Publications by authors named "Tatyana S Levchenko"

13 Publications

  • Page 1 of 1

In vitro transfection of bone marrow-derived dendritic cells with TATp-liposomes.

Int J Nanomedicine 2014 13;9:963-73. Epub 2014 Feb 13.

Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.

Dendritic cells (DC) are antigen-presenting cells uniquely capable of priming naïve T cells and cross-presenting antigens, and they determine the type of immune response elicited against an antigen. TAT peptide (TATp), is an amphipathic, arginine-rich, cationic peptide that promotes penetration and translocation of various molecules and nanoparticles into cells. TATp-liposomes (TATp-L) used for DC transfection were prepared using TATp derivatized with a lipid-terminated polymer capable of anchoring in the liposomal membrane. Here, we show that the addition of TATp to DNA-loaded liposomes increased the uptake of DNA in DC. DNA-loaded TATp-L increased the in vitro transfection efficiency in DC cultures as evidenced by a higher expression of the enhanced green fluorescent protein and bovine herpes virus type 1 glycoprotein D (gD). The de novo synthesized gD protein was immunologically stimulating when transfections were performed with TATp-L, as indicated by the secretion of interleukin 6.
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http://dx.doi.org/10.2147/IJN.S53432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928453PMC
May 2015

Liposomes in diagnosis and treatment of cardiovascular disorders.

Methodist Debakey Cardiovasc J 2012 Jan;8(1):36-41

Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts, USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405779PMC
http://dx.doi.org/10.14797/mdcj-8-1-36DOI Listing
January 2012

Liposomes for cardiovascular targeting.

Ther Deliv 2012 Apr;3(4):501-14

The Center for Pharmaceutical Biotechnology & Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Mugar Building, Room 312, 360 Huntington Avenue, Boston, MA 02115, USA.

Liposome-based pharmaceuticals used within the cardiovascular system are reviewed in this article. The delivery of diagnostic and therapeutic agents by plain liposomes and liposomes with surface-attached targeting antibodies or polyethylene glycol to prolong their circulation time and accumulation at vascular injuries, ischemic zones or sites of thrombi are also discussed. An overview of the advantages and disadvantages of liposome-mediated in vitro, ex vivo and in vivo targeting is presented, including discussion of the targeting of liposomes to pathological sites on the blood vessel wall and a description of liposomes that can be internalized by endothelial cells. Diagnostic liposomes used to target myocardial infarction and the relative importance of liposome size, targetability of immunoliposomes and prolonged circulation time on the efficiency of sealing hypoxia-induced plasma membrane damage to cardiocytes are discussed as a promising approach for therapy. The progress in the use of targeted liposomal plasmids for the transfection of hypoxic cardiomyocytes and myocardium is presented. Stent-mediated liposomal-based drug delivery is also reviewed briefly.
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http://dx.doi.org/10.4155/tde.12.18DOI Listing
April 2012

Do liposomal apoptotic enhancers increase tumor coagulation and end-point survival in percutaneous radiofrequency ablation of tumors in a rat tumor model?

Radiology 2010 Dec 21;257(3):685-96. Epub 2010 Sep 21.

Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA.

Purpose: To characterize effects of combining radiofrequency (RF) ablation with proapoptotic intravenous liposome-encapsulated paclitaxel and doxorubicin on tumor destruction, apoptosis and heat-shock protein (HSP) production, intratumoral drug accumulation, and end-point survival.

Materials And Methods: R3230 mammary adenocarcinomas (n = 177) were implanted in 174 rats in this animal care committee-approved study. Tumors received (a) no treatment, (b) RF ablation, (c) paclitaxel, (d) RF ablation followed by paclitaxel (RF ablation-paclitaxel), (e) paclitaxel before RF ablation (paclitaxel-RF ablation), (f) RF ablation followed by doxorubicin (RF ablation-doxorubicin), (g) paclitaxel followed by doxorubicin without RF ablation (paclitaxel-doxorubicin), or (h) paclitaxel before RF ablation, followed by doxorubicin (paclitaxel-RF ablation-doxorubicin). Tumor coagulation area and diameter were compared at 24-96 hours after treatment. Intratumoral paclitaxel uptake with and without RF ablation were compared. Immunohistochemical staining revealed cleaved caspase-3 and 70-kDa HSP (HSP70) expression. Tumors were randomized into eight treatment arms for Kaplan-Meier analysis of defined survival end-point (3.0-cm diameter).

Results: Paclitaxel-RF ablation increased tumor coagulation over RF ablation or paclitaxel (mean, 14.0 mm ± 0.9 [standard deviation], 6.7 mm ± 0.6, 2.5 mm ± 0.6, respectively; P < .001). Paclitaxel-RF ablation-doxorubicin had similar tumor coagulation (P < .05), compared with paclitaxel-RF ablation, at 24 and 96 hours. Mean intratumoral paclitaxel accumulation for paclitaxel-RF ablation (6.76 μg/g ± 0.35) and RF ablation-paclitaxel (9.28 μg/g ± 0.87) increased over that for paclitaxel (0.63 μg/g ± 0.25, P < .001). Paclitaxel substantially increased apoptosis and decreased HSP70 expression at coagulation margin. Mean end-point survival for paclitaxel-RF ablation-doxorubicin (56.8 days ± 25.3) was greater, compared with that for paclitaxel-RF ablation or RF ablation-paclitaxel (17.6 days ± 2.5), RF ablation-doxorubicin (30.3 days ± 4.9, P < .002), or paclitaxel-doxorubicin (27.9 days ± 4.1, P < .001).

Conclusion: Selecting adjuvant liposomal chemotherapies (paclitaxel, doxorubicin) to target cellular apoptosis and HSP production effectively increases RF ablation-induced tumor coagulation and end-point survival, and combined multidrug approach results in even better outcomes.

Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100500/-/DC1.
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http://dx.doi.org/10.1148/radiol.10100500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2984374PMC
December 2010

ATP-loaded liposomes for targeted treatment in models of myocardial ischemia.

Methods Mol Biol 2010 ;605:361-75

Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Northeastern University, Boston, MA, USA.

ATP cannot be effectively delivered to most tissues including the ischemic myocardium without protection from degradation by plasma endonucleotidases. However, it has been established that ATP can be delivered to various tissues by its encapsulation within liposomal preparations. We describe here, the materials needed and methods used to optimize the encapsulation of ATP in liposomes, enhance their effectiveness by increasing their circulation time and target injured myocardial cells with liposomal surface anti-myosin antibody. Additionally, we outline methods for ex vivo studies of these ATP liposomal preparations in an isolated ischemic rat heart model and for in vivo studies of rabbits with an induced myocardial infarction. The expectation is that these methods will provide a basis for continued studies of effective ways to deliver energy substrates to the ischemic myocardium.
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http://dx.doi.org/10.1007/978-1-60327-360-2_25DOI Listing
April 2010

ATP-loaded liposomes for treatment of myocardial ischemia.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2009 Sep-Oct;1(5):530-9

Departmentof Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.

A major obstacle to drug therapy for treatment of potential myocardial infarction is the limited access to the ischemic myocardium by drugs in an active form. Encouraging results have been reported with liposomes loaded with ATP in a variety of in vitro and in vivo models. We describe methods for optimized encapsulation of ATP in liposomes, enhancement of their effectiveness by increasing circulation time, and targeting of injured myocardial cells with surface attached antimyosin. In isolated ischemic rat hearts, ATP-loaded liposomes and ATP-loaded immunoliposomes effectively protected myocardium from ischemia/reperfusion damage as measured by systolic and diastolic functional improvements. In vivo, in rabbits with induced localized myocardial ischemia, liposomal encapsulation of ATP significantly diminished the proportion of ventricular muscle at risk that was irreversibly damaged during reperfusion. Therefore, ATP encapsulated in liposomes can provide an effective exogenous source for in vivo application which can protect ischemically damaged hearts.
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http://dx.doi.org/10.1002/wnan.46DOI Listing
March 2010

Near infrared planar tumor imaging and quantification using nanosized Alexa 750-labeled phospholipid micelles.

Int J Nanomedicine 2009 20;4:123-31. Epub 2009 Apr 20.

Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA.

A novel highly biocompatible near infrared nanosized contrast agent was developed and used for rapid tumor detection and quantification using planar optical imaging and analysis. With this in mind, the near infrared fluorescent dye Alexa 750 was covalently attached to polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugate, and double labeled (with Alexa and rhodamine) PEG-PE micelles were injected into mice and observed using planar optical imaging. Pixel intensity data from the tumor site were normalized versus the autofluorescence of the animal at the same time point and normalized as signal to noise over the scattered light from the various tissues of the mice. The detected signal from the tumor was higher than the background noise allowing for rapid detection of the tumor. The tumor was clearly visible within one hour. Some signal was also detected from the abdomen of the mice. As determined by microscopy analysis, other organs of accumulation were the liver and kidney, which corresponded well to the data from the whole body imaging animal studies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720747PMC
August 2009

Improved transfection of spleen-derived antigen-presenting cells in culture using TATp-liposomes.

J Control Release 2009 Feb 21;134(1):41-6. Epub 2008 Nov 21.

Instituto de Virología, Centro de Investigaciones en Ciencias Veterinarias y Agronómicas, INTA-Castelar, Buenos Aires, Argentina.

Antigen presenting cells (APC) are among the most important cells of the immune system since they link the innate and the adaptative immune responses, directing the type of immune response to be elicited. To modulate the immune response in immune preventing or treating therapies, gene delivery into immunocompetent cells could be used. However, APC are very resistant to transfection. To increase the efficiency of APC transfection, we have used liposome-based lipoplexes additionally modified with cell-penetrating TAT peptide (TATp) for better intracellular delivery of a model plasmid encoding for the enhanced-green fluorescent protein (pEGFP). pEGFP-bearing lipoplexes made of a mixture of PC:Chol:DOTAP (60:30:10 molar ratio) with the addition of 2% mol of polyethylene glycol-phosphatidylethanolamine (PEG-PE) conjugate (plain-L) or TATp-PEG-PE (TATp-L) were shown to effectively protect the incorporated DNA from degradation. Uptake assays of rhodamine-labeled lipoplexes and transfections with the EGFP reporter gene were performed with APC derived from the mouse spleen. TATp-L-based lipoplexes allowed for significantly enhanced both, the uptake and transfection in APC. Such a tool could be used for the APC transfection as a first step in immune therapy.
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http://dx.doi.org/10.1016/j.jconrel.2008.11.006DOI Listing
February 2009

A DNA vaccine prime followed by a liposome-encapsulated protein boost confers enhanced mucosal immune responses and protection.

J Immunol 2008 May;180(9):6159-67

Oral Vaccine Institute, 10 New Bond Street, Worcester, MA 01606, USA.

A variety of DNA vaccine prime and recombinant viral boost immunization strategies have been developed to enhance immune responses in humans, but inherent limitations to these strategies exist. There is still an overwhelming need to develop safe and effective approaches that raise broad humoral and T cell-mediated immune responses systemically and on mucosal surfaces. We have developed a novel mucosal immunization regimen that precludes the use of viral vectors yet induces potent T cell responses. Using hepatitis B surface Ag (HBsAg), we observed that vaccination of BALB/c mice with an i.m. HBsAg-DNA vaccine prime followed by an intranasal boost with HBsAg protein encapsulated in biologically inert liposomes enhanced humoral and T cell immune responses, particularly on mucosal surfaces. Intranasal live virus challenge with a recombinant vaccinia virus expressing HBsAg revealed a correlation between T cell immune responses and protection of immunized mice. A shortened immunization protocol was developed that was successful in both adult and neonatal mice. These results support the conclusion that this new approach is capable of generating a Th-type-1-biased, broad spectrum immune response, specifically at mucosal surfaces. The success of this design may provide a safe and effective vaccination alternative for human use.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633597PMC
http://dx.doi.org/10.4049/jimmunol.180.9.6159DOI Listing
May 2008

Protective effect of coenzyme Q10-loaded liposomes on the myocardium in rabbits with an acute experimental myocardial infarction.

Pharm Res 2007 Nov 27;24(11):2131-7. Epub 2007 Jul 27.

Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA.

Purpose: We assessed whether the infusion of Coenzyme Q10-loaded liposomes (CoQ10-L) in rabbits with an experimental myocardial infarction can result in increased intracellular delivery of CoQ10 and thus limit the fraction of the irreversibly damaged myocardium.

Methods: CoQ10-L, empty liposomes (EL), or Krebs-Henseleit (KH) buffer were administered by intracoronary infusion, followed by 30 min of occlusion and 3 h of reperfusion. Unisperse Blue dye was used to demarcate the net size of the occlusion-induced ischemic zone ("area at risk") while nitroblue tetrazolium staining was used to detect the final fraction of the irreversibly damaged myocardium within the total area at risk.

Results: The total size of the area at risk in all experimental animals was approx. 20% wt. of the left ventricle (LV). The final irreversible damage in CoQ10-L-treated animals was only ca. 30% of the total area at risk as compared with ca. 60% in the group treated with EL (p < 0.006) and ca. 70% in the KH buffer-treated group (p < 0.001).

Conclusions: CoQ10-L effectively protected the ischemic heart muscle by enhancing the intracellular delivery of CoQ10 in hypoxic cardiocytes in rabbits with an experimental myocardial infarction as evidenced by a significantly decreased fraction of the irreversibly damaged heart within the total area at risk. CoQ10-L may provide an effective exogenous source of the CoQ10 in vivo to protect ischemic cells.
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http://dx.doi.org/10.1007/s11095-007-9334-0DOI Listing
November 2007

ATP-loaded immunoliposomes specific for cardiac myosin provide improved protection of the mechanical functions of myocardium from global ischemia in an isolated rat heart model.

J Drug Target 2006 Jun;14(5):273-80

Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.

Earlier demonstrated cardio-protection by ATP-loaded liposomes (ATP-L) was further improved by attachment of cardiac myosin-specific monoclonal 2G4 antibody onto the surface of ATP-L. ATP-IL were infused for 1 min duration before starting the global ischemia for 25 min followed by reperfusion for 30 min in an isolated rat heart. The left ventricular developed pressure at the end of reperfusion in ATP-IL group significantly recovered to above 80% of the baseline compared to ca 25% in the Kreb's-Henseleit (KH) buffer, ca 60% in the IL, and ca 70% in the ATP-L treated groups. At the end of the reperfusion, left ventricular end diastolic pressure significantly reduced to 15 +/- 2 mmHg in ATP-IL group compared to 59 +/- 6 mmHg in the KH buffer, 31 +/- 4 mmHg in the IL and 23 +/- 3 mmHg in the ATP-L controls. The extent of preservation depended on the amount of the antibody present on the surface of the ATP-IL.
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http://dx.doi.org/10.1080/10611860600763103DOI Listing
June 2006

Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo.

Nat Med 2005 Jun 8;11(6):678-82. Epub 2005 May 8.

E.L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, MA 02114, USA.

A solid tumor is an organ composed of cancer and host cells embedded in an extracellular matrix and nourished by blood vessels. A prerequisite to understanding tumor pathophysiology is the ability to distinguish and monitor each component in dynamic studies. Standard fluorophores hamper simultaneous intravital imaging of these components. Here, we used multiphoton microscopy techniques and transgenic mice that expressed green fluorescent protein, and combined them with the use of quantum dot preparations. We show that these fluorescent semiconductor nanocrystals can be customized to concurrently image and differentiate tumor vessels from both the perivascular cells and the matrix. Moreover, we used them to measure the ability of particles of different sizes to access the tumor. Finally, we successfully monitored the recruitment of quantum dot-labeled bone marrow-derived precursor cells to the tumor vasculature. These examples show the versatility of quantum dots for studying tumor pathophysiology and creating avenues for treatment.
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http://dx.doi.org/10.1038/nm1247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2686110PMC
June 2005

Cell transfection in vitro and in vivo with nontoxic TAT peptide-liposome-DNA complexes.

Proc Natl Acad Sci U S A 2003 Feb 5;100(4):1972-7. Epub 2003 Feb 5.

Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.

Liposomes modified with TAT peptide (TATp-liposomes) showed fast and efficient translocation into the cell cytoplasm with subsequent migration into the perinuclear zone. TATp-liposomes containing a small quantity (
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http://dx.doi.org/10.1073/pnas.0435906100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC149943PMC
February 2003