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Research old

WE HAVE SEVERAL AREAS OF RESEARCH INTEREST BROADLY IN THE AREA OF IMMUNOMODULATION USING MICRO/NANOPARTICLES AND OTHER CARRIER SYSTEMS.

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FORMULATION OF HOST-DIRECTED AND OTHER THERAPEUTIC COMPOUNDS

For this aspect of our work we apply both polymeric and liposomal carriers to delivery immunomodulatory drugs and/or therapeutics to phagocytic and other cells. With this aspect of our work, we strive to focus on scalable production of delivery vehicles. A large focus of this work is on host-directed therapeutics which manipulate the mammalian host cell environment to make it less hospitable for the pathogen inside it, in an effort to reduce the emergence of drug resistance in that pathogen as well as potentially sensitize the pathogen to conventional antibiotics.

Publications focused on Host-directed therapeutics

  1. Hoang KV, Curry H, Collier MA, Borteh H, Bachelder E, Schlesinger LS, Gunn JS, Ainslie K. Needle-free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge. Antimicrob Agents Chemother. 2016 Jan 19. (link)
  2. Collier MA, Peine KJ, Gautam S, Oghumu S, Varikuti S, Borteh H, Papenfuss TL, Sataoskar AR, Bachelder EM, Ainslie KM. Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles. Int J Pharm. 2016 Feb 29;499(1-2):186-94. (link)
  3. Gupta G, Peine KJ, Abdelhamid D, Snider H, Shelton AB, Rao, Kotha SR, Huntsman HC, Varikuti S, Oghumu S, Naman CB, Pan L, Parinandi NL, Papenfuss TL, Kinghorn AD, Bachelder EM, Ainslie KM, Fuchs JR,  Satoskar AR. A Novel Sterol Isolated from a Plant Used by Mayan Traditional Healers Is Effective in Treatment of Visceral Leishmaniasis Caused by Leishmania donovani. ACS Infectious Diseases 2015 1 (10), 497-506. (link)
  4. Peine KJ, Gupta G, Brackman DJ, Papenfuss TL, Ainslie KM, Satoskar AR, Bachelder EM. Liposomal resiquimod for the treatment of Leishmania donovani infection. J Antimicrob Chemother. 2014 Jan;69(1):168-75 (link)
  5. Hoang KV, Borteh HM, Rajaram MV, Peine KJ, Curry H, Collier MA, Homsy ML, Bachelder EM, Gunn JS, Schlesinger LS, Ainslie KM. Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection. Int J Pharm. 2014 Dec 30;477(1-2):334-43. (pdf)
  6. Collier MA, Gallovic MD, Peine KJ, Duong AD, Bachelder EM, Gunn JS, Schlesinger LS, Ainslie KM. Delivery of host cell-directed therapeutics for intracellular pathogen clearance.Expert Rev Anti Infect Ther. 2013 Nov;11(11):1225-35. (link)
  7. Duong AD, Sharma S, Peine KJ, Gupta G, Satoskar AR, Bachelder EM, Wyslouzil BE, and Ainslie KM. Electrospray Encapsulation of Toll-Like Receptor Agonist Resiquimod in Polymer Microparticles for the Treatment of Visceral Leishmaniasis. Mol Pharm, 2013 (link)
  8. Duong AD, Collier MA, Bachelder EM, Wyslouzil BE, Ainslie KM. One Step Encapsulation of Small Molecule Drugs in Liposomes via Electrospray-Remote Loading. Mol Pharm. 2016 Jan 4;13(1):92-9. (link)
  9. Peine KJ, Bachelder EM, Vangundy Z, Papenfuss T, Brackman DJ, Gallovic MD, Schully K, Pesce J, Keane-Myers A, Ainslie KM. Efficient delivery of the toll-like receptor agonists polyinosinic:polycytidylic acid and CpG to macrophages by acetalated dextran microparticles. Mol Pharm. 2013 Aug 5;10(8):2849-57. (link)
  10. Kauffman, KJ; Kanthamneni, N; Meenach, SA; Pierson, BC; Bachelder, EM; Ainslie, KM. Optimization of rapamycin-loaded acetalated dextran microparticles for immunosuppression. Int J Pharm. 2012 Jan 17;422(1-2):356-63. (link)

Received Funding

  • NIH R21 Ai123692 – Microparticle Resiquimod For The Treatment Of Visceral Leishmaniasis (2016-2018)
  • NIH R01 Ai125147 – Host Targeted Therapy For Drug Resistant Salmonella And Francisella Infection (2016-2021)
  • NIH R33 Ai102252 – Celecoxib Derivative: Host Cell-Directed Inhibitors Of Intracellular Pathogens (2014-2017)
  • NIH R21 Ai102252 – Celecoxib Derivative: Host Cell-Directed Inhibitors Of Intracellular Pathogens (2011-2013)
  • Defense Threat Reduction Agency (DTRA) – Stimulation of broad spectrum protection via TLR 7,8&9 (2009-2010)
  • Arno Therapeutics (2013-2014)
  • NIH R21 – miRNA Regulation of Macrophages after Spinal Cord Injury (2012-2014) Bachelder    

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IMPROVED FORMULATION OF VACCINES

We can significantly improve cellular vaccine response to safe subunit (e.g. protein) based vaccines by using Acetalated Dextran (Ac-DEX), an acid-sensitive, pH neutral, and tunable degrading biopolymer.

Publications

  1. Schully KL, Bell MG, Prouty AM, Gallovic MD, Gautam S, Peine KJ, Sharma S, Bachelder EM, Pesce JT, Elberson MA, Ainslie KM, Keane-Myers A. Evaluation of a biodegradable microparticulate polymer as a carrier for Burkholderia pseudomallei subunit vaccines in a mouse model of melioidosis. Int J Pharm. 2015 Nov 30;495(2):849-61. (link)
  2. Schully KL; Sharma S; Peine KJ; Pesce J; Elberson MA; Fonseca ME; Prouty AM; Bell MG; Borteh H; Gallovic M; Bachelder EM;, Keane-Myers A; and Ainslie KM. Rapid Vaccination Using an Acetalated Dextran Microparticulate Subunit Vaccine Confers Protection Against Triplicate Challenge by Bacillus Anthracis. Pharm Res, 2013(link)
  3. Bachelder, EM;Beaudette, TT; Broaders, KE; Fréchet, JM; Albrecht, MT; Mateczun, AJ; Ainslie, KM; Pesce, JT; Keane-Myers, AM. In Vitro Analysis of Acetalated Dextran Microparticles as a Potent Delivery Platform for Vaccine Adjuvants. Mol Pharm. 2010 Apr 1. (link)
  4. Kanthamneni, N; Sharma, S; Meenach, SA; Billet, B; Zhao, Ji-Cheng; Bachelder, EM; Ainslie, KM. Enhanced stability of horseradish peroxidase encapsulated in acetalated dextran microparticles stored outside cold chain condition. Int J Pharm. 2012 Jul 15;431(1-2):101-10. (link)

Received Funding to Lab

  • OSU IMR – High throughput Production of Multi-component Multi-layered Acetalated Dextran-based Nanoparticle for Vaccination (2011-2012)
  • DARPA – Optimization of Resiquimod in Vaccine Microparticulate Carrier to Modify Immune Cells for Vaccine Formulation (2011-2012)
  • DARPA W911NF-10-1-0264 – Universal vaccine microparticulate carrier that encapsulates immune modifiers and antigens in a novel polymeric matrix to passively target dendritic cells (2010-2013)
  • DTRA – Development of needle-free, multi-formulation nanoparticle vaccine (2013-2014)
  • R01GM066115 – Bacterial sepsis and Reactivation of Latent Cytomegalovirus (2011-2013) Bachelder 

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ANTIGEN SPECIFIC TREATMENT OF AUTOIMMUNE DISEASES 

In the same way that vaccines specifically prime the immune system towards a disease, we aim to turn-down the autoimmune response in a specific manner, rather than the blanket suppression used currently to treat autoimmune diseases.

Publications

  1. Chen N, Peine KJ, Bachelder EM, Ainslie KM. Micro- and Nano-particulate Strategies for Antigen Specific Immune Tolerance to Treat Autoimmune Diseases. Pharmaceutical Nanotechnology, 2015 3(2): 85-100 (link)
  2. Peine KJ, Guerau-de-Arellano M, Lee P, Kanthamneni N, Severin M, Probst GD, Peng H, Yang Y, Vangundy Z, Papenfuss TL, Lovett-Racke AE, Bachelder EM, Ainslie KM. Treatment of Experimental Autoimmune Encephalomyelitis by Codelivery of Disease Associated Peptide and Dexamethasone in Acetalated Dextran Microparticles. Mol Pharm. 2014 (link)

Received Funding to Lab

  • R21 NS072813-01 – Encapsulated Active Vitamin D Vaccine for the Treatment of Multiple Sclerosis (2011-2013)
  • R21 AI095773 – Regulatory myeloid cells in inflammatory disease: Therapy and targeted generation with micro particles (2012-2014) Bachelder
  • JDRF – Tolergenic Nanoparticle Vaccine for the Treatment of Type 1 Diabetes (2012-2014) Bachelder

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DEVELOPMENT OF NEW POLYMERS

There are several polymers that are currently used for drug and vaccine delivery and many of them have significant drawbacks. For example polyesters (e.g. poly(lactic-co-glycoic) acid (PLGA), poly(β-aminoesters), polycaprolactone) have acidic by products that have been shown to reduce local pH, to where it can be even lower than pH 3 (Mikos lab). For vaccine purposes, one of the failures of the PLGA tetanus nanoparticulate vaccine was that the vaccine cargo was denatured when the particle degraded inside-out, resulting in a shell-like particle with an internal pH <5.8 (Schendamen lab). Moreover, these materials are not ideal for immune applications. Acid-sensitive materials have been shown to increase immune responses above that of slow-degrading, non-acid sensitive materials. Also, materials with highly tunable degradation products can facilitate enhanced controlled release.

Publications

  1. Gallovic MD, Bandyopadhyay S, Borteh H, Montjoy DG, Collier MA, Peine KJ, Wyslouzil BE,  Bachelder EM, Ainslie KM. Microparticles formulated from a family of novel silylated polysaccharides demonstrate inherent immunostimulatory properties and tunable hydrolytic degradability. J. Mater. Chem. B, 2016. (link)
  2. Gallovic MD, Montjoy DG, Collier MA, Do C, Wyslouzil BE, Bachelder EM, Ainslie KM. Chemically modified inulin microparticles serving dual function as a protein antigen delivery vehicle and immunostimulatory adjuvant. Biomater Sci. 2016 Feb 23;4(3):483-93. (link)
  3. Kauffman KJ; Do C; Sharma S; Gallovic MD; Bachelder EM; Ainslie KM. Synthesis and characterization of acetalated dextran polymer and microparticles with ethanol as a degradation product. ACS Appl Mater Interfaces. 2012 Aug 22;4(8):4149-55 (link)

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ACETALATED DEXTRAN (AC-DEX) PLATFORMS & SCALABLE TECHNOLOGIES

We primarily apply Ac-DEX in micro/nanoparticles, but we are always pursuing new platforms for the novel biopolymer. Additionally, we are interested in new platforms that can be more easily scalable than common batch processes like emulsion.

Publications

  1. Collier MA, Gallovic MD, Bachelder EM, Sykes CD, Kashuba A, Ainslie KM. Saquinavir Loaded Acetalated Dextran Microconfetti – a Long Acting Protease Inhibitor Injectable. Pharm Res. 2016 May 6. (link)
  2. Borteh HM, Gallovic MD, Sharma S, Peine KJ, Miao S, Brackman DJ, Gregg K, Xu Y, Guo X, Guan J, Bachelder EM, Ainslie KM. Electrospun acetalated dextran scaffolds for temporal release of therapeutics. Langmuir. 2013 Jun 25;29(25):7957-65. (link)
  3. Meenach, SA; Kim, YJ; Kauffman, KJ; Kanthamneni, N; Bachelder, EM; Ainslie, KM. Synthesis, optimization, and characterization of camptothecin-loaded acetalated dextran porous microparticles for pulmonary delivery. Mol Pharm. 2012 Feb 6;9(2):290-8. (link)

Received Funding to Lab

  • NIH R01 – Nanofiber matrices to improve neural stem cell-mediated cancer therapy (2016-2021) (PI Hingtgen)

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TOPICAL DELIVERY

Topical delivery can be advantageous for treatment of several immune specific conditions.

Received Funding to Lab

  • CDMRP – Novel ttherapeutic for treatment of cutaneousus leishmaniasis (2014-2017) Bachelder
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Ainslie Lab | 4229 Marsico Hall |                          125 Mason Farm Road | Chapel Hill, NC 27599