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Drug Delivery Projects

The following are examples of our drug delivery projects that have been published. We are currently pursuing these and other areas of related research. We consider our biomaterials research to be drug delivery research.
  1. Cervical cancer treatment with a locally insertable controlled release system
  2. Matrix metalloprotease triggered local delivery of cancer chemotherapeutics from hydrogel matrixes
  3. Extracellular protease activation of chemotherapeutics from hydrogel matrices: A new paradigm for local chemotherapy
  4. Cisplatin Delivery From Poly(Acrylic Acid-co-Methyl Methacrylate) Microparticles
  5. Development of amine-containing polymeric nanoparticles
  6. Assessment of a Modular Transfection System based upon Cellular Localization of DNA
  7. Cellular Fate of a Modular DNA Delivery System Mediated by Silica Nanoparticles

Cervical cancer treatment with a locally insertable controlled release system
Keskar, Mohanty, Gemeinhart and Gemeinhart
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Manuscript
Abstract: Local delivery of cancer chemotherapeutics enables sustained drug levels at the site of action thereby reducing systemic side effects. A novel insertable polymeric drug delivery system for cervical cancer treatment is presented. Cisplatin, the first line of therapy employed for cervical cancers, was incorporated in a poly(ethylene-co-vinyl acetate) (EVAc) device that is similar to those currently used for vaginal contraceptive delivery. Cisplatin crystals were uniformly dispersed in the polymeric system without undergoing significant dissolution in the polymer matrix. Cisplatin dissolution from the devices was biphasic, consistent with a matrix-type controlled-release system with an initial rapid release phase followed by a slower, linear release phase. Depending on the drug loading in the polymeric devices, the near-linear release phase varied in rate according both empirical, linear curve-fitting (0.38±0.15 µg/day to 46.9±10.0 µg/day) and diffusion analysis based upon diffusion through a porous structure (Dapp from 1.3±0.5x10-9 cm2/s to 5.8±0.3x10-12 cm2/s). The devices were tested for in vitro activity and found to be effective against both HPV positive and HPV negative cervical cancer cell lines. Preliminary studies indicate that this delivery system would be a good candidate for investigation as a choice of treatment in cervical cancers.
Matrix metalloprotease triggered local delivery of cancer chemotherapeutics from hydrogel matrixes
Tauro and Gemeinhart
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Manuscript
Abstract: Glioblastoma Multiforme (GBM) is a highly advanced and invasive brain tumor due to which current treatments cannot completely treat GBM or prevent recurrence. Therefore, adjunctive treatments are required. As part of the invasive and angiogenic nature of GBM, it has been well established that matrix metalloprotease-2 (MMP-2) and MMP-9 are overactive. To better treat GBM using chemotherapy, we have designed a hydrogel-based delivery system which can control the release of drugs based on the activity of MMPs. A model chemotherapeutic agent, cisplatin, complexed to an MMP substrate (peptide-linker) was incorporated into poly(ethylene glycol) diacrylate hydrogel wafers having different poly(ethylene glycol) chain lengths (Mn ~574 and 4000). Hydrogel wafers were studied for physical characteristics and drug release in the presence and absence of MMPs. There was a substantial increase in cisplatin release for the poly(ethylene glycol) 4000 hydrogel indicating that this chain length provides a mesh size that is sufficient to permit MMP activity within the hydrogel. Cisplatin bioactivity increased when the cell media was spiked with MMPs (0% cell survival) in case of the longer chain length as compared to in the absence of MMPs (approximately 50% cell survival). The results suggest that this system can be used for selective, local delivery of drugs where higher amounts of the drug are released in response to metastasis, angiogenesis, and invasion promoting proteases. This strategy may prove to be a novel and effective method to overcome inadequacies in current controlled drug release systems.
Extracellular protease activation of chemotherapeutics from hydrogel matrices: A new paradigm for local chemotherapy
Tauro and Gemeinhart
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Manuscript
Abstract: A novel paradigm for local cancer chemotherapy, based upon local activation of chemotherapeutic molecules by soluble proteases, is presented. In the presence of matrix metalloproteases, a family of cancer-associated proteases, cisplatin is release from a hydrogel matrix in an active form. In the absence of matrix metalloproteases, cisplatin is released at a much lower rate. The mesh size of the polymer controls metalloprotease-based cisplatin release from the hydrogel matrix with approximately doubling of cisplatin release in the presence of matrix metalloprotease. Overall, this novel paradigm shows much potential for local chemotherapy where local chemotherapeutic release is in response to the invasive properties of the tumor.
Cisplatin Delivery From Poly(Acrylic Acid-co-Methyl Methacrylate) Microparticles
Yan and Gemeinhart
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Manuscript
Abstract: To develop a platform for tumor chemotherapy, poly(acrylic acid-co-methyl methacrylate) microparticles have been synthesized. Carboxylate containing monomers were included to complex therapeutic agents, specifically cisplatin. Microparticles were prepared by free radical emulsion polymerization in aqueous media. Particle diameter, -potential, in vitro cytotoxicity, and in vivo acute toxicity were characterized for both cisplatin-loaded microparticles and unloaded microparticles. In vitro cytotoxicity and FT-IR were used to characterize cisplatin released from cisplatin-loaded microparticles. Acrylic acid feed mole fraction determined several key microparticle properties, including particle size, -potential, and yield. A burst release of cisplatin (40%) in the first day was followed by a zero-order release phase. The interaction between cisplatin and microparticles allowed approximately 20% additional cisplatin release in the next five days. Cisplatin-loaded and unloaded microparticles are non-toxic (LC50 > 15 mM) to the cell line used in in vitro tests. Cisplatin released from cisplatin-loaded microparticles retained activity, but that activity was slightly lower than freshly prepared cisplatin. Other than a slight reduction in cisplatin activity, microparticles exhibited low in vivo acute toxicity (LD50 > 170 mg/kg), which suggests that this hydrogel particulate system and the hydrogel complexation mechanism should further be studied for drug delivery.
Development of amine-containing polymeric nanoparticles
Tauro and Gemeinhart
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Manuscript
Abstract: The objective of this study was to synthesize and characterize particles as a drug delivery platform for gliomas, a highly advanced and invasive stage of brain tumor with poor prognosis. Poly(aminoethyl methacrylate-co-methyl methacrylate) particles were prepared by suspension polymerization and poly(aminoethyl methacrylate-co-poly(ethylene glycol) methacrylate) particles were prepared by emulsion (w/o) polymerization. Amine groups of the particles were complexed with tetrachloroplatinate to form a cisplatin-like molecule. Particles were characterized with respect to size, -potential, amine content, loading efficiency and drug release. Poly(aminoethyl methacrylate-co-methyl methacrylate) particles had diameters of below 10 m, whereas the poly(aminoethyl methacrylate-co-poly(ethylene glycol) methacrylate) particles had diameters of approximately 1 m. Poly(aminoethyl methacrylate-co-poly(ethylene glycol) methacrylate) particles had a more positive -potential as compared to poly(aminoethyl methacrylate-co-methyl methacrylate) particles, although the amino group content of both particles was almost equivalent. The net positive charge on the particles decreased after complexation with tetrachloroplatinate for both types of particles. Both particles had very high platinum loading efficiency (>85%) and showed slow release of platinum over time. Particles had relatively low cytotoxicity (LC50 > 100 g/mL) and demonstrated a high degree of association with cells. Complexation with poly(aminoethyl methacrylate-co-methyl methacrylate) particles significantly reduced the toxicity of platinum. The poly(aminoethyl methacrylate-co-poly(ethylene glycol) methacrylate) particles have potential for being an effective drug delivery platform and continued investigation is warranted.
Assessment of a Modular Transfection System based upon Cellular Localization of DNA
Guo and Gemeinhart
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Manuscript
Abstract: Delivery of plasmid DNA for protein production in mammalian cells is not an efficient process. In this study, the theory that cellular localization of plasmid DNA increases transfection efficiency is examined with an emphasis on the understanding of the cellular association of the components of a ternary transfection complex. Mammalian cells take up transfection reagent-DNA complexes primarily from their local environment. By complexing DNA-transfection reagent into a ternary complex with a heavy particle, such as silica, the efficiency of transfection is substantially increased. We have analyzed cells transfected with the ternary complexes to determine if sedimentation alone affects the percentage of cells that contain the complexes or specific components of the complex. A significant fraction of cells associate with the ternary complexes including silica nanoparticles. The percentage of cells that associate with DNA was not significantly influenced by the use of the ternary complex. This result suggests that the role of the silica nanoparticles is more than just a sedimentation agent, but the silica nanoparticles are a secondary transfection reagent. This data also confirms that cells may contain transfection reagent-DNA complex but do not express the protein of interest. This knowledge will be used in further research to better design transfection reagents that will increase the efficiency of protein production.
Cellular Fate of a Modular DNA Delivery System Mediated by Silica Nanoparticles
Gemeinhart, Luo, and Saltzman
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Manuscript
Abstract: Development of efficient molecular medicines, including gene therapeutics, RNA therapeutics, and DNA vaccines, depends upon efficient means of transfer of DNA or RNA into the cell. Potential problems, including toxicity and immunogenicity, surrounding viral methods of DNA delivery have necessitated the use of non-viral, synthetic carriers. To better design synthetic carriers, or transfection reagents, the modular design of viruses has inspired a modular approach to DNA and RNA delivery. Each modular component can be designed to circumvent each of the many barriers. The modular approach will allow modification of individual components for a specific application. By utilizing a dense silica nanoparticle to form a ternary complex, transfection efficiency of a DNA-transfection reagent complex was increased by a factor of approximately 10 by concentrating the DNA at the surface of cells. Surface modification of the silica nanoparticles allowed determination of the cellular uptake mechanism with only minor alteration of transfection efficiency. Nanoparticles are internalized by an endosome-lysosomal route followed by perinuclear accumulation. The modification mechanism confirms that surface modification of the modular system can allow specific moieties to be incorporated into the modular system without significant alteration of the transfection efficiency. By showing that the modular system based upon concentration of DNA at the level of the cell can be used to increase transfection efficiency, we have shown that further modification of the system may better target DNA delivery and overcome other barriers of DNA expression.
Input Richard A. Gemeinahrt: BPS, College of Pharmacy in Other
Designed and implemented by R. A. Gemeinhart, Ph.D. All rights researved. © 2001-2011 Last Modified: 10/20/2011
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Inspired by many websites online, but in particular those implemented by Tonglei Li (http://xtal.gws.uky.edu/).
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