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Wang Y.,Center for Drug Delivery and Nanomedicine | Wang Y.,China Pharmaceutical University | Xie Y.,Center for Drug Delivery and Nanomedicine | Li J.,Center for Drug Delivery and Nanomedicine | And 5 more authors.
ACS Nano | Year: 2017

Poor tumor penetration is a major challenge for the use of nanoparticles in anticancer therapy. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in inadequate exposure to antitumor therapeutics and contributes to development of chemoresistance and increased metastasis. In the present study, we developed iRGD-modified nanoparticles for simultaneous tumor delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ). The iRGD-modified nanoparticles loaded with ICG and TPZ showed significantly improved penetration in both 3D tumor spheroids in vitro and orthotopic breast tumors in vivo. ICG-mediated photodynamic therapy upon irradiation with a near-IR laser induced hypoxia, which activated antitumor activity of the codelivered TPZ for synergistic cell-killing effect. In vivo studies demonstrated that the nanoparticles could efficiently deliver the drug combination in 4T1 orthotopic tumors. Primary tumor growth and metastasis were effectively inhibited by the iRGD-modified combination nanoparticles with minimal side effects. The results also showed the anticancer benefits of codelivering ICG and TPZ in a single nanoparticle formulation in contrast to a mixture of nanoparticles containing individual drugs. The study demonstrates the benefits of combining tumor-penetrating nanoparticles with hypoxia-activated drug treatment and establishes a delivery platform for PDT and hypoxia-activated chemotherapy. © 2017 American Chemical Society.


Raja S.M.,Eppley Institute for Research in Cancer and Allied DiseasesNE | Raja S.M.,Northwestern University | Desale S.S.,Center for Drug Delivery and Nanomedicine | Mohapatra B.,Eppley Institute for Research in Cancer and Allied DiseasesNE | And 12 more authors.
Oncotarget | Year: 2016

Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla®; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor endocytosis and lysosomal routing can provide a novel strategy to significantly improve therapy with ANPs and ADCs.


Kirthivasan B.,St. John's University | Singh D.,St. John's University | Singh D.,Center for Drug Delivery and Nanomedicine | Bommana M.M.,St. John's 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.


Luxenhofer R.,TU Dresden | Luxenhofer R.,University of Würzburg | 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.


Zhao Y.,Center for Drug Delivery and Nanomedicine | Zhao Y.,University of Nebraska Medical Center | Haney M.J.,Center for Drug Delivery and Nanomedicine | Haney M.J.,University of Nebraska Medical Center | And 20 more authors.
Nanomedicine | Year: 2011

Background: We posit that cell-mediated drug delivery can improve transport of therapeutic enzymes to the brain and decrease inflammation and neurodegeneration seen during Parkinsons disease. Our prior works demonstrated that macrophages loaded with nanoformulated catalase ('nanozyme) then parenterally injected protect the nigrostriatum in a murine model of Parkinsons disease. Packaging of catalase into block ionomer complex with a synthetic polyelectrolyte block copolymer precludes enzyme degradation in macrophages. Methods: We examined relationships between the composition and structure of block ionomer complexes with a range of block copolymers, their physicochemical characteristics, and loading, release and catalase enzymatic activity in bone marrow-derived macrophages. Results: Formation of block ionomer complexes resulted in improved aggregation stability. Block ionomer complexes with -polylysine and poly(L-glutamic acid)-poly(ethylene glycol) demonstrated the least cytotoxicity and high loading and release rates. However, these formulations did not efficiently protect catalase inside macrophages. Conclusion: Nanozymes with polyethyleneimine- and poly(L-lysine) 10-poly(ethylene glycol) provided the best protection of enzymatic activity for cell-mediated drug delivery. © 2011 Future Medicine 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.


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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