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Kirthivasan B.,St. Johns University | Singh D.,St. Johns University | Singh D.,Center for Drug Delivery and Nanomedicine | Bommana M.M.,St. Johns University | And 3 more authors.
Nanotechnology | Year: 2012

Magnetic nanoparticles (NP) were developed for the active brain targeting of water-soluble P-glycoprotein (P-gp) substrate rhodamine 123 (Rh123). The NP matrix of poly(lactide-co-glycolide) (PLGA) and methoxy poly(ethyleneglycol)- poly(lactic acid) (M-PEG-PLA) was prepared by single emulsion solvent evaporation of polymers with oleic acid-coated magnetic nanoparticles (OAMNP) and Rh123. All formulations were characterized in terms of morphology, particle size, magnetic content and Rh123 encapsulation efficiency. The maximum encapsulation efficiency of Rh123 was 45±3% and of OAMNP was 42±4%. The brain targeting and biodistribution study was performed on Sprague Dawley rats (3 groups, n=6). Rh123 (0.4mgkg 1) was administered in saline form, NP containing Rh123, and NP containing Rh123 in the presence of a magnetic field (0.8T). The fluorimetric analysis of brain homogenates revealed a significant uptake (p<0.05) of Rh123 in the magnetically targeted group relative to controls. These results were supported by fluorescence microscopy. This study reveals the ability of magnetically targeted nanoparticles to deliver substances to the brain, the permeation of which would otherwise be inhibited by the P-gp system. © 2012 IOP Publishing Ltd.

Sahay G.,Center for Drug Delivery and Nanomedicine | Gautam V.,University of Nebraska Medical Center | Luxenhofer R.,Center for Drug Delivery and Nanomedicine | Kabanov A.V.,Center for Drug Delivery and Nanomedicine | Kabanov A.V.,Moscow State University
Biomaterials | Year: 2010

Amphiphilic triblock copolymer, poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Pluronic® P85, is unexpectedly shown to utilize sophisticated cellular trafficking mechanisms and enter brain microvessel endothelial cells and primary neurons that are poorly penetrable. Though caveolae serve as a primary entry site for the copolymer single chains, in cells devoid of caveolae, the copolymer can still exploit caveolae- and clathrin-independent routes. This parallels the copolymer's trafficking itinerary with that of biological pathogens. The similarity is reinforced since both bypass early endosomes/lysosomes and transport to the endoplasmic reticulum. The copolymer finally reaches the mitochondrion that serves as its final destination. Notably, it also succeeds to gain entry in brain microvessel endothelial cells through caveolae and in primary neurons through caveolae- and clathrin-independent pathway. In neurons the copolymer accumulates in the cell body followed by anterograde trafficking towards the axons/dendrites. Overall, dissecting the trafficking of a synthetic polymer in multiple cell types triggers development of novel delivery systems that can selectively target intracellular compartments and provide entry in cells currently considered impenetrable.

Luxenhofer R.,TU Dresden | Luxenhofer R.,University of Wurzburg | Huber S.,TU Munich | Hytry J.,TU Dresden | And 5 more authors.
Journal of Polymer Science, Part A: Polymer Chemistry | Year: 2013

We describe the synthesis and characterization of the first water-soluble and chiral poly(2,4-disubstituted-2-oxazoline)s. While poly(2,4-dimethyl-2- oxazoline)s are water soluble up to 100 °C, aqueous solutions of poly(2-ethyl-4-methly-2-oxazoline) exhibit a lower critical solution temperature. This is discussed in context with its constitutional isomers poly(2-oxazoline)s and poly(2-oxazine)s. Circular dichroism spectroscopy revealed strong Cotton effects, which are also responsive to temperature in aqueous solution. It is therefore hypothesized that structures, comparable to polyproline helices, are formed in aqueous solution. In contrast to polyproline, poly(2,4-disubstituted-2-oxazoline)s are highly water soluble and therefore represent very interesting pseudo-polypeptides that may be useful to develop responsive biomimetic biomaterials. © 2012 Wiley Periodicals, Inc.

Sahay G.,Center for Drug Delivery and Nanomedicine | Kim J.O.,Center for Drug Delivery and Nanomedicine | Kabanov A.V.,Center for Drug Delivery and Nanomedicine | Kabanov A.V.,Moscow State University | Bronich T.K.,Center for Drug Delivery and Nanomedicine
Biomaterials | Year: 2010

Polymeric micelles with cross-linked ionic cores of poly(methacrylic acid) and nonionic shell of poly(ethylene oxide) (cl-micelles) are shown here to readily internalize in epithelial cancer cells but not in normal epithelial cells that form tight junctions (TJ). The internalization of such cl-micelles in the cancer cells proceeded mainly through caveolae-mediated endocytosis. In confluent normal epithelial cells this endocytosis route was absent at the apical side and the cl-micelles sequestered in TJ regions of the cell membrane without entering the cells for at least 24 h. Disruption of the TJ by calcium deprivation resulted in redistribution of cl-micelles inside the cells. In cancer cells following initial cellular entry the cl-micelles bypassed the early endosomes and reached the lysosomes within 30 min. This allowed designing cl-micelles with cytotoxic drug, doxorubicin, linked via pH-sensitive hydrazone bonds, which were cleaved in the acidic environment of lysosomes resulting in accumulation of the drug in the nucleus after 5 h. Such pH-sensitive cl-micelles displayed selective toxicity to cancer cells but were non-toxic to normal epithelial cells. In conclusion, we describe major difference in interactions of cl-micelles with cancer and normal cells that can lead to development of novel drug delivery system with reduced side effects and higher efficacy in cancer chemotherapy.

Zhang H.,Center for Drug Delivery and Nanomedicine | Zhang H.,University of Massachusetts Medical School | Gerson T.,Center for Drug Delivery and Nanomedicine | Varney M.L.,University of Nebraska Medical Center | And 2 more authors.
Pharmaceutical Research | Year: 2010

Purpose To enhance transfection efficacy of pDNA through the application ofmultifunctional peptide-PEG-tris-acridine conjugates ( pPAC) and the formation of biodegradable core-shell polyplexes for gene delivery to the blood-brain barrier (BBB). Methods pPAC-mediated transfection was compositionally optimized in mouse BBB cells (bEnd.3). Cellular uptake and trafficking, and brain accumulation of pDNA was evaluated by fluorescent imaging and histochemistry. We constructed anti- MRP4 siRNA-producing vectors and evaluated the efficacy of MRP4 down-regulation of MRP4 by Western blot and qPCR, and its effect on the uptake of 3H-AZT, an MRP4 substrate. Results A core-shell gene delivery system (GDS) was assembled from pDNA and pPAC, carrying multifunctional peptides with NLS, TAT, and brain-specific BH, or ApoE sequences, and biodegradable pLPEI polyamine. This GDS demonstrated better cellular and nuclear accumulation, and a 25-fold higher transfection efficacy in slow-dividing bEnd.3 cells compared to ExGen500. Inclusion of brain-targeting pPAC enhanced in vivo accumulation of functional pDNA in brain capillaries. Treatment by encapsulated anti-MRP4 siRNAproducing pDNA caused transient down-regulation of MRP4, and, after intravenous injection in Balb/c mice, enhanced AZT uptake in the brain by 230-270%. Conclusions The pPAC represent novel efficient components of GDS that could find various gene therapy applications, including genetic modulation of the BBB. © Springer Science+Business Media, LLC 2010.

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