Arlene McDowell's publications
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Characterization of Peptide Polymer Interactions in Poly(alkylcyanoacrylate) Nanoparticles: A Mass Spectrometric Approach

Characterization of Peptide Polymer Interactions in Poly(alkylcyanoacrylate) Nanoparticles: A Mass Spectrometric Approach | Arlene McDowell's publications | Scoop.it

Drug/polymer interactions occur during in situ polymerization of poly(alkylcyanoacrylate) (PACA) formulations. We have used MALDI ionization coupled tandem time-of-flight (TOF) mass spectrometry as an accurate method to characterize covalent peptide/polymer interactions of PACA nanoparticles with the bioactives D-Lys6-GnRH, insulin, [Asn1-Val5]-angiotensin II, and fragments of insulin-like growth factor 1 (IGF-1 (1-3)) and human adrenocorticotropic hormone (h-ACTH, (18-39)) at the molecular level. Covalent interactions of peptide with alkylcyanoacrylate were identified for D-Lys6-GnRH, [Asn1-Val5]-angiotensin II and IGF-1 (1-3). D-Lys6-GnRH and [Asn1-Val5]-angiotensin II were modified at their histidine side chain within the peptide, whilst IGF-1 (1-3) was modified at the C-terminal glutamic acid residue. The more complex protein insulin was not modified despite the presence of 2 histidine residues. This might be explained by the engagement of histidine residues in the folding and sterical arrangement of insulin under polymerization conditions. As expected, h-ACTH (18-39) that does not contain histidine residues did not interfere in the polymerisation process. Lowering the pH did not prevent the covalent association of PACA with D-Lys6-GnRH or IGF-1 (1-3). Conclusively, protein and peptide bioactives are potentially reactive towards alkylcyanoacrylate monomers via various mechanisms with limited interference of pH. Histidines and C-terminal glutamic acid residues have been identified as potential sites of interaction. The likelihood of their engagement in the polymerisation process (initiators), however, seems dependant on their sterical availability. The reactivity of nucleophilic functional groups should always be considered and bioactives examined for their potential to covalently interfere with alkylcyanoacrylate monomers, especially when designing PACA delivery systems for protein and peptide biopharmaceuticals.


Kafka AP, Kelffmann T, Rades T and McDowell A (2010).  Current Drug Delivery 7: 208

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Release and bioactivity of PACA nanoparticles containing D-Lys6-GnRH for brushtail possum fertility control

Release and bioactivity of PACA nanoparticles containing D-Lys6-GnRH for brushtail possum fertility control | Arlene McDowell's publications | Scoop.it

Poly(ethylcyanoacrylate) (PECA) nanoparticles containing the chemical sterilitant D-Lys6-GnRH were prepared by an in situ interfacial polymerization technique. Their potential as a peroral delivery system for biocontrol of the brushtail possum, a major pest species in New Zealand, was evaluated. Peptide release from resulting particles was studied in vitro in artificial gastric juice (AGJ), simulated intestinal fluids (SIF) and brushtail possum plasma. The nanoparticles released a small fraction of bioactive over 6 h in AGJ and SIF (< 5%), while staying intact and retaining fractions of intact D-Lys6-GnRH. In contrast, 60% of D-Lys6-GnRH was released after 1 h in possum plasma. The nanoparticles were also administered in vivo into the caecum of brushtail possums. A significant biological response, measured as an increase in plasma luteinizing hormone (LH), was evident 10 min after administration. This demonstrates not only that PECA nanoparticles were able to facilitate the uptake of D-Lys6-GnRH from the caecum into systemic circulation but also that sufficient bioactive peptide reached the pituitary to exert a significant LH response following GnRH receptor mediated endocytosis. Hence, it can be concluded that PECA nanoparticles comprise a promising formulation strategy for the peroral delivery of the chemical sterilitant D-Lys6-GnRH to the brushtail possum in New Zealand.


Kafka AP, McLeod BJ, Rades T and McDowell A (2011).  Joural of Controlled Release 149: 307

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Long Acting Animal Health Drug Products - Fundamentals and Applications

Long Acting Animal Health Drug Products - Fundamentals and Applications | Arlene McDowell's publications | Scoop.it
This authoritative book is a comprehensive guide on the theories, applications, and challenges associated with the design and development of long acting veterinary formulations.  The volume acts as a reference to the animal health ...

 

Rathbone, Michael J.; McDowell, Arlene (Eds.)


Book Chapter

Delivery Systems for Wildlife by A. McDowell


Delivery remains a key challenge that hinders the successful remote administration of compounds utilized in the management of free-ranging wildlife. Pest wildlife occurs worldwide and management of this group of animals is shifting from lethal control methods to administration of agents that reduce the fertility of the pest species. Oral delivery of biocontrol agents is the favored route of administration; however, significant hurdles need to be overcome to achieve therapeutic in vivo effects. Regulation requirements for products to control fertility in wildlife are evolving as novel products are being developed. This chapter will outline current strategies for delivery of a number of bioactive compounds to wild animals and includes contemporary research in the field.

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Histidine Residues in the Peptide D-Lys6-GnRH: Potential for Copolymerization in Polymeric Nanoparticles

Histidine Residues in the Peptide D-Lys6-GnRH: Potential for Copolymerization in Polymeric Nanoparticles | Arlene McDowell's publications | Scoop.it

Poly(ethylcyanoacrylate) (PECA) nanoparticles containing the bioactive d-Lys6-GnRH were manufactured by an in situ interfacial polymerization process using a w/o-microemulsion template containing the peptide in the dispersed aqueous pseudophase of the microemulsion. Polymeric nanoparticles were characterized using PCS, RP-HPLC (bulk level) and MALDI TOF mass spectrometry (molecular level). The peptide d-Lys6-GnRH was reactive with the alkylcyanoacrylate monomer, resulting in some of the peptide copolymerizing with the monomer. MALDI TOF/TOF (tandem) analysis revealed that the histidine residue in position 2 of d-Lys6-GnRH interacts covalently in the polymerization process. A reaction mechanism for this nucleophilic interference is suggested. The copolymerization reaction appeared to occur within seconds after the addition of the monomer to the microemulsion. The surface charge of resulting nanoparticles was less negative (−3 mV) compared with the zeta potential of empty nanoparticles (−27.5 mV). The copolymerization yielded high entrapment rates of 95 ± 4% of peptide, but showed limited release (11%) of free peptide over 5 days. A separate experiment demonstrated that the addition of d-Lys6-GnRH to preformed empty PECA nanoparticles (ex situ) also yielded fractions of copolymerized peptide suggesting a certain proportion of polymer remains available for copolymerization possibly through an unzipping depolymerization/repolymerization process. Therefore, the reactivity of histidine residues in bioactives needs to be considered whenever using the bioactive in situ or ex situ with polymeric PECA nanoparticles.

 

Kafka AP, Kleffmann T, Rades T and McDowell A (2009).  Molecular Pharmaceutics 6: 1483

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