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Sanna V.,Laboratory of Nanomedicine
Journal of Polymer Science, Part A: Polymer Chemistry | Year: 2016

Polydiolcitrates are an emerging class of biocompatible polyesters with a great potential in the field of biomedicine and packaging for food and drug materials. In this work, a new type of (co-)polydiolcitrates made of citric acid (CA) and ethylene glycol (EG) and/or poly(ethylene glycol) (PEG) is investigated. By varying both the EG/PEG and the CA/diol molar ratios, materials exhibiting very different swelling behavior, mechanical and thermal properties are obtained. In particular, the substitution of EG segments with longer and flexible PEG ones results in an increase in crosslinking density, with remarkable effects on swelling capacity, glass transition temperature, and Young modulus. Moreover, polyesters with CA/diol molar ratio equal to 1:1 exhibit shape memory properties, with full capacity of keeping the temporary shape and high capacity of recovering the original shape. This work demonstrates that the appropriate choice of polyester composition allows modulating the sample properties, that permits to these materials to cover a wide range of possible applications. © 2016 Wiley Periodicals, Inc.


Bogart L.K.,University of Liverpool | Pourroy G.,CNRS Institute of Genetics and of Molecular and Cellular Biology | Murphy C.J.,University of Illinois at Urbana - Champaign | Puntes V.,Catalan Institution for Research and Advanced Studies | And 6 more authors.
ACS Nano | Year: 2014

Nanoparticles have the potential to contribute to new modalities in molecular imaging and sensing as well as in therapeutic interventions. In this Nano Focus article, we identify some of the current challenges and knowledge gaps that need to be confronted to accelerate the developments of various applications. Using specific examples, we journey from the characterization of these complex hybrid nanomaterials; continue with surface design and (bio)physicochemical properties, their fate in biological media and cells, and their potential for cancer treatment; and finally reflect on the role of animal models to predict their behavior in humans. © 2014 American Chemical Society.


Dvash R.,Laboratory of NanoMedicine | Dvash R.,Tel Aviv University | Khatchatouriants A.,Tel Aviv University | Solmesky L.J.,Laboratory for Neurodegenerative Diseases and Personalized Medicine | And 5 more authors.
Journal of Controlled Release | Year: 2013

In spite of significant insolubility and toxicity, carbon nanotubes (CNTs) erupt into the biomedical research, and create an increasing interest in the field of nanomedicine. Single-walled CNTs (SWCNTs) are highly hy-drophobic and have been shown to be toxic while systemically administrated. Thus, SWCNTs have to be functionalized to render water solubility and biocompatibility. Herein, we introduce a method for functionalizing SWCNT using phospholipids (PL) conjugated to hyaluronan (HA), a hydrophilic glycosaminoglycan, with known receptors on many types of cancer and immune cells. This functionalization allowed for CNT solubi-lization, endowed the particles with stealth properties evading the immune system, and reduced immune and mitochondrial toxicity both in vitro and in vivo. The CNT-PL-HA internalized into macrophages and showed low cytotoxicity. In addition, CNT-PL-HA did not induce an inflammatory response in macrophages as evidenced by the cytokine profiling and the use of image-based high-content analysis approach in contrast to non-modified CNTs. In addition, systemic administration of CNT-PL-HA into healthy C57BL/6 mice did not alter the total number of leukocytes nor increased liver enzyme release as opposed to CNTs. Taken together, these results suggest an immune protective mechanism by the PL-HA coating that could provide future therapeutic benefit. © 2013 Elsevier B.V. All rights reserved.


Cohen Z.R.,Sheba Medical Center | Ramishetti S.,Laboratory of NanoMedicine | Ramishetti S.,Tel Aviv University | Peshes-Yaloz N.,Sheba Medical Center | And 6 more authors.
ACS Nano | Year: 2015

Glioblastoma multiforme (GBM) is one of the most infiltrating, aggressive, and poorly treated brain tumors. Progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, yet the vast majority of these leading drug candidates for the treatment of GBM are ineffective, mainly due to restricted passages across the blood-brain barrier. Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects. Herein, we devised a localized strategy to deliver RNA interference (RNAi) directly to the GBM site using hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNP's surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells. We found that HA-LNPs can successfully bind to GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA-LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, our results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM. © 2015 American Chemical Society.


Elinav E.,Weizmann Institute of Science | Peer D.,Laboratory of NanoMedicine | Peer D.,Tel Aviv University
ACS Nano | Year: 2013

Inflammatory bowel disease (IBD) has been extensively studied in the last four decades both in animal models and humans. The treatment options remain disappointing, nonspecific, and associated with multiple systemic adverse effects. In this Perspective, we highlight issues related to emerging nanotechnologies designed particularly for treatment and disease management of IBD and discuss potential therapeutic target options with novel molecular imaging modalities. © 2013 American Chemical Society.


Sanna V.,University of Sassari | Sanna V.,University of Wisconsin - Madison | Siddiqui I.A.,University of Wisconsin - Madison | Sechi M.,University of Sassari | And 3 more authors.
Molecular Pharmaceutics | Year: 2013

Nanoencapsulation of antiproliferative and chemopreventive phytoalexin trans-resveratrol (RSV) is likely to provide protection against degradation, enhancement of bioavailability, improvement in intracellular penetration and control delivery. In this study, polymeric nanoparticles (NPs) encapsulating RSV (nano-RSV) as novel prototypes for prostate cancer (PCa) treatment were designed, characterized and evaluated using human PCa cells. Nanosystems, composed of a biocompatible blend of poly(epsilon-caprolactone) (PCL) and poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) conjugate (PLGA-PEG-COOH), were prepared by a nanoprecipitation method, and characterized in terms of morphology, particle size and zeta potential, encapsulation efficiency, thermal analyses, and in vitro release studies. Cellular uptake of NPs was then evaluated in PCa cell lines DU-145, PC-3, and LNCaP using confocal fluorescence microscopy, and antiproliferative efficacy was assessed using MTT assay. With encapsulation efficiencies ranging from 74% to 98%, RSV was successfully loaded in PCL:PLGA-PEG-COOH NPs, which showed an average diameter of 150 nm. NPs were able to control the RSV release at pH 6.5 and 7.4, mimicking the acidic tumoral microenvironment and physiological conditions, respectively, with only 55% of RSV released within 7 h. In gastrointestinal simulated fluids, NPs released about 55% of RSV in the first 2 h in acidic medium, and their total RSV content within the subsequent 5 h at pH 7.4. Confocal fluorescence microscopy observations revealed that NPs were efficiently taken up by PCa cell lines. Furthermore, nano-RSV significantly improved the cytotoxicity compared to that of free RSV toward all three cell lines, at all tested concentrations (from 10 μM to 40 μM), proving a consistent sensitivity toward both the androgen-independent DU-145 and hormone-sensitive LNCaP cells. Our findings support the potential use of developed nanoprototypes for the controlled delivery of bioactive RSV for PCa chemoprevention/chemotherapy. © 2013 American Chemical Society.


Peer D.,Laboratory of NanoMedicine | Peer D.,Tel Aviv University
Immunological Reviews | Year: 2013

RNA interference (RNAi) has advanced into clinical trials. In spite of the progress made in systemic RNAi delivery to the liver and solid tumors, delivery of RNAi to leukocytes remains challenging and less advanced. Manipulating leukocyte function with RNAi holds great promise for streamlining the drug discovery process by facilitating in vivo drug target validation and for facilitating the development of RNAi-based therapy platforms for leukocyte-implicated diseases, such as blood cancer, inflammation, and leukocyte-tropic viral infections. In this review, progress in delivery strategies of RNAi payloads to leukocytes, which are notoriously difficult cells to transduce with RNAi, is discussed with special emphasis on the challenges and potential opportunities for manipulating leukocyte function with RNAi. © 2013 John Wiley & Sons A/S.


Cao Y.,Tianjin University | Gao M.,Tianjin University | Chen C.,Tianjin University | Fan A.,Tianjin University | And 6 more authors.
Nanotechnology | Year: 2015

Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on-demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6±5.9 (nm) with a zeta potential of -10.6±0.7 (mV). The critical micelle concentration was determined at 6.7±0.4 (μg mL-1). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond-linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC50) in HeLa cells at 18.5±1.4 (μg mL-1), whereas the IC50 of control micelles was 41.0±2.4 (μg mL-1). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox-sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice. © 2015 IOP Publishing Ltd.


Weinstein S.,Laboratory of Nanomedicine | Weinstein S.,Tel Aviv University | Peer D.,Laboratory of Nanomedicine | Peer D.,Tel Aviv University
Nanotechnology | Year: 2010

RNAi, as a novel therapeutic modality, has an enormous potential to bring the era of personalized medicine one step further from notion into reality. However, delivery of RNAi effector molecules into their target tissues and cells remain extremely challenging. Major attempts have been made in recent years to develop sophisticated nanocarriers that could overcome these hurdles. This review will present the recent progress with the challenges and opportunities in this emerging field, focusing mostly on the invivo applications with special emphasis on the strategies for RNAi delivery into immune cells. © 2010 IOP Publishing Ltd.


PubMed | Laboratory of Nanomedicine
Type: Journal Article | Journal: Advanced drug delivery reviews | Year: 2012

RNA interference (RNAi) has just made it through the pipeline to clinical trials. However, in order for RNAi to serve as an ideal personalized therapeutics and be clinically approved-safe, specific, and potent strategies must be devised for efficient delivery of RNAi payloads to specific cell types, which despite the immense potential, remains a challenge. Through evaluating the recent reported studies in this field, we introduce the progress in designing targeted nano-scaled strategies that are anticipated to overcome the delivery drawbacks and along with the exciting omics discipline to personalize RNAi-based therapeutics.

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