The Salem Laboratory
of Advanced Drug and Gene Delivery
The Salem Laboratory
of Advanced Drug and Gene Delivery
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Research in the Salem group is broadly split into three areas:
1) Developing innovative delivery strategies to promote antigen-specific immune responses by delivering CpG oligonucleotides, antigens or plasmid DNA Representative recent publications: R. Goforth, A.K. Salem, X. Zhu, S. Miles, X.Q. Zhang, J. Lee, A.D. Sandler. Immune stimulatory antigen loaded particles combined with depletion of regulatory T-cells induce potent tumor specific immunity in a mouse model of melanoma. Cancer Immunology, Immunotherapy. 2009 Y. Krishnamachari and A.K. Salem. Innovative Strategies for Co-delivering Antigens and CpG Oligonucleotides. Advanced Drug Delivery Reviews. 2009 J. Intra, J.M Glasgow, H. Q. Mai, A.K. Salem. Pulsatile release of biomolecules from polydimethylsiloxane (PDMS) chips with hydrolytically degradable seals. Journal of Controlled Release. 2008 Y. Krishnamachari, M.E. Pearce, A.K. Salem. Self-assembly of cell-microparticle hybrids. Advanced Materials. 2008 X.Q. Zhang, C.E. Dahle, G.J. Weiner and A.K. Salem. A comparative study of the antigen-specific immune response induced by co-delivery of CpG ODN and antigen using fusion molecules or biodegradable microparticles. Journal of Pharmaceutical Sciences. 2007 X.Q. Zhang, C.E. Dahle, N.K. Baman, N. Rich, G.J. Weiner and A.K. Salem. Potent antigen-specific immune responses stimulated by co-delivery of CpG ODN and antigens in degradable microparticles. Journal of Immunotherapy, 30 (5): 469-478 July/August 2007
2) Developing and optimizing novel drug or gene delivery vehicles Representative recent publications: J. Intra, A.K. Salem. Fabrication, characterization and in vitro evaluation of poly lactic-co-glycolic acid microparticles loaded with polyamidoamine-plasmid DNA dendriplexes for applications in non-viral gene delivery. Journal of Pharmaceutical Sciences 2009 J. Intra, A.K. Salem. Characterization of the transgene expression generated by branched and linear polyethylenimine (PEI)-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo. Journal of Controlled Release 2008 M.E. Pearce, H.Q. Mai, N. Lee, S.C. Larsen, A.K. Salem. Silicalite nanoparticles that promote transgene expression. Nanotechnology 2008 X.Q. Zhang, J. Intra, A.K. Salem. Comparative study of poly (lactic-co-glycolic acid)-poly ethyleneimine-plasmid DNA microparticles prepared using double emulsion methods. Journal of Microencapsulation. 2008 A.O. Abbas, M.D. Donovan, A.K. Salem. Formulating PLGA particles for plasmid DNA delivery. Journal of Pharmaceutical Sciences. 2008 X.Q. Zhang, J. Intra, A.K. Salem. Conjugation of polyamidoamine dendrimers on biodegradable microparticles for non-viral gene delivery. Bioconjugate Chemistry. 2007 M.E. Pearce, J.B. Melanko, A.K. Salem. Biomedical applications of multifunctional nanorods. Pharmaceutical Research. 2007
3) Optimizing control over cell-material interactions. Representative recent publications: A. Petushkov, J. Intra, J.B. Graham, S.C. Larsen, A.K. Salem. Effect of Crystal Size and Surface Functionalization on the Cytotoxicity of Silicalite-1 Nanoparticles. Chemical Research in Toxicology. 2009 J.D. Clapper, M.E. Pearce, C.A. Guymon, A.K. Salem. Biotinylated Biodegradable Nanotemplated Hydrogel Networks for Cell Interactive Applications. Biomacromolecules 2008 J. Sinclair, A.K. Salem. Rapid localized cell trapping on biodegradable polymers using cell surface derivatization and microfluidic networking. Biomaterials. 27 2090-2094 MAR 2006 N.K Baman, G.B. Schneider, T.L. Terry, R. Zaharias, A.K. Salem. Spatial control over cell attachment by partial solvent entrapment of poly lysine in microfluidic channels. International Journal of Nanomedicine, 1 (2): APR 2006
Examples of research projects that the Salem group are currently involved in investigating:
Stimulating
immune responses against carcinomas using degradable particles and CpG
oligonucleotide motifs as adjuvants to prompt the T-helper 1 response. Collaborator: Prof George
Weiner MD, Director, Project Description: Bacterial DNA and synthetic oligodeoxynucleotides containing the cytosine-phosphorothioate-guanine oligodeoxynucleotide motifs (CpG ODN) have shown significant potential in acting as an effective adjuvant to antigens for generating strong immune responses against lymphomas. We have recently shown that the CpG motif must be co-delivered with the antigen in order for the CpG motif to be an effective adjuvant to the antigen. In addition, when the CpG motifs and antigens are injected intravenously, they remain susceptible to enzymatic degradation. The use of biodegradable particles for delivering antigens is an attractive approach for immunization. These particles can target specific cell types (with targeting ligand strategies), are non-toxic to cells, protect antigens and CpG ODN from enzymatic degradation, enable preferential uptake by antigen presenting cells ensuring both components are delivered to the same cell, and can provide sustained release of antigens/CpG ODNs, negating the requirement for repeat doses or boosters.
Developing patient specific bench to clinic immunotherapeutics using degradable particles and resected tumors, CpG ODN, GM-CSF and other immunostimulatory molecules. Collaborator: Prof Tony Sandler MD, Department of Pediatric Surgery, Childrens National Medical Center, Washington DC
Developing combined non-viral nanoparticles and adenoviruses as an immunotherapeutic vaccine for treatment and prevention of prostate cancer. Prostate cancer affects over 15% of all men. Prostate cancer, when metastatic, is ultimately incurable. As a result, alternative strategies including immunotherapy are being increasingly investigated. PSA is an ideal target antigen for immunotherapy because it has a narrow distribution in tissues and is expressed in virtually all prostate cancers. Gene delivery techniques have the potential to stimulate potent anti-tumor immunity. To date, studies have either focused on non-viral delivery systems such as plasmid DNA-polycation complex co-acervates or viral approaches such as the use of adenoviruses encoding prostate specific antigen (PSA). Non-viral plasmid DNA sequences contain CpG motifs. CpG motifs enhance the efficacy of Ad5-PSA vaccines tumor protection. CpG ODN delivered in particulate form is significantly more potent than delivery in solution. Chitosan is a safe natural polymer that complexes with plasmid DNA (with CpG motifs) to form non-viral gene delivery nanoparticles. The objective of this proposal is to test the hypothesis that co-delivery of chitosan-pcDNA-PSA nanoplexes with AdPSA will enhance tumor protection in a murine model of prostate cancer. Collaborator: Prof David Lubaroff, Department of Urology, Carver College of Medicine, University of Iowa.
Using localized solvent implosion to prepare porous particles for pulmonary drug delivery applications. Collaborator: Prof. Victor Rodgers, University of California Project Description: Porous particles hold significant advantages over regular non-porous particles in pulmonary drug delivery applications because of superior airborne properties. We have recently developed a novel single step procedure for preparing porous particles with well-defined porous architectures by fine-tuning the localized implosion of solvents during evaporation. Below is an example of a degradable polymeric particle prepared using our novel procedure. Currently we are evaluating the impact of co-solvents and various other parameters on particle preparation. These porous particles are then being assessed for aerodynamic properties, density and impaction measurements.
Image taken by graduate student Treniece Terry
Developing single dose injectable depots that provide controlled release of dopamine reuptake inhibitors to provide sustained intervention of the rewards of methamphetamine and cocaine. Collaborators: Rodefer, Prisinzano and Donovan Project Description:
GBR 12909 and analogues are Dopamine Reuptake Inhibitors that interfere with the reward mechanisms in cocaine and methamphetamine abuse.
Developing
gene delivery applications for zeolite tubes with nanoporous structures. Collaborator: Prof Sarah
Larsen, Chemistry Project Description: The
objective of this project is to test the hypothesis that novel ZSM-5 tubes with
electrostatically bound plasmids encoding the reporter genes luciferase or green
fluorescent protein (GFP) can generate strong transgene expression in human
embryonic kidney 293 (HEK293) cells.
Combining microfabrication techniques, microfluidic patterning, surface engineering, polymer synthesis and novel cell culture methodologies to improve and optimize spatial control of cell binding and cell-cell interactions.
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