Microneedle mediated intradermal delivery of adjuvanted recombinant HIV-1 CN54gp140 effectively primes mucosal boost inoculations

Dissolving polymeric microneedle arrays formulated to contain recombinant CN54 HIVgp140 and the TLR4 agonist adjuvant MPLA were assessed for their ability to elicit antigen-specific immunity. Using this novel microneedle system we successfully primed antigen-specific responses that were further boosted by an intranasal mucosal inoculation to elicit significant antigen-specific immunity. This prime-boost modality generated similar serum and mucosal gp140-specific IgG levels to the adjuvanted and systemic subcutaneous inoculations. While the microneedle primed groups demonstrated a balanced Th1/Th2 profile, strong Th2 polarization was observed in the subcutaneous inoculation group, likely due to the high level of IL-5 secretion from cells in this group. Significantly, the animals that received a microneedle prime and intranasal boost regimen elicited a high level IgA response in both the serum and mucosa, which was greatly enhanced over the subcutaneous group. The splenocytes from this inoculation group secreted moderate levels of IL-5 and IL-10 as well as high amounts of IL-2, cytokines known to act in synergy to induce IgA. This work opens up the possibility for microneedle-based HIV vaccination strategies that, once fully developed, will greatly reduce risk for vaccinators and patients, with those in the developing world set to benefit most.

Novel semi-interpenetrating hydrogel networks with enhanced mechanical properties and thermoresponsive engineered drug delivery, designed as bioactive endotracheal tube biomaterials

Thermoresponsive polymeric platforms are used to optimise drug delivery in pharmaceutical systems and bioactive medical devices. However, the practical application of these systems is compromised by their poor mechanical properties. This study describes the design of thermoresponsive semi-interpenetrating polymer networks (s-IPNs) based on cross-linked p(NIPAA) or p(NIPAA-co-HEMA) hydrogels containing poly(e-caprolactone) designed to address this issue. Using DSC, the lower critical solution temperature of the co-polymer and p(NIPAA) matrices were circa 34 °C and 32 °C, respectively. PCL was physically dispersed within the hydrogel matrices as confirmed using confocal scanning laser microscopy and DSC and resulted in marked changes in the mechanical properties (ultimate tensile strength, Young's modulus) without adversely compromising the elongation properties. P(NIPAA) networks containing dispersed PCL exhibited thermoresponsive swelling properties following immersion in buffer (pH 7), with the equilibrium-swelling ratio being greater at 20 °C than 37 °C and greatest for p(NIPAA)/PCL systems at 20 °C. The incorporation of PCL significantly lowered the equilibrium swelling ratio of the various networks but this was not deemed practically significant for s-IPNs based on p(NIPAA). Thermoresponsive release of metronidazole was observed from s-IPN composed of p(NIPAA)/PCL at 37 °C but not from p(NIPAA-co-HEMA)/PCL at this temperature. In all other platforms, drug release at 20 °C was significantly similar to that at 37 °C and was diffusion controlled. This study has uniquely described a strategy by which thermoresponsive drug release may be performed from polymeric platforms with highly elastic properties. It is proposed that these materials may be used clinically as bioactive endotracheal tubes, designed to offer enhanced resistance to ventilator associated pneumonia, a clinical condition associated with the use of endotracheal tubes where stimulus responsive drug release from biomaterials of significant mechanical properties would be advantageous. © 2012 Elsevier B.V. All rights reserved.

Hydrogels as drug-delivery platforms:Physicochemical barriers and solutions

The properties of hydrogels, in particular their high biocompatibility and water sorption uptake, make hydrogels very attractive in drug delivery and biomedical devices. These favorable features of hydrogels are compromised by certain structural limitations such as those associated with their low mechanical strength in the swollen state. This review highlights the most important challenges that may seriously affect the practical implementation of hydrogels in clinical practice and the solutions that may be applied to overcome these limitations. © 2012 Future Science Ltd.

Silicone lntravaginal rings: a new delivery technology for HIV microbicides?

B-222

Design of a silicone intravaginal ring for the delivery of oxybutynin

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Pathways for delivery of surface water nutrients to receptors

Diffuse contaminants can make their way into rivers via a number of different pathways, including overland flow, interflow, and shallow and deep groundwater. Identification of the key pathway(s) delivering contaminants to a receptor is important for implementing effective water management strategies. The ‘Pathways Project’, funded by the Irish Environmental Protection Agency, is developing a catchment management tool that will enable practitioners to identify the critical source areas for diffuse contaminants, and the key pathways of interest in assessing contaminant problems on a catchment and sub-catchment scale.
One of the aims of the project is to quantify the flow and contaminant loadings being delivered to the stream via each of the main pathways. Chemical separation of stream event hydrographs is being used to supplement more traditional physical hydrograph separation methods. Distinct, stable chemical signatures are derived for each of the pathway end members, and the proportion of flow from each during a rainfall event can be determined using a simple mass balance approach.
Event sampling was carried out in a test catchment underlain by poorly permeable soils and bedrock, which is predominantly used for grazing with a number of one-off rural residential houses. Results show that artificial field drainage, which includes subterranean land drains and collector drains around the perimeters of the 1 to 10 ha fields, plays an important role in the delivery of flow and nutrients to the streams in these types of hydrogeological settings.
Nitrate infiltrates with recharge and is delivered to the stream primarily via the artificial drains and the shallow groundwater pathway. Longitudinal stream profiles show that the nitrate load input is relatively uniform over the 8 km length of the stream at high flows, suggesting widespread diffuse contaminant input. In contrast, phosphorus is adsorbed in the clay-rich soil and is transported mainly via the overland flow pathway and the artificial drains. Longitudinal stream profiles for phosphorus suggest a pattern of more discrete points of phosphorus inputs, which may be related to point sources of contamination.
These techniques have application elsewhere within a toolkit of methods for determining the key pathways delivering contaminants to surface water receptors.

Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery

Unique microneedle arrays prepared from crosslinked polymers, which contain no drug themselves, are described. They rapidly take up skin interstitial fluid upon skin insertion to form continuous, unblockable, hydrogel conduits from attached patch-type drug reservoirs to the dermal microcirculation. Importantly, such microneedles, which can be fabricated in a wide range of patch sizes and microneedle geometries, can be easily sterilized, resist hole closure while in place, and are removed completely intact from the skin. Delivery of macromolecules is no longer limited to what can be loaded into the microneedles themselves and transdermal drug delivery is now controlled by the crosslink density of the hydrogel system rather than the stratum corneum, while electrically modulated delivery is also a unique feature. This technology has the potential to overcome the limitations of conventional microneedle designs and greatly increase the range of the type of drug that is deliverable transdermally, with ensuing benefits for industry, healthcare providers and, ultimately, patients.

Infection-Responsive Drug Delivery from Urinary Biomaterials Controlled by a Novel Kinetic and Thermodynamic Approach

Purpose. The pH-dependent physicochemical properties of the antimicrobial quinolone, nalidixic acid, were exploited to achieve ‘intelligent’ drug release from a potential urinary catheter coating, poly(2-hydroxyethylmethacrylate) (p(HEMA)), in direct response to the elevated pH which occurs at the onset of catheter infection.
Methods. p(HEMA) hydrogels, and reduced-hydrophilicity copolymers incorporating methyl methacrylate, were loaded with nalidixic acid by a novel, surface particulate localization method, and characterized in terms of pH-dependent drug release and microbiological activity against the common urease-producing urinary pathogen Proteus mirabilis.
Results. The pH-dependent release kinetics of surface-localized nalidixic acid were 50- and 10-fold faster at pH 9, representing the alkaline conditions induced by urease-producing urinary pathogens, compared to release at pH 5 and pH 7 respectively. Furthermore, microbiological activity against P. mirabilis was significantly enhanced after loading surface particulate nalidixic acid in comparison to p(HEMA) hydrogels conventionally loaded with dispersed drug. The more hydrophobic methyl methacrylate-containing copolymers also demonstrated this pH responsive behavior, but additionally exhibited a sustained period of zero-order release.
Conclusions. The paradigm presented here provides a system with latent, immediate infection-responsive drug release followed by prolonged zero-order antimicrobial delivery, and represents an ‘intelligent’, infection-responsive, self-sterilizing biomaterial.

In-vitro investigation of out-of-field cell survival following the delivery of conformal, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans

The aim of this work is to determine the out-of-field survival of cells irradiated with either the primary field or scattered radiation in the presence and absence of intercellular communication following delivery of conformal, IMRT and VMAT treatment plans. Single beam, conformal, IMRT and VMAT plans were created to deliver 3 Gy to half the area of a T80 flask containing either DU-145 or AGO-1522 cells allowing intercellular communication between the in-and out-of-field cell populations. The same plans were delivered to a similar custom made phantom used to hold two T25 culture flasks, one flask in-field and one out-of-field to allow comparison of cell survival responses when intercellular communication is physically inhibited. Plans were created for the delivery of 8 Gy to the more radio-resistant DU-145 cells only in the presence and absence of intercellular communication. Cell survival was determined by clonogenic assay. In both cell lines, the out-of-field survival was not statistically different between delivery techniques for either cell line or dose. There was however, a statistically significant difference between survival out-of-field when intercellular communication was intact (single T80 culture flask) or inhibited (multiple T25 culture flasks) to in-field for all plans. No statistically significant difference was observed in-field with or without cellular communication to out-of-field for all plans. These data demonstrate out-of-field effects as important determinants of cell survival following exposure to modulated irradiation fields when cellular communication between differentially irradiated cell populations is present. This data is further evidence that refinement of existing radiobiological models to include indirect cell killing effects is required.