon acidification as shown by calcein dequenching and particle size increase. Adjusting the mole percentages of T-80 and OAlc in the formulation could regulate the stability and pH-sensitive properties of these liposomes. Liposomes with a higher T-80 content exhibited greater stability but were less sensitive to acid-induced destabilization. Meanwhile, formulations with a higher OAlc content exhibited greater content release in response to low pH. The pH-triggered liposomal destabilization did not produce membrane fusion according to an octadecylrhodamine B chloride (R18) lipid-mixing assay. Compared to DOPE-based pH-sensitive liposomes, the above formulations showed much better retention of their pH-sensitive properties in the presence of 10% serum. These liposomes were then evaluated for intracellular delivery of entrapped cytosine-β-d-arabinofuranoside (araC) in KB human oral cancer cells, which have elevated folate receptor (FR) expression. The FR, which is amplified in many types of human tumors, has been shown to mediate the internalization of folate-derivatized liposomes into an acidic intracellular compartment. FR-targeted OAlc-based pH-sensitive liposomes, entrapping 200 mM araC, showed ∼17-times greater FR-dependent cytotoxicity in KB cells compared to araC delivered via FR-targeted non-pH-sensitive liposomes. These data indicated that pH-sensitive liposomes based on OAlc, combined with FR-mediated targeting, are promising delivery vehicles for membrane impermeable therapeutic agents. [Copyright &y& Elsevier]
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- 2002
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11. Efficient intracellular drug and gene delivery using folate receptor-targeted pH-sensitive liposomes composed of cationic/anionic lipid combinations
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Shi, Guangfeng, Guo, Wenjin, Stephenson, Stacy M., and Lee, Robert J.
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LIPOSOMES , *LIPIDS , *DRUG delivery systems - Abstract
pH-sensitive liposomes are designed to promote efficient release of entrapped agents in response to low pH. In this study, novel pH-sensitive liposomes consisting of cationic/anionic lipid combinations are evaluated for intracellular drug and gene delivery. First, liposomes composed of egg phosphatidylcholine, dimethyldioctadecylammonium bromide (DDAB), cholesteryl hemisuccinate (CHEMS), and Tween-80 (25:25:49:1, mol/mol) were shown to stably entrap calcein at pH 7.4 and undergo rapid content release and irreversible aggregation under acidic pH. Compared to pH-sensitive liposomes incorporating dioleoylphosphatidylethanolamine, these liposomes showed improved retention of pH-sensitivity in the presence of serum. The folate receptor (FR), which is amplified in a wide variety of human tumors, could be targeted by incorporating 0.1 mol% folate-polyethyleneglycol-phosphatidylethanolamine (f-PEG-PE) into liposomes. f-PEG-PE has been shown to facilitate FR-mediated endocytosis of liposomes into KB human oral cancer cells, which express amplified FR. FR-targeted pH-sensitive liposomes produced increased cytosolic release of entrapped calcein, as shown by fluorescence microscopy, and enhanced cytotoxicity of entrapped cytosine-β-d-arabinofuranoside, as shown by an 11-fold reduction in the IC50 in KB cells, compared to FR-targeted non-pH-sensitive liposomes. Furthermore, FR-targeted pH-sensitive liposomes composed of DDAB/CHEMS/f-PEG-PE, combined with polylysine-condensed plasmid DNA, were shown to mediate FR-specific delivery of a luciferase reporter gene into KB cells in the presence of 10% serum. These findings suggest that cationic lipid-containing pH-sensitive liposomes, combined with FR targeting, are effective vehicles for intracellular drug and gene delivery. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
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