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Palmer C.D.,Boston Childrens Hospital | Palmer C.D.,Harvard University | Palmer C.D.,Massachusetts Institute of Technology | Ninkovic J.,Boston Childrens Hospital | And 12 more authors.
Biomaterials | Year: 2014

Neonates and infants are susceptible to infection due to distinct immune responses in early life. Therefore, development of vaccine formulation and delivery systems capable of activating human newborn leukocytes is of global health importance. Poly[di(carboxylatophenoxy)phosphazene] (PCPP) belongs to a family of ionic synthetic polyphosphazene polyelectrolyte compounds that can form non-covalent interactions with protein antigens and demonstrate adjuvant activity in animals and in human clinical trials. However, little is known about their ability to activate human immune cells. In this study, we characterized the effects of PCPP alone or in combination with a model antigen (recombinant HIV-Gag (Gag)), on the maturation, activation and antigen presentation by human adult and newborn dendritic cells (DCs) in vitro. PCPP treatment induced DC activation as assessed by upregulation of co-stimulatory molecules and cytokine production. Studies benchmarking PCPP to Alum, the most commonly used vaccine adjuvant, demonstrated that both triggered cell death and release of danger signals in adult and newborn DCs. When complexed with Gag antigen, PCPP maintained its immunostimulatory characteristics while permitting internalization and presentation of Gag by DCs to HIV-Gag-specific CD4+ T cell clones. The PCPP vaccine formulation outlined here has intrinsic adjuvant activity, can facilitate effective delivery of antigen to DCs, and may be advantageous for induction of beneficial T cell-mediated immunity. Moreover, polyphosphazenes can further reduce cost of vaccine production and distribution through their dose-sparing and antigen-stabilizing properties, thus potentially eliminating the need for cold chain distribution. © 2014 Elsevier Ltd.


PubMed | Apogee Technology Inc., Boston Childrens Hospital and Harvard University
Type: Journal Article | Journal: Biomaterials | Year: 2014

Neonates and infants are susceptible to infection due to distinct immune responses in early life. Therefore, development of vaccine formulation and delivery systems capable of activating human newborn leukocytes is of global health importance. Poly[di(carboxylatophenoxy)phosphazene] (PCPP) belongs to a family of ionic synthetic polyphosphazene polyelectrolyte compounds that can form non-covalent interactions with protein antigens and demonstrate adjuvant activity in animals and in human clinical trials. However, little is known about their ability to activate human immune cells. In this study, we characterized the effects of PCPP alone or in combination with a model antigen (recombinant HIV-Gag (Gag)), on the maturation, activation and antigen presentation by human adult and newborn dendritic cells (DCs) invitro. PCPP treatment induced DC activation as assessed by upregulation of co-stimulatory molecules and cytokine production. Studies benchmarking PCPP to Alum, the most commonly used vaccine adjuvant, demonstrated that both triggered cell death and release of danger signals in adult and newborn DCs. When complexed with Gag antigen, PCPP maintained its immunostimulatory characteristics while permitting internalization and presentation of Gag by DCs to HIV-Gag-specific CD4(+) T cell clones. The PCPP vaccine formulation outlined here has intrinsic adjuvant activity, can facilitate effective delivery of antigen to DCs, and may be advantageous for induction of beneficial T cell-mediated immunity. Moreover, polyphosphazenes can further reduce cost of vaccine production and distribution through their dose-sparing and antigen-stabilizing properties, thus potentially eliminating the need for cold chain distribution.


Andrianov A.K.,Apogee Technology Inc. | Mutwiri G.,University of Saskatchewan
Vaccine | Year: 2012

A vast number of studies explore the potential of intradermal immunization, its role in the developing of new and improved vaccines and providing access to them globally. The advancement of microneedle technology offers new avenues for the practical realization of this approach, but, on certain instances, introduces new limitations and challenges in the formulation development, which involve the concern over its compatibility with existing and emerging immunoadjuvants. The present paper attempts to review various aspects of immunoadjuvant enhanced microneedle immunization and focuses on the potential of synthetic biomaterials that can play a multifunctional role in such approach. PCPP, a synthetic polyphosphazene macromolecular compound, is discussed as an example of such material that can potentially enable the technology as a microfabrication agent and a potent intradermal immunoadjuvant. © 2011 Elsevier Ltd.


Andrianov A.K.,Apogee Technology Inc. | Marin A.,Apogee Technology Inc. | Decollibus D.P.,Apogee Technology Inc.
Pharmaceutical Research | Year: 2011

Purpose: Intradermal immunization using microneedles requires compatible immunoadjuvant system. To address this challenge, we investigated microneedles coated with polyphosphazene polyelectrolyte, which served both as microfabrication material and an immunoadjuvant compound. Methods: Coated microneedles were fabricated by depositing formulations containing Poly[di(carboxylatophenoxy)phosphazene], PCPP, on metal shafts, and their physico-chemical characterization was conducted. Results: Microfabrication of PCPP-coated microneedles exhibited strong dependence on protein-PCPP interactions in solutions and allowed for high efficiency of protein encapsulation. 70°C thermal inactivation studies demonstrated a remarkable increase in functional stability of protein in coated microneedles compared to solution formulation. A potential for modulation of protein release from coated microneedles has been demonstrated through ionic complexation of PCPP with small ions. Conclusions: Microneedles containing PCPP coatings provide improved protein stability, modulated release, and protein-friendly microfabrication process. © 2010 Springer Science+Business Media, LLC.


Marin A.,Apogee Technology Inc. | Andrianov A.K.,Apogee Technology Inc.
Journal of Applied Polymer Science | Year: 2011

Microneedles containing sodium carboxymethylcellulose (CMC) formulations were fabricated to include an external chitosan (CS) layer to modulate their hydration profile, an important parameter affecting their application as intradermal delivery devices and their storage. The microfabrication process was carried out under conditions that enabled the formation of polyelectrolyte complexes between these oppositely charged macromolecules. CMC-CS microneedles were characterized by water uptake in a humid environment, contact angle measurements, dissolution in aqueous solutions, and protein-release profiles. The results demonstrate that the microneedles containing CMC-CS formulations displayed suppressed moisture sensitivity in water vapors compared to their unmodified CMC counterparts while the maintaining quick protein-release characteristics required for their uses. This approach also showed the potential for sustained protein-release applications, as the CMC-CS formulations could be combined in layers to fabricate multicompartment microneedle coatings with delayed release characteristics. © 2011 Wiley Periodicals, Inc.


Decollibus D.P.,Apogee Technology Inc. | Marin A.,Apogee Technology Inc. | Andrianov A.K.,Apogee Technology Inc.
Biomacromolecules | Year: 2010

Degradation of a water-soluble polyphosphazene, poly[di(carboxylatophenoxy) phosphazene], disodium salt (PCPP) has been studied in aqueous solutions at elevated temperature. This synthetic polyelectrolyte is of interest as vaccine adjuvant and its degradability constitutes an important component of its safety and formulation stability profiles. The degradation process is manifested by a gradual reduction in the molecular weight of the polymer and cleavage of side groups, which is consistent with previously reported data on hydrolytical breakdown of water-soluble polyphosphazenes. The kinetics of hydrolytical degradation exhibits distinct pH dependence and the process is faster in solutions with lower pH. Remarkably, a number of hydrogen bond forming additives, such as polyethylene glycol and Tween displayed a dramatic accelerating effect on the degradation of PCPP, whereas inorganic salts, such as sodium chloride and potassium chloride, showed a trend for its retardation. The results can be potentially explained on the basis of acid promoted hydrolysis mechanism and macromolecular interactions in the system. © 2010 American Chemical Society.


Marin A.,Apogee Technology Inc. | Decollibus D.P.,Apogee Technology Inc. | Andrianov A.K.,Apogee Technology Inc.
Biomacromolecules | Year: 2010

Applications of polyelectrolytes as pharmaceutical excipients or biologically active agents generated an increased interest in formulations, in which ionic macromolecules share the same milieu with protein drugs or vaccine antigens. Macromolecular interactions, which often take place in such systems, can potentially impact formulation activity and stability. The present article reports that poly[di(carboxylatophenoxy)phosphazene], disodium salt (PCPP), which has been previously shown to be a potent vaccine adjuvant, also displays a strong protein stabilizing effect in aqueous solutions that can be significantly amplified in the presence of nonionic surfactants. The phenomenon is studied in the context of macromolecular interactions in the system and is linked to the formation of PCPP-protein and PCPP-protein-surfactant complexes. © 2010 American Chemical Society.


Andrianov A.K.,Apogee Technology Inc. | Decollibus D.P.,Apogee Technology Inc. | Marin A.,Apogee Technology Inc. | Webb A.,St Jude Childrens Research Hospital | And 2 more authors.
Journal of Pharmaceutical Sciences | Year: 2011

The potential impact of an influenza pandemic can be mitigated through the realization of a successful vaccination program. The implementation of antigen stabilization and dose-sparing technologies is an important step in improving availability of vaccines at the time of a pandemic outbreak. We investigated poly[di(carboxylatophenoxy)phosphazene] (PCPP) as a potential stabilizing and immunostimulating agent for H5N1 influenza vaccine. Physicochemical characterization of PCPP-formulated H5N1 influenza vaccine revealed macromolecular complexation in the system, whereas single radial immunodiffusion assay verified antigenicity of the formulation in vitro. PCPP-enhanced formulation displayed a fourfold increase in the half-life at 40°C compared with a nonadjuvanted vaccine. Lethal challenge studies in ferrets demonstrated 100% protection for low-antigen dose PCPP-adjuvanted formulations (1 μg of hemagglutinin) and at least a 10-fold antigen-sparing effect. Therefore, PCPP demonstrated an ability to improve thermal stability of H5N1 influenza vaccine in solutions and provide for a substantial dose-sparing effect in vivo. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association.


PubMed | Apogee Technology Inc.
Type: Journal Article | Journal: Journal of pharmaceutical sciences | Year: 2013

The potential impact of an influenza pandemic can be mitigated through the realization of a successful vaccination program. The implementation of antigen stabilization and dose-sparing technologies is an important step in improving availability of vaccines at the time of a pandemic outbreak. We investigated poly[di(carboxylatophenoxy)phosphazene] (PCPP) as a potential stabilizing and immunostimulating agent for H5N1 influenza vaccine. Physicochemical characterization of PCPP-formulated H5N1 influenza vaccine revealed macromolecular complexation in the system, whereas single radial immunodiffusion assay verified antigenicity of the formulation in vitro. PCPP-enhanced formulation displayed a fourfold increase in the half-life at 40C compared with a nonadjuvanted vaccine. Lethal challenge studies in ferrets demonstrated 100% protection for low-antigen dose PCPP-adjuvanted formulations (1 g of hemagglutinin) and at least a 10-fold antigen-sparing effect. Therefore, PCPP demonstrated an ability to improve thermal stability of H5N1 influenza vaccine in solutions and provide for a substantial dose-sparing effect in vivo.


PubMed | Apogee Technology Inc.
Type: Journal Article | Journal: Vaccine | Year: 2012

A vast number of studies explore the potential of intradermal immunization, its role in the developing of new and improved vaccines and providing access to them globally. The advancement of microneedle technology offers new avenues for the practical realization of this approach, but, on certain instances, introduces new limitations and challenges in the formulation development, which involve the concern over its compatibility with existing and emerging immunoadjuvants. The present paper attempts to review various aspects of immunoadjuvant enhanced microneedle immunization and focuses on the potential of synthetic biomaterials that can play a multifunctional role in such approach. PCPP, a synthetic polyphosphazene macromolecular compound, is discussed as an example of such material that can potentially enable the technology as a microfabrication agent and a potent intradermal immunoadjuvant.

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