74 results on '"Prausnitz, Mark R."'
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2. The promise of microneedle technologies for drug delivery
- Author
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Donnelly, Ryan F. and Prausnitz, Mark R.
- Abstract
Microneedle (MN) technologies offer the opportunity to improve patient access and target delivery of drugs and vaccines to specific tissues. When in the form of skin patches, MNs can be administered by personnel with minimal training, or could be self-administered by patients, which can improve access to medication, especially those usually requiring injection. Because MNs are small (usually sub-millimetre), they can be used for precise tissue targeting. MN patches have been extensively studied to administer vaccines and drugs in preclinical work as well as in multiple clinical trials. When formulated with biodegradable polymer, MNs can enable long-acting therapies by slowly releasing drug as the MNs biodegrade. Targeted drug delivery by hollow MNs has resulted in FDA-approved products that are able to inject vaccines to skin-resident immune cells to improve immune response and to target specific parts of the eye (e.g., suprachoroidal space) for increased efficacy and avoidance of side effects in other parts of the eye. Cosmetic products based on MN technologies are already in widespread use, mostly as anti-aging agents. With extensive research coupled with FDA-approved products, MN technology promises to continue is growth in research leading to products that can benefit patients.
- Published
- 2024
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3. Interrogating Encapsulated Protein Structure within Metal–Organic Frameworks at Elevated Temperature.
- Author
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Murty, Rohan, Bera, Mrinal K., Walton, Ian M., Whetzel, Christina, Prausnitz, Mark R., and Walton, Krista S.
- Published
- 2023
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4. Interrogating Encapsulated Protein Structure within Metal–Organic Frameworks at Elevated Temperature
- Author
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Murty, Rohan, Bera, Mrinal K., Walton, Ian M., Whetzel, Christina, Prausnitz, Mark R., and Walton, Krista S.
- Abstract
Encapsulating biomacromolecules within metal–organic frameworks (MOFs) can confer thermostability to entrapped guests. It has been hypothesized that the confinement of guest molecules within a rigid MOF scaffold results in heightened stability of the guests, but no direct evidence of this mechanism has been shown. Here, we present a novel analytical method using small-angle X-ray scattering (SAXS) to solve the structure of bovine serum albumin (BSA) while encapsulated within two zeolitic imidazolate frameworks (ZIF-67 and ZIF-8). Our approach comprises subtracting the scaled SAXS spectrum of the ZIF from that of the biocomposite BSA@ZIF to determine the radius of gyration of encapsulated BSA through Guinier, Kratky, and pair distance distribution function analyses. While native BSA exposed to 70 °C became denatured, in situ SAXS analysis showed that encapsulated BSA retained its size and folded state at 70 °C when encapsulated within a ZIF scaffold, suggesting that entrapment within MOF cavities inhibited protein unfolding and thus denaturation. This method of SAXS analysis not only provides insight into biomolecular stabilization in MOFs but may also offer a new approach to study the structure of other conformationally labile molecules in rigid matrices.
- Published
- 2023
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5. Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.
- Author
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Chen, Qian, Xiao, Zhisheng, Wang, Chao, Chen, Guojun, Zhang, Yuqi, Zhang, Xudong, Han, Xiao, Wang, Jinqiang, Ye, Xiao, Prausnitz, Mark R., Li, Song, and Gu, Zhen
- Published
- 2022
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6. Effect of Surface Interactions on Microsphere Loading in Dissolving Microneedle Patches.
- Author
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Jang, Derek, Tang, Jie, Schwendeman, Steven P., and Prausnitz, Mark R.
- Published
- 2022
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7. HOW CHEMICAL ENGINEERING STUDENTS HAVE CHANGED OVER TWO DECADES: A PERSPECTIVE FROM GEORGIA TECH.
- Author
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Prausnitz, Mark R., Cuba-Torres, Christian M., Nian Liu, and Yunki Lee
- Subjects
CHEMICAL engineering education ,ENGINEERING students ,COVID-19 vaccines ,CHEMICAL engineers - Published
- 2022
8. Computational modelling of scleral photocrosslinking: from rat to minipig to human
- Author
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Wood-Yang, Amy J., Gerberich, Brandon G., and Prausnitz, Mark R.
- Abstract
Selective scleral crosslinking has been proposed as a novel treatment to increase scleral stiffness to counteract biomechanical changes associated with glaucoma and high myopia. Scleral stiffening has been shown by transpupillary peripapillary scleral photocrosslinking in rats, where the photosensitizer, methylene blue (MB), was injected retrobulbarly and red light initiated crosslinking reactions with collagen. Here, we adapted a computational model previously developed to model this treatment in rat eyes to additionally model MB photocrosslinking in minipigs and humans. Increased tissue length and subsequent diffusion and light penetration limitations were found to be barriers to achieving the same extent of crosslinking as in rats. Per cent inspired O2, injected MB concentration and laser fluence were simultaneously varied to overcome these limitations and used to determine optimal combinations of treatment parameters in rats, minipigs and humans. Increasing these three treatment parameters simultaneously resulted in maximum crosslinking, except in rats, where the highest MB concentrations decreased crosslinking. Additionally, the kinetics and diffusion of photocrosslinking reaction intermediates and unproductive side products were modelled across space and time. The model provides a mechanistic understanding of MB photocrosslinking in scleral tissue and a basis for adapting and screening treatment parameters in larger animal models and, eventually, human eyes.
- Published
- 2024
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9. Effect of Surface Interactions on Microsphere Loading in Dissolving Microneedle Patches
- Author
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Jang, Derek, Tang, Jie, Schwendeman, Steven P., and Prausnitz, Mark R.
- Abstract
Microneedle (MN) patches enable simple self-administration of drugs via the skin. In this study, we sought to deliver drug-loaded microspheres (MSs) using MN patches and found that the poly(lactic-co-glycolic acid) (PLGA) MSs failed to localize in the MN tips during fabrication, thereby decreasing their delivered dose and delivery efficiency into skin. We determined that surface interactions between the hydrophobic MSs and the poly(dimethylsiloxane) (PDMS) mold caused MSs to adhere to the mold surface during casting in aqueous formulations, with hydrophobic interactions largely responsible for adhesion. Further studies with polystyrene MSs that similarly carry a negative charge like the PLGA MSs demonstrated both repulsive electrostatic interactions as well as adhesive hydrophobic interactions. Reducing hydrophobic interactions by addition of a surfactant or modifying mold surface properties increased MS loading into MN tips and delivery into porcine skin ex vivo by 3-fold. We conclude that surface interactions affect the loading of hydrophobic MSs into MN patches during aqueous fabrication procedures and that their modulation with the surfactant can increase loading and delivery efficiency.
- Published
- 2022
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10. Fabrication of pure-drug microneedles for delivery of montelukast sodium
- Author
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Azizoglu, Erkan, Ozer, Ozgen, and Prausnitz, Mark R.
- Abstract
Graphical abstract:
- Published
- 2022
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11. Role of drug delivery technologies in the success of COVID-19 vaccines: a perspective
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Labouta, Hagar I., Langer, Robert, Cullis, Pieter R., Merkel, Olivia M., Prausnitz, Mark R., Gomaa, Yasmine, Nogueira, Sara S., and Kumeria, Tushar
- Abstract
The triumphant success of mRNA vaccines is a testimony to the important role drug delivery technologies have played in protecting billions of people against SARS-CoV-2 (or the Corona Virus Disease 2019; COVID-19). Several lipid nanoparticle (LNP) mRNA vaccines were developed and have been instrumental in preventing the disease by boosting the immune system against the pathogen, SARS-CoV-2. These vaccines have been built on decades of scientific research in drug delivery of mRNA, vaccines, and other biologicals. In this manuscript, several leading and emerging scientists in the field of drug delivery share their perspective on the role of drug delivery technologies in developing safe and efficacious vaccines, in a roundtable discussion. The authors also discussed their viewpoint on the current challenges, and the key research questions that should drive this important area of research.
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- 2022
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12. Human Suction Blister Fluid Composition Determined Using High-Resolution Metabolomics
- Author
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Niedzwiecki, Megan M., Samant, Pradnya, Walker, Douglas I., Tran, ViLinh, Jones, Dean P., Prausnitz, Mark R., and Miller, Gary W.
- Abstract
Interstitial fluid (ISF) surrounds the cells and tissues of the body. Since ISF has molecular components similar to plasma, as well as compounds produced locally in tissues, it may be a valuable source of biomarkers for diagnostics and monitoring. However, there has not been a comprehensive study to determine the metabolite composition of ISF and to compare it to plasma. In this study, the metabolome of suction blister fluid (SBF), which largely consists of ISF, collected from 10 human volunteers was analyzed using untargeted high-resolution metabolomics (HRM). A wide range of metabolites were detected in SBF, including amino acids, lipids, nucleotides, and compounds of exogenous origin. Various systemic and skin-derived metabolite biomarkers were elevated or found uniquely in SBF, and many other metabolites of clinical and physiological significance were well correlated between SBF and plasma. In sum, using untargeted HRM profiling, this study shows that SBF can be a valuable source of information about metabolites relevant to human health.
- Published
- 2024
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13. Hybrid Lipid Nanocapsules: A Robust Platform for mRNA Delivery
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Yadava, Sunil Kumar, Reddy, B. Pradeep Kumar, Prausnitz, Mark R., and Cicerone, Marcus T.
- Abstract
The success of the mRNA vaccine against COVID-19 has garnered significant interest in the development of mRNA therapeutics against other diseases, but there remains a strong need for a stable and versatile delivery platform for these therapeutics. In this study, we report on a family of robust hybrid lipid nanocapsules (hLNCs) for the delivery of mRNA. The hLNCs are composed of kolliphore HS15, labrafac lipophile WL1349, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and a conjugate of oleic acid (OA) and polyethylenimines of varying size (PEI─0.8, 1.8, and 25 kDa). They are prepared by a solvent-free, temperature-phase inversion method, yielding an average size of ∼40 nm and a particle distribution index (PDI) < 0.2. We demonstrate that the PDI remains <0.2 over a wide pH range and in a wide range of medium. We further show that the PDI and the functionality of mRNA condensed on the particles are robust to drying in a sugar glass and subsequent rehydration. Finally, we demonstrate that mRNA-loaded hLNCs yield reasonable transfection in vitro and in vivo settings.
- Published
- 2024
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14. A microneedle patch for measles and rubella vaccination: a game changer for achieving elimination.
- Author
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Prausnitz, Mark R, Goodson, James L, Rota, Paul A, and Orenstein, Walter A
- Abstract
While morbidity and mortality associated with measles and rubella (MR) have dramatically decreased, there are still >100 000 estimated deaths due to measles and an estimated 100 000 infants born with congenital rubella syndrome annually. Given highly effective MR vaccines, the primary barrier to global elimination of these diseases is low vaccination coverage, especially among the most underserved populations in resource-limited settings. In contrast to conventional MR vaccination by hypodermic injection, microneedle patches are being developed to enable MR vaccination by minimally trained personnel. Simplified supply chain, reduced need for cold chain storage, elimination of vaccine reconstitution, no sharps waste, reduced vaccine wastage, and reduced total system cost of vaccination are advantages of this approach. Preclinical work to develop a MR vaccine patch has proceeded through successful immunization studies in rodents and non-human primates. On-going programs seek to make MR vaccine patches available to support MR elimination efforts around the world. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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15. Cutaneous vaccination ameliorates Zika virus-induced neuro-ocular pathology via reduction of anti-ganglioside antibodies
- Author
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Beaver, Jacob T., Mills, Lisa K., Swieboda, Dominika, Lelutiu, Nadia, Esser, Edward S., Antao, Olivia Q., Scountzou, Eugenia, Williams, Dahnide T., Papaioannou, Nikolaos, Littauer, Elizabeth Q., Romanyuk, Andrey, Compans, Richard W., Prausnitz, Mark R., and Skountzou, Ioanna
- Abstract
ABSTRACTZika virus (ZIKV) causes moderate to severe neuro-ocular sequelae, with symptoms ranging from conjunctivitis to Guillain-Barré Syndrome (GBS). Despite the international threat ZIKV poses, no licensed vaccine exists. As ZIKV and DENV are closely related, antibodies against one virus have demonstrated the ability to enhance the other. To examine if vaccination can confer robust, long-term protection against ZIKV, preventing neuro-ocular pathology and long-term inflammation in immune-privileged compartments, BALB/c mice received two doses of unadjuvanted inactivated whole ZIKV vaccine (ZVIP) intramuscularly (IM) or cutaneously with dissolving microneedle patches (MNP). MNP immunization induced significantly higher B and T cell responses compared to IM vaccination, resulting in increased antibody titers with greater avidity for ZPIV as well as increased numbers of IFN-γ, TNF-α, IL- and IL-4 secreting T cells. When compared to IM vaccination, antibodies generated by cutaneous vaccination demonstrated greater neutralization activity, increased cross-reactivity with Asian and African lineage ZIKV strains (PRVABC59, FLR, and MR766) and Dengue virus (DENV) serotypes, limited ADE, and lower reactivity to GBS-associated gangliosides. MNP vaccination effectively controlled viremia and inflammation, preventing neuro-ocular pathology. Conversely, IM vaccination exacerbated ocular pathology, resulting in uncontrolled, long-term inflammation. Importantly, neuro-ocular pathology correlated with anti-ganglioside antibodies implicated in demyelination and GBS. This study highlights the importance of longevity studies in ZIKV immunization, and the need of exploring alternative vaccination platforms to improve the quality of vaccine-induced immune responses.
- Published
- 2020
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16. STAR particles for enhanced topical drug and vaccine delivery
- Author
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Tadros, Andrew R., Romanyuk, Andrey, Miller, Ian C., Santiago, Andrea, Noel, Richard K., O’Farrell, Laura, Kwong, Gabriel A., and Prausnitz, Mark R.
- Abstract
Drug delivery to the skin is highly constrained by the stratum corneum barrier layer1. Here, we developed star-shaped particles, termed STAR particles, to dramatically increase skin permeability. STAR particles are millimeter-scale particles made of aluminum oxide or stainless steel with micron-scale projections designed to create microscopic pores across the stratum corneum. After gentle topical application for 10 s to porcine skin ex vivo, delivery of dermatological drugs and macromolecules, including those that cannot be given topically, was increased by 1 to 2 orders of magnitude. In mice treated with topical 5-fluorouracil, use of STAR particles increased the efficacy of the drug in suppressing the growth of subcutaneous melanoma tumors and prolonging survival. Moreover, topical delivery of tetanus toxoid vaccine to mice using STAR particles generated immune responses that were at least as strong as delivery of the vaccine by intramuscular injection, albeit at a higher dose for topical than intramuscular vaccine administration. STAR particles were well tolerated and effective at creating micropores when applied to the skin of human participants. Use of STAR particles provides a simple, low-cost and well-tolerated method for increasing drug and vaccine delivery to the skin and could widen the range of compounds that can be topically administered.
- Published
- 2020
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17. Plasmonic Paper Microneedle Patch for On-Patch Detection of Molecules in Dermal Interstitial Fluid.
- Author
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Kolluru, Chandana, Gupta, Rohit, Qisheng Jiang, Williams, Mikayla, Gholami Derami, Hamed, Cao, Sisi, Noel, Richard K., Singamaneni, Srikanth, and Prausnitz, Mark R.
- Published
- 2019
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18. Effect of laser fluence, nanoparticle concentration and total energy input per cell on photoporation of cells.
- Author
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Holguin, Stefany Y., Thadhani, Naresh N., and Prausnitz, Mark R.
- Subjects
CANCER cells ,CELL survival ,NANOPARTICLES ,FLOW cytometry ,PROSTATE cancer & genetics - Abstract
Intracellular delivery of molecules can be increased by laser-exposure of carbon black nanoparticles to cause photoporation of the cells. Here we sought to determine effects of multiple laser exposure parameters on intracellular uptake and cell viability with the goal of determining a single unifying parameter that predicts cellular bioeffects. DU145 human prostate cancer cells in suspension with nanoparticles were exposed to near-infrared nanosecond laser pulses over a range of experimental conditions. Increased bioeffects (i.e., uptake and viability loss determined by flow cytometry) were seen when increasing laser fluence, number of pulses and nanoparticle concentration, and decreasing cell concentration. Bioeffects caused by different combinations of these four parameters were generally predicted by their cumulative energy input per cell, which served as a unifying parameter. This indicates that photoporation depends on what appears to be the cumulative effect of multiple cell–nanoparticle interactions from neighboring nanoparticles during a series of laser pulses. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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19. Human Suction Blister Fluid Composition Determined Using High-Resolution Metabolomics.
- Author
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Niedzwiecki, Megan M., Samant, Pradnya, Walker, Douglas I., Tran, ViLinh, Jones, Dean P., Prausnitz, Mark R., and Miller, Gary W.
- Published
- 2018
- Full Text
- View/download PDF
20. Electrospun Transdermal Patch for Contraceptive Hormone Delivery
- Author
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Mofidfar, Mohammad and Prausnitz, Mark R.
- Abstract
Background: A transdermal patch for delivery of Levonorgestrel (LNG) can be used for long-acting contraception. Objective: In this study, we designed and characterized a patch made of nonwoven electrospun microfibers comprised of Polycaprolactone (PCL) encapsulating LNG for slow release in a mineral oil matrix. Methods and Results: Scanning electron microscopy showed uniform, randomly oriented PCL fibers with large interconnected voids filled with mineral oil. Thermogravimetric analysis indicated that LNG loaded into PCL fibers had thermal stability up to ~200°C. Differential Scanning Calorimetry suggested that LNG was dispersed in the electrospun fibers without interaction between the LNG and PCL, and without formation of drug crystals. Fourier Transform Infrared spectroscopy and X-ray diffraction results further supported the conclusion that there was no chemical drug–polymer interaction in LNGloaded fibers. Effective in vitro flux (i) from patches into mineral oil was 1.9 μgcm-2h-1, (ii) from mineral oil across porcine skin was 4.6 μgcm-2h-1 and (iii) from patches across porcine skin was 1.7 μgcm- 2h-1, indicating that transdermal delivery rate was controlled by a combination of the patch and the skin. Conclusion: The LNG-loaded patches demonstrated steady delivery of LNG across skin for up to 5 days in vitro. With additional development, LNG-loaded electrospun PCL patches could be used for long-acting contraception.
- Published
- 2019
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21. Electrospun Transdermal Patch for Contraceptive Hormone Delivery
- Author
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Mofidfar, Mohammad and Prausnitz, Mark R.
- Abstract
Background: A transdermal patch for delivery of Levonorgestrel (LNG) can be used for long-acting contraception. Objective: In this study, we designed and characterized a patch made of nonwoven electrospun microfibers comprised of Polycaprolactone (PCL) encapsulating LNG for slow release in a mineral oil matrix. Methods and Results: Scanning electron microscopy showed uniform, randomly oriented PCL fibers with large interconnected voids filled with mineral oil. Thermogravimetric analysis indicated that LNG loaded into PCL fibers had thermal stability up to ~200°C. Differential Scanning Calorimetry suggested that LNG was dispersed in the electrospun fibers without interaction between the LNG and PCL, and without formation of drug crystals. Fourier Transform Infrared spectroscopy and X-ray diffraction results further supported the conclusion that there was no chemical drug–polymer interaction in LNGloaded fibers. Effective in vitro flux (i) from patches into mineral oil was 1.9 µgcm-2h-1, (ii) from mineral oil across porcine skin was 4.6 µgcm-2h-1 and (iii) from patches across porcine skin was 1.7 μgcm- 2h-1, indicating that transdermal delivery rate was controlled by a combination of the patch and the skin. Conclusion: The LNG-loaded patches demonstrated steady delivery of LNG across skin for up to 5 days in vitro. With additional development, LNG-loaded electrospun PCL patches could be used for long-acting contraception.
- Published
- 2019
22. Parameters affecting intracellular delivery of molecules using laser-activated carbon nanoparticles.
- Author
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Chakravarty, Prerona, Lane, Christopher D., Orlando, Thomas M., and Prausnitz, Mark R.
- Subjects
MOLECULAR physics ,BIOMACROMOLECULES ,NANOPARTICLES ,ACTIVATED carbon ,CARBON - Abstract
Previous studies showed that carbon nanoparticles exposed to nanosecond laser pulses cause intracellular uptake of molecules. In this study, prostate cancer cells incubated with carbon-black (CB) nanoparticles and fluorescent marker compounds were exposed to 10 ns laser pulses at 1064 nm wavelength, after which intracellular uptake was measured by flow cytometry. Calcein and dextran (150 kDa) were delivered into > 50% of cells, whereas larger dextrans (≤ 2000 kDa) were taken up by ~ 10% of cells. Under all conditions studied, cell viability loss was minimal. Uptake also increased with increasing laser power, increasing CB nanoparticle concentration, increasing CB nanoparticle size and decreasing laser wavelength. CB nanoparticles enabled uptake better than gold nanoparticles or multi-walled carbon nanotubes under the conditions studied. Proof-of-principle experiments showed intracellular uptake by cells in vivo. We conclude that intracellular uptake of molecules using laser-activated CB nanoparticles provides a promising approach to deliver molecules into cells. From the Clinical Editor Delivery of drugs using nanoparticles as carriers is promising. The authors in this study investigated the use of laser-activated carbon nanoparticles to increase the cellular uptake of payloads in various parameters. The positive data generated should provide further platform for a new approach for intracellular delivery of molecules. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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23. The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial
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Rouphael, Nadine G, Paine, Michele, Mosley, Regina, Henry, Sebastien, McAllister, Devin V, Kalluri, Haripriya, Pewin, Winston, Frew, Paula M, Yu, Tianwei, Thornburg, Natalie J, Kabbani, Sarah, Lai, Lilin, Vassilieva, Elena V, Skountzou, Ioanna, Compans, Richard W, Mulligan, Mark J, Prausnitz, Mark R, Beck, Allison, Edupuganti, Srilatha, Heeke, Sheila, Kelley, Colleen, and Nesheim, Wendy
- Abstract
Microneedle patches provide an alternative to conventional needle-and-syringe immunisation, and potentially offer improved immunogenicity, simplicity, cost-effectiveness, acceptability, and safety. We describe safety, immunogenicity, and acceptability of the first-in-man study on single, dissolvable microneedle patch vaccination against influenza.
- Published
- 2017
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24. Energy Transfer Mechanisms during Molecular Delivery to Cells by Laser-Activated Carbon Nanoparticles
- Author
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Sengupta, Aritra, Gray, Michael D., Kelly, Sean C., Holguin, Stefany Y., Thadhani, Naresh N., and Prausnitz, Mark R.
- Abstract
Previous studies have shown that exposure of carbon black nanoparticles to nanosecond pulsed near-infrared laser causes intracellular delivery of molecules through hypothesized transient breaks in the cell membrane. The goal of this study is to determine the underlying mechanisms of sequential energy transfer from laser light to nanoparticle to fluid medium to cell. We found that laser pulses on a timescale of 10 ns rapidly heat carbon nanoparticles to temperatures on the order of 1200 K. Heat is transferred from the nanoparticles to the surrounding aqueous medium on a similar timescale, causing vaporization of the surrounding water and generation of acoustic emissions. Nearby cells can be impacted thermally by the hot bubbles and mechanically by fluid mechanical forces to transiently increase cell membrane permeability. The experimental and theoretical results indicate that transfer of momentum and/or heat from the bubbles to the cells are the dominant mechanisms of energy transfer that results in intracellular uptake of molecules. We further conclude that neither thermal expansion of the nanoparticles nor a carbon-steam chemical reaction play a significant role in the observed effects on cells, and that acoustic pressure appears to be concurrent with, but not essential to, the observed bioeffects.
- Published
- 2017
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25. Collection of Analytes from Microneedle Patches.
- Author
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Romanyuk, Andrey V., Zvezdin, Vasiliy N., Samant, Pradnya, Grenader, Mark I., Zemlyanova, Marina, and Prausnitz, Mark R.
- Published
- 2014
- Full Text
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26. Electrical Impedance Spectroscopy for Rapid and Noninvasive Analysis of Skin Electroporation.
- Author
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Walker, John M., Jaroszeski, Mark J., Heller, Richard, Gilbert, Richard, Pliquett, Uwe, and Prausnitz, Mark R.
- Abstract
Transient disruption of skin's barrier properties using high-voltage pulses involves complex changes in skin microstructure believed to be due to electroporation. Electroporation of cell membranes is a well known phenomenon which has found extensive use as a method of DNA transfection in biological laboratories (1-3). More recently, it has been shown that the multilamellar lipid bilayer membranes found in skin can also be electroporated (4-17). The dramatic and reversible increases in skin permeability caused by electroporation indicate that drugs might be delivered transdermally at significantly enhanced rates. Especially for macromolecules, such as protein- and gene-based drugs, electroporation-mediated transdermal drug delivery could be an important pharmaceutical approach. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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27. Mechanistic Studies of Skin Electroporation Using Biophysical Methods.
- Author
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Walker, John M., Jaroszeski, Mark J., Heller, Richard, Gilbert, Richard, Prausnitz, Mark R., Pliquett, Uwe, and Vanbever, Rita
- Abstract
The mechanism by which high-voltage pulses transiently disrupt lipid bilayers in cell membranes has been the subject of controversy since electroporation was first observed almost three decades ago. Determining the mechanism by which such pulses permeabilize the complex, multilamellar bilayer structures in skin poses an even greater challenge. To address this issue, a range of methods have been employed to perform biophysical characterization for skin electroporation studies. In this chapter, we provide an overview of these methods and highlight representative findings which biophysical characterization has yielded. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
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28. Drug delivery using microneedle patches: not just for skin
- Author
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Lee, Jeong Woo and Prausnitz, Mark R.
- Published
- 2018
- Full Text
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29. UNDERGRADUATE LABORATORY MODULE ON SKIN DIFFUSION.
- Author
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NORMAN, JAMES J., ANDREWS, SAMANTHA N., and PRAUSNITZ, MARK R.
- Subjects
LIFE science education ,CURRICULUM ,TISSUES ,LABORATORIES - Abstract
The article discusses the development of a skin diffusion laboratory program for a biological sciences course that is added to the curriculum of the Georgia Institute of Technology in 2003, after it is renamed as the School of Chemical and Biomolecular Engineering. It focuses on the topics of the course that include the importance of skin barrier to health, molecular diffusion and handling of biological tissues.
- Published
- 2011
30. DRUG DESIGN, DEVELOPMENT, AND DELIVERY: An Interdisciplinary Course on Pharmaceuticals.
- Author
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PRAUSNITZ, MARK R. and BOMMARIUS, ANDREAS S.
- Subjects
INTERDISCIPLINARY education ,ACADEMIC programs ,DRUG design ,DRUG development ,DRUG delivery systems ,CHEMICAL engineering education - Abstract
This article offers an interdisciplinary academic program that focuses on drug design, development and delivery, the "D4" course that is being offered by the School of Chemical and Biomolecular Engineering (ChBE) at Georgia Institute of Technology (Georgia Tech). It addresses the beginnings of the program, the reasons for its implementation and how it can be used in drug research and development. It then shows the course framework and syllabus and how it is employed in an exemplar case study which was drawn from the U.S. drug industry.
- Published
- 2011
31. Layer-by-Layer Assembly of DNA- and Protein-Containing Films on Microneedles for Drug Delivery to the Skin.
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Saurer, Eric M., Flessner, Ryan M., Sullivan, Sean P., Prausnitz, Mark R., and Lynn, David M.
- Published
- 2010
- Full Text
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32. Influenza immunization with trehalose-stabilized virus-like particle vaccine using microneedles.
- Author
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Kim, Yeu-Chun, Quan, Fu-Shi, Song, Jae-Min, Vunnava, Aswani, Yoo, Dae-Goon, Park, Kyoung-Mi, Compans, Richard W., Kang, Sang-Moo, and Prausnitz, Mark R
- Subjects
MYCOSES ,INFLUENZA vaccines ,HEMAGGLUTINATION tests ,MORTALITY ,IMMUNOGLOBULINS ,VIRAL antibodies ,METALS in medicine - Abstract
Abstract: Morbidity and mortality due to seasonal and pandemic influenza could be reduced by simpler vaccination methods that enable improved vaccination coverage. In this study, solid metal microneedles coated with influenza virus-like particle (VLP) vaccine were inserted into skin for intradermal immunization. Microneedles were applied to the skin by hand and designed for simple administration with little or no training. Inclusion of trehalose in the coating formulation significantly increased vaccine stability during coating by maintaining hemagglutination activity. Mice vaccinated with stabilized microneedles developed strong antibody responses comparable to conventional intramuscular vaccination and were fully protected against subsequent viral challenge. Whereas, coating microneedles with a coating solution lacking trehalose led to only partial protection against lethal viral challenge. Therefore, our results show that microneedles coated with trehalose-stabilized VLP vaccine can be a promising tool for improving influenza vaccination. [Copyright &y& Elsevier]
- Published
- 2010
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33. Optimization of intracellular macromolecule delivery by nanoparticle-mediated photoporation.
- Author
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Kumar, Simple, Li, Andrew, Thadhani, Naresh N., and Prausnitz, Mark R.
- Subjects
BILAYER lipid membranes ,MACROMOLECULES ,LASER pulses ,PULSED lasers ,NANOCARRIERS ,CELL membranes ,LASER beams ,PHOSPHOLIPIDS - Abstract
Nanoparticle-mediated photoporation is a novel delivery platform for intracellular molecule delivery. We studied the dependence of macromolecular delivery on molecular weight and sought to enhance delivery efficiency. DU145 prostate cancer cells were exposed to pulsed laser beam in the presence of carbon-black nanoparticles. Intracellular uptake of molecules decreased with increasing molecular weight. Attributing this dependence to molecular diffusivity, we hypothesized that macromolecular delivery efficiency could be enhanced by increasing either laser fluence or laser exposure duration at low fluence. We observed increased percentages of macromolecule uptake by cells in both cases. However, trade-off between cell uptake and viability loss was most favorable at low laser fluence (25-29 mJ/cm
2 ) and longer exposure durations (4-5 min). We conclude that long exposure at low laser fluence optimizes intracellular macromolecule delivery by nanoparticle-mediated photoporation, which may be explained by longer time for macromolecules to diffuse into cells, during and between laser pulses. Intracellular delivery of macromolecules to access the cytosol requires crossing the phospholipid bilayer of cell membranes. Nanoparticle-mediated photoporation enables transient poration of cell membranes, providing a diffusive pathway for transport. We optimized conditions for intracellular delivery of a widely sized range of macromolecules using nanoparticle-mediated photoporation using long-duration exposures at low laser fluence. [Display omitted] [ABSTRACT FROM AUTHOR]- Published
- 2021
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34. Efficient Intracellular Delivery of Molecules with High Cell Viability Using Nanosecond-Pulsed Laser-Activated Carbon Nanoparticles
- Author
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Sengupta, Aritra, Kelly, Sean C., Dwivedi, Nishant, Thadhani, Naresh, and Prausnitz, Mark R.
- Abstract
Conventional physical and chemical methods that efficiently deliver molecules into cells are often associated with low cell viability. In this study, we evaluated the cellular effects of carbon nanoparticles believed to emit photoacoustic waves due to nanosecond-pulse laser activation to test the hypothesis that this method could achieve efficient intracellular delivery while maintaining high cell viability. Suspensions of DU145 human prostate carcinoma cells, carbon black (CB) nanoparticles, and calcein were exposed to 5–9 ns long laser pulses of near-infrared (1064 nm wavelength) light and then analyzed by flow cytometry for intracellular uptake of calcein and cell viability by propidium iodide staining. We found that intracellular uptake increased and in some cases saturated at high levels with only small losses in cell viability as a result of increasing laser fluence, laser exposure time, and as a unifying parameter, the total laser energy. Changing interpulse spacing between 0.1 and 10 s intervals showed no significant change in bioeffects, suggesting that the effects of each pulse were independent when spaced by at least 0.1 s intervals. Pretreatment of CB nanoparticles to intense laser exposure followed by mixing with cells also had no significant effect on uptake or viability. Similar uptake and viability were seen when CB nanoparticles were substituted with India ink, when DU145 cells were substituted with H9c2 rat cardiomyoblast cells, and when calcein was substituted with FITC-dextran. The best laser exposure conditions tested led to 88% of cells with intracellular uptake and close to 100% viability, indicating that nanosecond-pulse laser-activated carbon nanoparticles can achieve efficient intracellular delivery while maintaining high cell viability.
- Published
- 2014
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35. Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery
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Chen, Qian, Xiao, Zhisheng, Wang, Chao, Chen, Guojun, Zhang, Yuqi, Zhang, Xudong, Han, Xiao, Wang, Jinqiang, Ye, Xiao, Prausnitz, Mark R., Li, Song, and Gu, Zhen
- Abstract
Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin viaa competitive interaction with GLUT, leading to a quick release of Glu-Insulin and subsequent regulation of blood glucose (BG) levels in vivo. To prolong the effective glucose-responsive insulin release from MNs, additional free Glu-Insulin, which serves as “stored insulin”, is loaded after RBC vesicles or liposome nanoparticles bound with Glu-Insulin. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, this smart GLUT-based insulin patch can effectively control BG levels without causing hypoglycemia.
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- 2022
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36. Long-Term Protective Immunity from an Influenza Virus-Like Particle Vaccine Administered with a Microneedle Patch
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Quan, Fu-Shi, Kim, Yeu-Chun, Song, Jae-Min, Hwang, Hye Suk, Compans, Richard W., Prausnitz, Mark R., and Kang, Sang-Moo
- Abstract
ABSTRACTSkin vaccination with influenza virus-like particles (VLPs) using microneedles has been shown to induce protection similar to or better than that induced by intramuscular immunization. In this study, we examined the long-term protective efficacy of influenza (H1N1 A/PR/8/34) VLPs after skin vaccination using microneedle patches coated with the vaccine. Microneedle vaccination of mice in the skin induced 100% protection against lethal challenge infection with influenza A/PR/8/34 virus 14 months after a single vaccine dose. Influenza virus-specific total IgG response and hemagglutination inhibition (HAI) titers were maintained at high levels for over 1 year after microneedle vaccination. Microneedle vaccination also induced substantial levels of lung IgG and IgA antibody responses, and antibody-secreting plasma cells from spleen and bone marrow, as well as conferring effective control of lung viral loads, resulting in complete protection 14 months after vaccination. These strong and long-lasting immune responses were enabled in part by stabilization of the vaccine by formulation with trehalose during microneedle patch fabrication. Administration of the stabilized vaccine using microneedles was especially effective at enabling strong recall responses measured 4 days after lethal virus challenge, including increased HAI and antibody-secreting cells in the spleen and reduced viral titer and inflammatory response in the lung. The results in this study indicate that skin vaccination with VLP vaccine using a microneedle patch provides long-term protection against influenza in mice.
- Published
- 2013
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37. Rapid Release of Plasmid DNA from Surfaces Coated with Polyelectrolyte Multilayers Promoted by the Application of Electrochemical Potentials
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Aytar, Burcu S., Prausnitz, Mark R., and Lynn, David M.
- Abstract
We report an approach to the rapid release of DNA based on the application of electrochemical potentials to surfaces coated with polyelectrolyte-based thin films. We fabricated multilayered polyelectrolyte films (or “polyelectrolyte multilayers”, PEMs) using plasmid DNA and a model hydrolytically degradable cationic poly(β-amino ester) (polymer 1) on stainless steel substrates using a layer-by-layer approach. The application of continuous reduction potentials in the range of −1.1 to −0.7 V (vs a Ag/AgCl electrode) to film-coated electrodes in PBS at 37 °C resulted in the complete release of DNA over a period of 1–2 min. Film-coated electrodes incubated under identical conditions in the absence of applied potentials required 1–2 days for complete release. Control over the magnitude of the applied potential provided control over the rate at which DNA was released. The results of these and additional physical characterization experiments are consistent with a mechanism of film disruption that is promoted by local increases in pH at the film/electrode interface (resulting from electrochemical reduction of water or dissolved oxygen) that disrupt ionic interactions in these materials. The results of cell-based experiments demonstrated that DNA was released in a form that remains intact and able to promote transgene expression in mammalian cells. Finally, we demonstrate that short-term (i.e., non-continuous) electrochemical treatments can also be used to promote faster film erosion (e.g., over 1–2 h) once the potential is removed. Past studies demonstrate that PEMs fabricated using polymer 1can promote surface-mediated transfection of cells and tissues in vitro and in vivo. With further development, the electrochemical approaches reported here could thus provide new methods for the rapid, triggered, or spatially patterned transfer of DNA (or other agents) from surfaces of interest in a variety of fundamental and applied contexts.
- Published
- 2012
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38. Microneedle Vaccination with Stabilized Recombinant Influenza Virus Hemagglutinin Induces Improved Protective Immunity
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Weldon, William C., Martin, Maria P., Zarnitsyn, Vladimir, Wang, Baozhong, Koutsonanos, Dimitrios, Skountzou, Ioanna, Prausnitz, Mark R., and Compans, Richard W.
- Abstract
ABSTRACTThe emergence of the swine-origin 2009 influenza pandemic illustrates the need for improved vaccine production and delivery strategies. Skin-based immunization represents an attractive alternative to traditional hypodermic needle vaccination routes. Microneedles (MNs) can deliver vaccine to the epidermis and dermis, which are rich in antigen-presenting cells (APC) such as Langerhans cells and dermal dendritic cells. Previous studies using coated or dissolvable microneedles emphasized the use of inactivated influenza virus or virus-like particles as skin-based vaccines. However, most currently available influenza vaccines consist of solubilized viral protein antigens. Here we test the hypothesis that a recombinant subunit influenza vaccine can be delivered to the skin by coated microneedles and can induce protective immunity. We found that mice vaccinated via MN delivery with a stabilized recombinant trimeric soluble hemagglutinin (sHA) derived from A/Aichi/2/68 (H3) virus had significantly higher immune responses than did mice vaccinated with unmodified sHA. These mice were fully protected against a lethal challenge with influenza virus. Analysis of postchallenge lung titers showed that MN-immunized mice had completely cleared the virus from their lungs, in contrast to mice given the same vaccine by a standard subcutaneous route. In addition, we observed a higher ratio of antigen-specific Th1 cells in trimeric sHA-vaccinated mice and a greater mucosal antibody response. Our data therefore demonstrate the improved efficacy of a skin-based recombinant subunit influenza vaccine and emphasize the advantage of this route of vaccination for a protein subunit vaccine.
- Published
- 2011
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39. Enabling skin vaccination using new delivery technologies
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Kim, Yeu-Chun and Prausnitz, Mark R.
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The skin is known to be a highly immunogenic site for vaccination, but few vaccines in clinical use target skin largely because conventional intradermal injection is difficult and unreliable to perform. Now, a number of new or newly adapted delivery technologies have been shown to administer vaccine to the skin either by non-invasive or minimally invasive methods. Non-invasive methods include high-velocity powder and liquid jet injection, as well as diffusion-based patches in combination with skin abrasion, thermal ablation, ultrasound, electroporation, and chemical enhancers. Minimally invasive methods are generally based on small needles, including solid microneedle patches, hollow microneedle injections, and tattoo guns. The introduction of these advanced delivery technologies can make the skin a site for simple, reliable vaccination that increases vaccine immunogenicity and offers logistical advantages to improve the speed and coverage of vaccination.
- Published
- 2011
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40. Microneedle Delivery of H5N1 Influenza Virus-Like Particles to the Skin Induces Long-Lasting B- and T-Cell Responses in Mice
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Song, Jae-Min, Kim, Yeu-Chun, Lipatov, Aleksandr S., Pearton, Marc, Davis, C. Todd, Yoo, Dae-Goon, Park, Kyoung-Mi, Chen, Li-Mei, Quan, Fu-Shi, Birchall, James C., Donis, Ruben O., Prausnitz, Mark R., Compans, Richard W., and Kang, Sang-Moo
- Abstract
ABSTRACTA simple method suitable for self-administration of vaccine would improve mass immunization, particularly during a pandemic outbreak. Influenza virus-like particles (VLPs) have been suggested as promising vaccine candidates against potentially pandemic influenza viruses, as they confer long-lasting immunity but are not infectious. We investigated the immunogenicity and protective efficacy of influenza H5 VLPs containing the hemagglutinin (HA) of A/Vietnam/1203/04 (H5N1) virus delivered into the skin of mice using metal microneedle patches and also studied the response of Langerhans cells in a human skin model. Prime-boost microneedle vaccinations with H5 VLPs elicited higher levels of virus-specific IgG1 and IgG2a antibodies, virus-specific antibody-secreting cells, and cytokine-producing cells up to 8 months after vaccination compared to the same antigen delivered intramuscularly. Both prime-boost microneedle and intramuscular vaccinations with H5 VLPs induced similar hemagglutination inhibition titers and conferred 100% protection against lethal challenge with the wild-type A/Vietnam/1203/04 virus 16 weeks after vaccination. Microneedle delivery of influenza VLPs to viable human skin using microneedles induced the movement of CD207+Langerhans cells toward the basement membrane. Microneedle vaccination in the skin with H5 VLPs represents a promising approach for a self-administered vaccine against viruses with pandemic potential.
- Published
- 2010
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41. Influenza immunization with trehalose-stabilized virus-like particle vaccine using microneedles
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Kim, Yeu-Chun, Quan, Fu-Shi, Song, Jae-Min, Vunnava, Aswani, Yoo, Dae-Goon, Park, Kyoung-Mi, Compans, Richard W., Kang, Sang-Moo, and Prausnitz, Mark R
- Abstract
Morbidity and mortality due to seasonal and pandemic influenza could be reduced by simpler vaccination methods that enable improved vaccination coverage. In this study, solid metal microneedles coated with influenza virus-like particle (VLP) vaccine were inserted into skin for intradermal immunization. Microneedles were applied to the skin by hand and designed for simple administration with little or no training. Inclusion of trehalose in the coating formulation significantly increased vaccine stability during coating by maintaining hemagglutination activity. Mice vaccinated with stabilized microneedles developed strong antibody responses comparable to conventional intramuscular vaccination and were fully protected against subsequent viral challenge. Whereas, coating microneedles with a coating solution lacking trehalose led to only partial protection against lethal viral challenge. Therefore, our results show that microneedles coated with trehalose-stabilized VLP vaccine can be a promising tool for improving influenza vaccination.
- Published
- 2010
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42. Modeling Transmembrane Transport through Cell Membrane Wounds Created by Acoustic Cavitation
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Zarnitsyn, Vladimir, Rostad, Christina A., and Prausnitz, Mark R.
- Abstract
Cells exposed to acoustic cavitation and other mechanical stresses can be transiently permeabilized to permit intracellular uptake of molecules, including drugs, proteins, and genes. Microscopic imaging and other studies suggest that intracellular loading occurs through plasma membrane wounds of submicrometer radius that reseal over time through the aggregation and fusion of lipid vesicles trafficked to the wound site. The goal of this study was to 1), determine the size of membrane wounds as a function of time after in vitro sonication of DU145 prostate cancer cells under conditions that caused extensive acoustic cavitation; and 2), theoretically model transport processes leading to intracellular loading. Our overall hypothesis was that intracellular loading is governed by passive diffusion through porous membrane wounds of up to 300-nm radius containing pores that permit entry of molecules up to at least 28-nm radius over a timescale of minutes. Experimental measurements showed intracellular loading of molecules with radii from 0.6 to 28nm, where most loading occurred after sonication over a timescale up to minutes and where smaller molecules were taken up to a greater extent and over a longer timescale than larger molecules. Theoretical modeling predicted that membrane wounds would have a 300-nm radius initially and then would shrink, with a half life of 20 to 50s. Uptake was shown to occur predominantly by diffusion and the increasing levels of uptake with decreasing molecular size was explained primarily by differences in molecular diffusivity and, for the largest molecule, geometrical hindrance within the wound. Mathematical modeling was simplified, because transport through porous wounds of possibly complex internal nanostructure was governed largely by transport at the edge of the wound, and depended only weakly on the size, number, and distribution of nanopores within the wound under the conditions relevant to this study. Overall, this study developed a theoretical framework for analysis of transmembrane transport through cell membrane wounds and thereby provided quantitative estimates of their size and lifetime.
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- 2008
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43. Ultrasound-Enhanced Chemotherapy and Gene Delivery for Glioma Cells
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Zarnitsyn, Vladimir G., Kamaev, Pavel P., and Prausnitz, Mark R.
- Abstract
Treatment of brain cancer is limited in part by inefficient intracellular delivery of drugs and DNA for chemotherapy and gene therapy, respectively. This study tested the hypothesis that ultrasound may be used to enhance intracellular delivery and efficacy of chemotherapeutics and genes in glioma cells in vitro.First, suitable ultrasound conditions were identified by measuring intracellular uptake of calcein and viability of GS 9L rat gliosarcoma cells after a range of different ultrasound exposures. We selected sonication at 10 J/cm2, which achieved intracellular delivery of ν106molecules/cell. Next, glial cells were sonicated with varying concentrations of model chemotherapeutics: BCNU and bleomycin. For both drugs, cytotoxicity was increased in a synergistic manner when accompanied by ultrasound exposure. Finally, expression of a plasmid DNA encoding a GFP reporter was increased up to 30-fold when exposed to ultrasound. Altogether, these findings suggest that ultrasound may be useful to increase the efficacy of chemotherapy and gene therapy of glioma cells.
- Published
- 2007
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44. Polymer Microneedles for Controlled-Release Drug Delivery
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Park, Jung-Hwan, Allen, Mark G., and Prausnitz, Mark R.
- Abstract
Purpose: As an alternative to hypodermic injection or implantation of controlled-release systems, this study designed and evaluated biodegradable polymer microneedles that encapsulate drug for controlled release in skin and are suitable for self-administration by patients. Methods: Arrays of microneedles were fabricated out of poly-lactide-co-glycolide using a mold-based technique to encapsulate model drugs—calcein and bovine serum albumin (BSA)—either as a single encapsulation within the needle matrix or as a double encapsulation, by first encapsulating the drug within carboxymethylcellulose or poly-
l -lactide microparticles and then encapsulating drug-loaded microparticles within needles. Results: By measuring failure force over a range of conditions, poly-lactide-co-glycolide microneedles were shown to exhibit sufficient mechanical strength to insert into human skin. Microneedles were also shown to encapsulate drug at mass fractions up to 10% and to release encapsulated compounds within human cadaver skin. In vitrorelease of calcein and BSA from three different encapsulation formulations was measured over time and was shown to be controlled by the encapsulation method to achieve release kinetics ranging from hours to months. Release was modeled using the Higuchi equation with good agreement (r2 ≥ 0.90). After microneedle fabrication at elevated temperature, up to 90% of encapsulated BSA remained in its native state, as determined by measuring effects on primary, secondary, and tertiary protein structure. Conclusions: Biodegradable polymer microneedles can encapsulate drug to provide controlled-release delivery in skin for hours to months.- Published
- 2006
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45. Assessment of Trueness of a Glucose Monitor Using Interstitial Fluid and Whole Blood as Specimen Matrix
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Vesper, Hubert W., Wang, Ping M., Archibold, Enada, Prausnitz, Mark R., and Myers, Gary L.
- Abstract
Background: Interstitial fluid (ISF) is a specimen of increasing interest for glucose measurements because it can be obtained in a minimally invasive manner. Our previous study showed that sufficient ISF can be obtained using microneedles to measure glucose with a conventional electrochemical glucose monitor. The aim of this study was to assess the trueness of this glucose monitor using split-sample comparison with whole blood. We used ISF as specimen and our gas chromatography/mass spectrometry (GC/MS) method as reference.Methods: We obtained 50 ISF samples and 40 whole blood samples from hairless Sprague- Dawley rats and analyzed for glucose by both methods.Results: For whole blood, a non-significant bias of 5.7% (±2 SD: −54.9% to 66.3%) was determined. ISF glucose measurements showed a significant constant bias of 29.5% (±2 SD: −85.0% to 144%), which seems to be caused in part by the lack of red blood cells in ISF. The correlation coefficients were 0.782 and 0.679 for whole blood and ISF, respectively.Conclusions: The assessed electrochemical glucose monitor shows a close agreement with our GC/MS reference method for whole blood, for which this monitor was optimized. When glucose measurements are performed with ISF as matrix, the observed bias needs to be taken into consideration. Further studies are necessary to elucidate the reasons for the wide dispersion of data for ISF.
- Published
- 2006
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46. Microneedle patch drug delivery in the gut
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Prausnitz, Mark R., Gomaa, Yasmine, and Li, Wei
- Abstract
A novel oral capsule can deploy microneedle patches that release drugs into the intestinal wall for uptake into the bloodstream as shown in animal studies, thereby avoiding injections.
- Published
- 2019
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47. Minimally Invasive Extraction of Dermal Interstitial Fluid for Glucose Monitoring Using Microneedles
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Wang, Ping M., Cornwell, Megan, and Prausnitz, Mark R.
- Abstract
Background: Compliance with glucose monitoring by patients with diabetes is poor because of the pain and inconvenience of conventional blood collection using lancets. To improve compliance, and thereby reduce morbidity and mortality associated with poor glucose control, this study sought to develop and test minimally invasive microneedles to extract dermal interstitial fluid (ISF) for glucose monitoring.Methods: We used a thermal puller to fabricate individual or multi-needle arrays of glass microneedles with tip radii of 15–40 µm to penetrate 700–1,500 µm deep into the skin of anesthetized hairless rats or conscious, normal, adult, human subjects. After applying a vacuum of 200–500 mm Hg for 2–10 min, we extracted ISF and measured glucose concentration. These measurements were compared with glucose levels in blood collected from the tail vein of rats or finger stick on humans.Results: Using this procedure, 1–10 µL of ISF was extracted out of holes punctured in the skin using microneedles. Human subjects generally reported the procedure as painless. ISF glucose concentration correlated well with blood levels based on 140 measurements on 15 rats and six measurements on six human subjects, where 95% of rat data and 100% of human data fell within the clinically acceptable A+B region in Clarke Error Grid analysis. A linear calibration factor was needed to correlate ISF and blood glucose concentrations using our standard procedure. Modifying the procedure to prevent ISF evaporation during extraction provided a one-to-one correlation that eliminated the need for calibration. ISF glucose measurements tracked rapidly changing blood glucose levels following insulin injection with a time lag of less than 20 min.Conclusions: These results suggest that microneedle devices can be used to extract ISF for painless glucose monitoring.
- Published
- 2005
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48. Tissue Electroporation: Quantification and Analysis of Heterogeneous Transport in Multicellular Environments
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Canatella, Paul J., Black, Matthew M., Bonnichsen, David M., McKenna, Conor, and Prausnitz, Mark R.
- Abstract
Although electroporation is gaining increased attention as a technology to enhance clinical chemotherapy and gene therapy of tissues, direct measurements of electroporation-mediated transport in multicellular environments are lacking. In this study, we used multicellular tumor spheroids of DU145 prostate cancer cells as a model tissue to measure the levels and distribution of molecular uptake in a multicellular environment as a function of electrical and other parameters. These measurements, and subsequent analysis, were used to test the hypothesis that cells in a multicellular environment respond to electroporation in a heterogeneous manner that differs from isolated cells in suspension due to differences in cell state, local solute concentration, and local electric field. In support of the hypothesis, molecular uptake was consistently lower for cells within spheroids than cells in dilute suspension and was spatially heterogeneous, with progressively less uptake observed for cells located deeper within spheroid interiors. Reduced uptake and heterogeneity can be explained quantitatively by accounting for the effects of cell size on transmembrane voltage and cell volume, limited extracellular solute reservoir, heterogeneous field strength due to influence of neighboring cells, and diffusional lag times.
- Published
- 2004
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49. Equilibrium loading of cells with macromolecules by ultrasound: Effects of molecular size and acoustic energy
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Guzmán, Héctor R, Nguyen, Daniel X., McNamara, Andrew J., and Prausnitz, Mark R.
- Abstract
Ultrasound has been shown to deliver small compounds, macromolecules, and DNA into cells, which suggests potential applications in drug and gene delivery. However, the effect of molecular size on intracellular uptake has not been quantified. This study measured the effect of molecule size (calcein, 623 Da; bovine serum albumin, 66 kDa; and two dextrans, 42 and 464 kDa) on molecular uptake and cell viability in DU145 prostate cancer cells exposed to 500 kHz ultrasound. Molecular uptake in viable cells was shown to be very similar for small molecules and macromolecules and found to correlate with acoustic energy exposure. Molecular uptake was seen to be heterogeneous among viable cells exposed to the same ultrasound conditions; this heterogeneity also correlated with acoustic energy exposure. In a fraction of these cells, molecular uptake reached thermodynamic equilibrium with the extracellular solution for the small molecule and all three macromolecules. The results demonstrate that ultrasound provides a means to load viable cells with large numbers of macromolecules, which may be of use for laboratory and possible clinical drug delivery applications. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1693-1701, 2002
- Published
- 2002
- Full Text
- View/download PDF
50. Equilibrium loading of cells with macromolecules by ultrasound: Effects of molecular size and acoustic energy
- Author
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Guzmán, Héctor R, Nguyen, Daniel X., McNamara, Andrew J., and Prausnitz, Mark R.
- Abstract
Ultrasound has been shown to deliver small compounds, macromolecules, and DNA into cells, which suggests potential applications in drug and gene delivery. However, the effect of molecular size on intracellular uptake has not been quantified. This study measured the effect of molecule size (calcein, 623 Da; bovine serum albumin, 66 kDa; and two dextrans, 42 and 464 kDa) on molecular uptake and cell viability in DU145 prostate cancer cells exposed to 500 kHz ultrasound. Molecular uptake in viable cells was shown to be very similar for small molecules and macromolecules and found to correlate with acoustic energy exposure. Molecular uptake was seen to be heterogeneous among viable cells exposed to the same ultrasound conditions; this heterogeneity also correlated with acoustic energy exposure. In a fraction of these cells, molecular uptake reached thermodynamic equilibrium with the extracellular solution for the small molecule and all three macromolecules. The results demonstrate that ultrasound provides a means to load viable cells with large numbers of macromolecules, which may be of use for laboratory and possible clinical drug delivery applications. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1693-1701, 2002
- Published
- 2002
- Full Text
- View/download PDF
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