Kumar A.,University of South Florida |
Jena P.K.,University of South Florida |
Behera S.,Transgenex Nanobiotech, Inc. |
Lockey R.F.,University of South Florida |
And 4 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine
A major problem associated with drug therapy is the inability to deliver pharmaceuticals to a specific site of the body without causing nonspecific toxicity. Development of magnetic nanoparticles and techniques for their safe transport and concentration in specific sites in the body would constitute a powerful tool for gene/drug therapy in vivo. Furthermore, drug delivery in vitro could improve further if the drugs were modified with antibodies, proteins, or ligands. For in vivo experiments, magnetic nanoparticles were conjugated with plasmid DNA expressing enhanced green fluorescent protein (EGFP) and then coated with chitosan. These particles were injected into mice through the tail vein and directed to the heart and kidneys by means of external magnets of 25 gauss or 2kA-kA/m. These particles were concentrated in the lungs, heart, and kidneys of mice, and the expression of EGFP in these sites were monitored. The expression of EGFP in specific locations was visualized by whole-body fluorescent imaging, and the concentration of these particles in the designated body locations was confirmed by transmission electron microscopy. In another model system, we used atrial natriuretic peptide and carcinoembryonic antigen antibodies coupled to the chitosan-coated magnetic nanoparticles to target cells in vitro. The present work demonstrates that a simple external magnetic field is all that is necessary to target a drug to a specific site inside the body without the need to functionalize the nanoparticles. However, the option to use magnetic targeting with external magnets on functionalized nanoparticles could prove as a more efficient means of drug delivery. From the Clinical Editor: This paper addresses targeted drug delivery with magnetic nanoparticles. The authors demonstrate that a simple external magnetic field is sufficient to target a drug to specific sites in the body without the need for functionalized nanoparticles, at least in selected organs and diseases. © 2010 Elsevier Inc. All rights reserved. Source
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 157.89K | Year: 2004
DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop a human-friendly and less-expensive method of prophylaxis for respiratory syncytial virus (RSV) infection and other respiratory viruses using intranasal administration of chitosan nanoparticles containing pDNA, which allows de novo expression of IFNs. Forty-five years after its discovery, no effective vaccine or treatment is currently available against RSV infection. Current prophylaxis for RSV comprises a monthly treatment with a humanized antibody to RSV fusion protein (Palivizumab, Synagis TM) that is only moderately effective in high risk infants, more expensive and its application to adults and elderly is unclear. This proposal focuses on a new concept for prophylaxis and is based on the discovery that intranasal administration of plasmid DNA(s) (pDNA) encoding IFN-gamma, (plFN-gamma) results in a significant decrease of RSV infection in a mouse model. Also, exogenous IFN-gamma/ prevents RSV infection of human epithelial cells and significantly decreases established infection. Also, a combination of plFN-gamma and plFN-beta induces more significant decrease in RSV infection of epithelial cells than either of them alone. Chitosan naoparticles have been developed that facilitate IFNgamma gene transfer in mice. The Transgenex Therapeutics (TGT), a start-up biotech company is developing biopolymers, called chlipoplexes, which protect the pDNAs and target them to the epithelial cells, macrophages or dendritic cells (DCs), where the virus replicates. Together, these developments have led to the working hypothesis that chlipoplexes will deliver effectively the pDNAs without any significant adverse effects in the nasal mucosa and provide significant protection against viral infections. These hypotheses will be tested in this proposal under the following specific aims. Aim #1. To screen and identify the most effective plFN(s) for RSV infection. It is planned to develop human-friendly, nonintegrating pDNA vectors for various IFNs, either singly or in combination and test their antiviral properties in human cell lines. Aim #2. To develop and test chlipoplexes for optimized delivery and expression of plFNs. It is planned to develop chlipoplexes containing pIFNs (CLIP) and test their effectiveness to attenuate RSV infection in the three dimensional air-liquid interphase (ALl) cultures, which mimics the nasal mucosa of humans. Aim #3. To test the selected CLIP(s) in mice. It is planned to test the selected top two CLIPs using the mouse model of RSV infection and investigate their antiviral activity in relation to dosage, safety, and immunological effects in mice. It is anticipated that the results of the studies proposed herein will enhance our understanding of the potential of CLIP as agents for prophylaxis against RSV infection and will move the promising CLIP(s) into phase I clinical trials.
Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase II | Award Amount: 730.47K | Year: 2006
Identification of effective treatments is urgently needed to provide patients with better options in treating ovarian cancer, which afflicts 25,580 Americans annually. Ovarian cancer is caused by genetic alternations; therefore, gene therapy offers a promising approach for the treatment of ovarian cancer. Transgenex Nanobiotech (TGN) Inc has developed a nanoencapsulated transposon system (NTS) for treatment of cancers using its proprietary drug candidate, TGN208. In phase I, TGN has identified nanoparticles that can specifically target to ovary, and optimized the nanotransposon system and identifieded the antineoplastic mechanisms of TGN208. Herein, in phase II TGN proposes to further its R & D on this NTS to pursue the safety and efficacy studies in mouse and rhesus monkey models. The specific technical objectives are: aim #1) to develop DNA constructs for enhanced integration of transposase–tagged transgene and ovary specific expression, aim #2) to identify the most effective transgene for ovarian cancer in mouse models and test the safety, toxicity and pharmacokinetics of the transgene expression and aim #3) to evaluate the untoward effects of TGN208 NTS in nonhuman primate model. These studies are expected to lead the filing of an IND and progress to phase-III involving human studies.
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 158.83K | Year: 2009
DESCRIPTION (provided by applicant): The main goal of this proposal is to design novel treatments for prostate cancer (PCa) that employ specific targeting of curcumin and genistein nanocomplexes to PCa cells. Prostate cancer is the third leading cause of death among men in America. While androgen deprivation has been found to be effective in treating androgen-dependent PCa, it is ineffective in treating advanced PCas which are the major cause of mortality. Recently, the natural products curcumin and genistein have demonstrated anti-inflammatory and anticancer effects in clinical studies, but their potential use for PCa prevention or treatment has been severely limited due to their poor bioavailability. Consequently, increasing solubility and bioavailability and targeted delivery of these products to specific cancer cells has been considered as the most promising strategy for these nontoxic natural products. Transgenex Nanobiotech, Inc. has developed novel nanoparticles for targeted delivery of small molecules such as curcumin and genistein that increase their solubility and stability. Chitosan-cyclodextrin-curcumin (3C) complexes significantly increase curcumin's half-life in biological media with serum. These results have led to the hypothesis that multifunctional 3C nanoparticles further complexed with genistein (3CG) can be delivered to the prostate to inhibit PCa progression and/or metastasis. The choice of curcumin and genistein as anti-PCa agents is based on their complementary effects in terms of bioavailability and synergistic actions in regulating gene expression and signaling, and inhibition of the growth of cancer cells. To test this hypothesis, we will conduct in vivo bioavailability and prostate-specific target ability studies for 3CG nanocomplexes in the first aim. Groups of mice will be given curcumin and genistein separately or together, either alone or in nanocomplxes. The drugs and complexes will be administered intraperitoneally or orally and the bioavailability of curcumin and genistein in the serum will be determined by HPLC. It is also planned to examine the potential of prostate cell specific delivery of 3CG nanoparticles coupled to peptide or antibodies against prostate stem cell antigen (PSCA). The results of Aim 1 will define the most effective route of delivery of 3CG-nanocompleses that will provide increased bioavailability and method for targeting nanoparticles to PCa tumors. In the second aim, it is planned to evaluate the antitumor efficacy of 3CG nanocomplexes delivered specifically to the prostate in TRAMP mice. All the methods and reagents needed for the study are available. Successful targeting of these nanocomplexes with improved bioavailability of the natural antitumor agents with proven safety records is expected to lead to new therapeutics for PCa and other cancers. PUBLIC HEALTH RELEVANCE: The main goal of this proposal is to design novel treatments for prostate cancer (PCa), the third leading cause of death among men in America, that employ specific targeting of curcumin and genistein nanocomplexes to PCa cells. Despite their proven safety record, neither curcumin nor genistein have been tested clinically because of their poor bioavailability. The proposed novel formulation is expected to eliminate the problem of bioavailability and to target the antitumor nanoparticles to prostate cancer cells thereby inhibiting their progression and/or metastasis.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2014