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PROJECT FINAL REPORT
Grant Agreement number: 246180Project acronym: PANOPTESProject title: Peptide-based Nanoparticles as Ocular Drug Delivery VehiclesFunding Scheme: NMP-2009-1.1-1Period covered: from 01/11/2010 to 31/10/2014Name, title and organisation of the scientific representative of the project's coordinator1: Professor Neil R. Cameron, Durham University
Tel: +44 191 3342000
Fax: +44 191 3844737
E-mail: [email protected]
Project website2 address: http://www.panoptesfp7.eu/
1 Usually the contact person of the coordinator as specified in Art. 8.1. of the Grant Agreement .2 The home page of the website should contain the generic European flag and the FP7 logo which are available in electronic format at the Europa website (logo of the European flag: http://europa.eu/abc/symbols/emblem/index_en.htm logo of the 7th FP: http://ec.europa.eu/research/fp7/index_en.cfm?pg=logos). The area of activity of the project should also be mentioned.
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4.1 Final publishable summary report
Executive SummaryThis report describes the progress and achievements of the FP7 project “Peptide-based Nanoparticles as Ocular Drug Delivery Vehicles” (PANOPTES). The 4 year project was conducted by 7 research groups in 6 institutions from 5 different European countries. The aim of the project was to produce peptide-based micro- and nanomaterials through self-assembly processes. These were to be employed as ocular drug delivery vehicles to give sustained delivery of drug molecules to the posterior segment of the eye (Figure 1). The original objectives of the project were achieved and several new successful drug delivery vehicles were established. The main achievements are as follows:
• Four different peptide-based materials platforms were successfully developed: self-assembling polypeptides; stimulus responsive elastin-like polypeptides (ELPs); polyesteramides (PEAs); and polyester-oxazoline block copolymers.
• The assembly of these polymers into a variety of micro- and nanostructures, including micelles, vesicles, nanoparticles, nanocapsules and microparticles, was achieved.
• The loading and release of various ocular drugs into these micro- and nanostructures was demonstrated.
• Extensive in vitro and ex vivo testing of the biocompatibility of the materials prepared, with and without loaded drugs, was conducted.
• Kinetic ocular modeling was undertaken to predict concentrations of drugs, delivery vehicle components and their breakdown products, in different compartments of the eye, following administration.
• In vivo assays of drug delivery vehicle biocompatibility and impact on retinal function were performed.
• The reproducibility of the processes for manufacturing the drug delivery vehicles was demonstrated.
• Extensive dissemination of the results of the project, to academia, industry and the general public, was undertaken.
• Significant numbers of researchers and samples were exchanged between the consortium partners.
Figure 1. Concept of self-assembling macromolecules that generate micro- and nanostructures for drug delivery to the eye.
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Project Context and ObjectivesAn unmet clinical need in the area of ocular drug delivery is the sustained delivery of a wide spectrum of drugs and other bioactive molecules to the posterior segment of the eye. Disorders affecting the posterior segment, which cause visual impairment and blindness, are occurring at an increasing rate as the European population ages. For example, there are currently around 6.5 million Europeans suffering from late stage age-related macular degeneration (AMD), a disorder of the posterior segment (see Figure 1). It has been estimated that within a few years about 30 million Americans will be affected by AMD. Successful ophthalmic therapy requires effective concentrations of the active substance in the different sections of the eye (e.g. vitreous, retina or choroids), depending on the disease. Injection of drugs into the vitreous cavity (intravitreal injection) provides therapeutic concentrations in the target site, however, when the disease is chronic, such as with uveitis, macular edema and AMD, frequent injections are required to achieve intraocular drug levels within the therapeutic range. This can cause severe secondary effects such as cataracts, retinal detachment, endophthalmitis and intravitreal haemorrhages. Even though intravitreal injection is accepted clinically, the risks of such complications increase dramatically as the number of required injections increases with the age of the patient. An effective drug delivery technology is required to solve this problem.
Sustained intraocular drug delivery systems, which allow the long-term release of the active substance with the same therapeutic effect as multiple injections, are available. Currently, micro- and nanoparticles prepared from linear, biodegradable polyesters such as poly(lactic-co-glycolic acid) (PLGA) are used widely. However, these have several major drawbacks: the polymers are prepared by relatively high energy processes; degradation produces acidic species that cause inflammation; several processing steps, involving organic solvents, surfactants and other additives, are required to produce particulate formulations; chemical functionalisation of the particle surface is non-trivial; drug release is difficult to control (i.e. non-zero order) and cannot be triggered; and peptides and proteins are difficult to encapsulate (the accurate control of the release of growth factors is essential as these drugs have a narrow therapeutic window and their effects may be different, even opposite, at the wrong concentrations). This necessitates the development of a new materials platform for ocular drug delivery, and in this project we have studied peptide-based micro- and nanomaterials prepared by self-assembly. Peptide-based materials have a number of attractive features in this context
biodegradation, through the action of enzymes such as proteases (present in elevated levels in the aging human vitreous), produces amino acids that are non-inflammatory
precise and controlled amino acid sequence (primary structure) formation of peptidic secondary structures, which facilitate self-assembly under low energy
conditions into nanoscale objects rich chemical diversity, allowing easy attachment of, inter alia, targeting vectors and species
to improve biocompatibility (eg poly(ethylene glycol), PEG) the ability to respond to external stimuli, such as temperature, light and the presence of
certain analytes, to trigger drug release.
The penetration of barriers is a challenge for posterior ocular segment treatment using sustained release systems administered either to the vitreous, or to the periocular or subconjunctival sites. The released drug must permeate across the tissue barriers to its site of action (in the neural retina, the retinal pigment epithelium (RPE) or in the choroid). After subconjunctival or periocular administration, the sclera, choroidal blood clearance and the RPE are the major barriers. Drugs administered intravitreally must overcome the barriers of the inner limiting membrane in the retina and the RPE. Nanoparticles and nanocapsules are expected to be beneficial in this context, as their
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choroidal blood clearance kinetics will be slow, and furthermore they can deliver drugs to the intracellular space of target cells in the sites mentioned above.
To overcome these problems and create new drug delivery technologies to treat diseases of the retina, we conducted an integrated research programme consisting of three tiers, or Platforms (Figure 2). The Synthesis Platform describes the classes of material to be synthesised, both chemically and using molecular biology approaches, and their advantageous properties. The Processing Platform outlines the types of object into which the materials from the top tier will be processed. The Delivery Platform describes the types of drugs to be loaded into the particles and capsules, and the desired outcomes of the delivery experiments. This platforms approach then guided the synthesis of a variety of peptide-based macromolecules capable of assembling into different micro- and nanostructures, which could then be used for the delivery of different drugs used in the ocular setting.
BiodegradableBiocompatible
Self-assemblingStimuli responsive
TargetingNon-immunogenic
Sustained, zero-order releaseScaleable
Reproducible
Penetration of barriersProlonged retention
BiocompatibleNo retinal detachment
Posterior segment drug delivery
PeptidesPolymers
Hybrid materials
Synt
hesis
Proc
essin
g
Deliv
ery
Micelles and vesiclesMicroparticlesNanoparticlesMicrocapsulesNanocapsules
Hydrophobic drugsHydrophilic drugs
PeptidesOligonucleotides
BiodegradableBiocompatible
Self-assemblingStimuli responsive
BiodegradableBiocompatible
Self-assemblingStimuli responsive
TargetingNon-immunogenic
Sustained, zero-order releaseScaleable
Reproducible
TargetingNon-immunogenic
Sustained, zero-order releaseScaleable
Reproducible
Penetration of barriersProlonged retention
BiocompatibleNo retinal detachment
Penetration of barriersProlonged retention
BiocompatibleNo retinal detachment
Posterior segment drug delivery
PeptidesPolymers
Hybrid materials
Synt
hesis
Proc
essin
g
Deliv
ery
Micelles and vesiclesMicroparticlesNanoparticlesMicrocapsulesNanocapsules
Hydrophobic drugsHydrophilic drugs
PeptidesOligonucleotides
PeptidesPolymers
Hybrid materials
Synt
hesis
Proc
essin
g
Deliv
ery
Micelles and vesiclesMicroparticlesNanoparticlesMicrocapsulesNanocapsules
Hydrophobic drugsHydrophilic drugs
PeptidesOligonucleotides
Figure 2. Platforms concept employed in the PANOPTES project
The principal objectives of the PANOPTES project were to1. Develop novel peptide-based micro- and nanomaterials utilising the concept of self-assembly2. Demonstrate the ability of these materials to give sustained and triggered release of a range of
ocular drug molecules3. Demonstrate that such micro- and nanomaterials have good biocompatibility, high activity
and prolonged retention at the site of interest4. Demonstrate that the nanomaterials can be manufactured by the industrial partner
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Main Scientific and Technological ResultsThe PANOPTES project involves 6 partners (beneficiaries) as shown in Table 1.
Table 1. PANOPTES consortium partners and main contacts
Beneficiary Number
Beneficiary name Beneficiary short name
Country
Main contact
1 (coordinator) University of Durham UDUR UK Prof Neil Cameron2 Radboud Universiteit
NijmegenRUN NL Prof Jan van Hest
3 DSM Ahead DSM NL Dr Aylvin Dias4 Helsingin Yliopisto UH FI Prof Arto Urtti5 Universidad Complutense
de MadridUCM ES Prof Rocio Herrero
Vanrell6 Eberhard Karls
Universitaet TuebingenEKUT DE Prof Eberhart Zrenner
The scientific and technological aspects of the project were arranged in 7 work packages (WPs) as given in Table 2.
Table 2. List of scientific and technological work packages
WP Number
WP Title Lead beneficiary number
1 Chemical synthesis of polypeptides and peptide hybrids 1
2 Synthesis of novel polyester and polyesteramide based materials 3
3 Synthesis of polypeptides and peptide hybrids by protein engineering
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4 Evaluation of micro- & nanoparticle preparation methods and physical characterization
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5 Particle and capsule release properties 5
6 Cellular biocompatibility and functionality in vitro 4
7 In vivo studies 6
In the following section, the main results obtained in each of these WPs are summarised.
WP1: Chemical synthesis of polypeptides and peptide hybridsBlock copolypeptides were synthesised by ring-opening polymerisation (ROP) of N-carboxyanhydrides (NCAs) by sequential monomer addition (Figure 3). Polymerisations are controlled, giving narrow chain dispersities (typically <1.2) and average molecular weights that agree well with predicted values. The most commonly employed strategy to achieve amphiphilicity was to prepare block copolypeptides where each block has a cleavable hydrophobic side chain protecting group. Thus, selective removal of either one of the protecting groups gives an amphiphilic block copolypeptide capable of self-assembling in aqueous solution into a nanostructure, the nature of which depends on the polymer chemical composition.
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Figure 3. Ring-opening polymerisation of NCAs and selective deprotection to prepare amphiphilic block copolypeptides.
The following is a summary of the most significant results from WP1. A series of N-carboxyanhydrides including benzylglutamate, Z-lysine, alanine and isoleucine,
were synthesized as building blocks for amphiphilic block copolypeptides. Controlled homopolymerization of benzylglutamate, Z-lysine and isoleucine NCAs was
achieved. Synthesis of amphiphilic block copolypeptides was achieved using the sequential monomer
addition method. One of the side-chain protecting groups of poly(benzylglutamate)-poly(Z-lysine) was
removed selectively to give block copolypeptides that self-assemble into nanostructures with either anionic or cationic coronas.
PEG-polypeptide hybrid polymers were prepared. Block copolypeptides with photocleavable side-chain protecting groups were prepared.
Representative polymerisation data for block copolypeptides are shown in Table 3.
Table 3. Molecular Data for Selected Block Copolypeptides Prepared from NCAs.
Sample Expected Mn [Da]
Obtained Mn
[Da] ƉMBlock ratio (E:K)
Yield [%]
PBnE50 11,057 11,100 1.15 n/a 66PBnE30-b-ZK30 14,700 15,800 1.17 49:51 91PBnE30-b-ZK15 10,607 14,500 1.17 60:40 88PBnE50-b-ZK50 24,157 30,500 1.27 50:50 68PBnE50-b-ZK25 17,607 20,400 1.28 71:29 72
a BnE = benzyl-L-glutamate, ZK = ε-carbobenzyloxy-L-lysine, subscript number denotes targeted average degree of polymerisation
WP2: Synthesis of novel polyester and polyesteramide based materialsThis WP involved the development of synthetic polymers that could be assembled into micro- and nanoparticles for ocular drug delivery. Two polymer types were developed: polyesteramides and polyester-polyoxazoline block copolymers. One polyesteramide candidate, with the code name PEA III AcBz, was investigated extensively as a material for formulation into microparticles for use as a drug delivery vehicle for the anti-inflammatory drug dexamethasone, which is commonly used in the ocular setting. The chemical structure of PEA III AcBz is shown in Figure 4.
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HN
OO
O
O
O O
NH
OO
8
O
NH
O
NH 8
0.75 0.25PEA-I-Ac-Bz
HN O
OO
ONH
O HN
O
HN
O O ONH
OO
OO
OO
OHN
O
O
0.300.100.60
PEA-II-Ac-Bz
O
O
HN
OO
O
O
O
NH
O
NH
OO
8
O
NH
O
NH 8
O
O
O
O HN
O O8
0.30
0.25
0.45
PEA-III-Ac-Bz
NH
O O
O
O
O
OHN
O
O
NH
OO
NH
O
O
0.75 0.25
PEA-IV-Ac-Bz
Tg ~ 35 0C
Tg ~ 65 0C
Tg ~ 50 0C
Tg ~ 80 0C
O
O
HN
OO
O
O
O
NH
O
NH
OO
8
O
NH
O
NH 8
O
O
O
O HN
O O8
0.30
0.25
0.45
Figure 4. Chemical structure of PEA III AcBz.
The following is a summary of the most significant results from WP2. Polyesteramides (PEAs) were prepared and were shown to degrade enzymatically over
periods ranging from several days to 3 months The polyesteramide PEA III AcBz was degraded both enzymatically and chemically, and the
degradation products were characterised. Polyester-polyoxazoline block copolymers with polyester blocks composed of
polycaprolactone or polylactide were prepared.
Chemical structures and representative characterisation data for polyesteramides are shown in Figure 5.
Figure 5. Polyesteramides synthesized and their associated glass transition (Tg) values.
WP3: Synthesis of polypeptides and peptide hybrids by protein engineeringWP3 involved preparing polypeptides by protein engineering, in which genes for the required peptide sequences are introduced into an expression host, most commonly the bacterium E. coli. The proteins are then expressed in this host, and can be isolated and purified. In the PANOPTES project, the peptides of interest are known as elastin-like polypeptides (ELPs). These mimic the behaviour of the structural protein elastin, which can form a number of self-assembled nanostructures. In ELPs, the temperature at which this assembly takes place (known as the LCST) can be tuned by varying the chemical structure.
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The process of ELP production and self-assembly is shown schematically in Figure 6.
Figure 6. Production of elastin-like polypeptides (ELPs) and their assembly into nanostructures.
The following is a summary of the most significant results from WP3. High molecular weight ELPs, with a LCST lower than 37 °C, were prepared by protein
engineering. Temperature-responsive ELPs were fused to more hydrophilic ELPs to produce amphiphilic
block copolymers capable of forming micelles or vesicles. ELP-PEG hybrid copolymers were prepared. ELPs containing lysine residues for subsequent crosslinking were prepared.
Representative characterisation data for ELPs are shown below.
Figure 7. Turbidity measurements for an example ELP at a solution concentration of 1mg/ml, showing an LCST at around 32 oC.
WP4: Evaluation of micro- & nanoparticle preparation methods and physical characterizationThe polymers produced in WPs1-3 were assembled into a variety of micro- and nanostructures in WP4. These included micelles, nanoparticles, vesicles, microparticles and microcapsules. The assembled structures were characterised extensively using a range of imaging, scattering and spectroscopic methods. The surface of nanostructures was functionalised to introduce species that would enhance uptake by cells. One of the shortcomings of micelles and vesicles when used as drug delivery vehicles is that their stability in vivo is poor. For this reason, significant effort was invested in crosslinking many of the assembled structures. In this WP, we also devoted time and effort to investigating the reproducibility of preparation of the various structures obtained, so that their scale-up and manufacture could be optimised.
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The following is a summary of the most significant results from WP4. Polyesteramide microparticles with an average diameter of around 30 m were prepared. Polyester-polyoxazoline nanoparticles with an average diameter of between 70 and 120 nm
were prepared. Polypeptide and ELP micelles and vesicles with various diameters were prepared. Polypeptide and ELP micelles were crosslinked into nanoparticles using different approaches. Nanoparticles were surface functionalised with cell-penetrating peptides to enhance cellular
uptake. Microparticles and nanoparticles prepared under controlled conditions were found to have
highly reproducible diameters. A self-consistent field theory model was developed to predict the diameter of nanoparticles
prepared from block copolypeptides.
Representative data for the various micro- and nanostructures are shown below.
Figure 8. SEM images and particle size distribution of non-sterilized (a) and sterilized (b) PEA microspheres.
Figure 9. TEM image of crosslinked ELP nanoparticles (scale bar represents 100 nm).
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Figure 10. Dynamic light scattering (DLS) traces of 3 repeat preparations of polypeptide nanoparticles.
WP5: Particle and capsule release propertiesIn this WP, the various micro- and nanostructures prepared in WP4 were loaded with representative drugs used in eth ocular setting. Dexamethasone (Dx) was chosen as a model hydrophobic drug, and loading and release in vitro of Dx from microparticles and nanoparticles with hydrophobic interiors was investigated. Cationic block copolypeptides containing varying amounts of lysine residues were prepared and their complexation with siRNA that targets interleukin-6 (IL-6) was studied. The transfection ability and cellular uptake of the polypeptide-nucleotide complexes was investigated in vitro using the retinal cell line ARPE-19. Crosslinked porous gelatin microspheres were prepared for the loading of hydrophilic drugs.
The following is a summary of the most significant results from WP5. PEA III AcBz microparticles of diameter 10-20 m were successfully loaded with
dexamethasone with a loading efficiency of around 85%. The loaded dexamethasone was released steadily in vitro; 54% was released after 90 days.
PEA III AcBz microparticles were also loaded with FITC-labelled human serum albumin (HAS) as a model hydrophilic drug, with a loading of 35%.
An ocular kinetic model was successfully developed, to predict concentrations of drugs and delivery vehicle components in various compartments of the eye following administration.
Porous, crosslinked gelatin microparticles were successfully prepared using a porous CaCO3
template. 200 nm diameter polypeptide nanoparticles with hydrophobic interiors were loaded with
dexamethasone with an efficiency of 90% The cumulative drug release after 16 days was 94%.
Cationic block copolypeptides and ELP polymers were used to complex siRNA. Complexation occurred at an N/P ratio of 4:1. In vitro transfection of ARPE-19 cells indicated modest gene knockdown after 48h. Complexes were shown by flow cytometry to be taken up by cells.
Representative data for drug-loaded micro- and nanostructures are shown below.
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Figure 11. The in vitro release data of dexamethasone from PEA microspheres versus the predicted dexamethasone release.
Figure 12. Release of dexamethasone from PE50-b-ZK25 nanoparticles (E = L-glutamic acid, ZK = ε-carbobenzyloxy-L-lysine).
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Figure 13. IL-6 secretion of PBnE30-b-K30-siRNA (N/P 7/1-9/1) complex-treated ARPE-19 cells, relative to lipopolysaccharide (LPS) treated cells (5h incubation time).
WP6: Cellular biocompatibility and functionality in vitroThe in vitro and ex vivo biocompatibility of the drug delivery vehicles prepared during the project was assessed in WP6. Methods used included cell-based assays and cultures involving explanted rat retinae. Two cell lines were employed: ARPE-19 retinal cells and RAW 264.7 macrophages. Toxicity was assessed by a combination of LIVE/DEAD and MTT assays. The materials tested included polypeptides in their unformulated state (ie not formulated into particles), degraded polymer cocktails, microparticles and nanoparticles, versus positive and negative controls. Few signs of toxicity were observed, the only notable exceptions being block copolypeptides with unprotected polylysine sequences (poly(L-lysine) is well known to be cytotoxic). The explant cultures were performed over both short (7 days) and long (20 days) terms, and the effect of loading microparticles with dexamethasone to give neuroprotection was investigated.
The following is a summary of the most significant results from WP6. Extensive in vitro cell-based biocompatibility assays of micro- and nanoparticles was
undertaken. Few signs of toxicity were observed, the only notable exceptions being block copolypeptides with unprotected polylysine sequences.
Biocompatibility of PEA III AcBz microparticles was further investigated ex vivo using explanted retinae in an organotypic culture (see Figure 14). No signs of toxicity, as assessed by TUNEL staining, were observed either in short or long term culture. Furthermore, no morphological changes in the explanted retinae were observed in long term culture. Internalisation of microparticles by glial cells was observed in long-term culture.
Dexamethasone-loaded PEA III AcBz microparticles gave a neuroprotective effect when cultured in retinal explants.
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Figure 14. Retinal organ culture system. Top: an air-medium interface retains the cell–cell interactions in an intact neural network. PEA III AcBz microparticles at the surface of whole mount retinas after 24 (bottom left) and 48 (bottom right) hours in culture.
Representative data for in vitro and ex vivo biocompatibility studies are shown below.
Figure 15. In vitro toxicity of selected block copolypeptides to macrophages (RAW 264.7), as determined by MTT assay. From left to right: poly(BnE-b-PEG-b-BnE); poly(A-b-PEG-b-A);
Cell viability %
Cell viability %
Cell viability %
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poly(BnE30-b-K30) where BnE = benzyl-L-glutamate, PEG = polyethylene glycol, A = L-alanine and K = L-lysine.
Figure 16. Cell survival in short term retinal explants cultured with PEA III AcBz microspheres. Radial sections of control retina (A) and retinas with 3, 15 and 25 mg/ml of particles (B, C and D respectively) labelled with TUNEL staining (blue: DAPI; green: TUNEL). These three concentrations represent 10, 50 and 75 times the recommended dose to inject (0.33 mg/ml). No difference in the thickness or structure of the retinal layering is observed. Quantification of TUNEL positive cells in the outer nuclear layer (ONL; E) and inner nuclear layer (INL; F) did not show increased cell death in cultures with PEA III AcBz retinas compared with control retinas. On the other hand, retinas with PEA III AcBz microspheres loaded with the cytotoxic Ionochromophore II showed a dose-dependent increase in the number of dying cells in both, the outer and the inner retinas. However, the number of cell rows in both ONL (G) and INL (H) remained unchanged in all
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the analysed groups. *P < 0.05; **P<0.001; ***P < 0.001. Error bars represents standard errors of means. These data represent the means of at least four treated animals. ONL: outer nuclear layer; INL: inner nuclear layer.
WP7: In vivo studiesFollowing positive results from in vitro and ex vivo biocompatibility testing of PEA III AcBz microspheres, in vivo evaluation of tolerance and impact on retinal function was carried out in WP7. For both studies, rat models were used. For tolerance studies, microparticle suspensions were injected intravitreally and sub-tenon, and the study length was 4 weeks. Biocompatibility was assessed by clinical examination, histological analysis, immunofluorescence staining and TUNEL staining. The retinal functional study duration was 90 days and impact on function was assessed by OCT, fundus autofluorescence and ERG.
The results from WP7 cannot be discussed in detail in this report as they are not in the public domain, however the following general statements can be made:
Evaluation of rat in vivo tolerance of PEA III AcBz microparticles compared to PLGA control microparticles has been performed.
Retinal functional assays have been conducted in rats following injection with PEA III AcBz microparticles.
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Potential ImpactThe potential impact of the PANOPTES project is measured in three ways:
Academic impact, through dissemination activities including presentations at conferences and publications in the scientific literature
Socio-economic impact, through patent applications and other commercial activity Wider societal impact, through publications in general media and posting of information on
the web.
The activities undertaken during the project to promote the project and generate impact are summarised below.
Academic impact Members of the consortium presented 19 lectures at major international conferences,
including American Chemical Society (ACS) National Meetings, the Macro Group UK Warwick Polymer Conference and the Pan-American Association of Ophthalmology Annual Meeting.
Members of the consortium presented 18 posters at major international conferences, including American Chemical Society (ACS) National Meetings, the European Biomaterials Congress (ESB) and the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting. Sander Groenen was awarded a poster prize at the Macro Group UK Warwick Polymer Conference in 2012 for his poster entitled “Synthesis and Self-Assembly of Block Copolypeptides from N-Carboxy Anhydrides”.
The PANOPTES project organised a very successful one-day symposium on ophthalmic drug delivery at the European Biomaterials Congress in Madrid, 8-12 September 2013 (ESB 2013) (Figure 17). As well as talks from PANOPTES researchers, there were lectures from the two invited speakers: Prof Uday Kompella, Dept. of Pharmaceutical Sciences, University of Colorado, USA; Prof Stefaan de Smedt, Faculty of Pharmaceutical Sciences, University of Ghent, Belgium. Attendance averaged around 40 people.
A successful symposium dedicated to the PANOPTES project (Peptide-based Materials in Nanomedicine) was organised at the 247th ACS National Meeting, Dallas, March 16-20, 2014. The symposium ran over 2.5 days and featured talks from 20 invited international speakers as well as members of the PANOPTES consortium. Some of the papers presented at this symposium were published in a special issue of the journal Macromolecular Bioscience on Peptide-based Materials in Nanomedicine (2015, volume 15, issue 1). This special issue will be available open access for the whole of 2015 (http://onlinelibrary.wiley.com/doi/10.1002/mabi.v15.1/issuetoc).
A total of 17 papers in the scientific literature are planned arising directly from work conducted during the project. Of these, 7 are already in print, and several are in the late stage of preparation for submission.
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Figure 17. Photos from PANOPTES symposium at ESB 2013. Top left: Prof Uday Kompella; top right: Dr Sarah Hehir; bottom left: questions and discussions; bottom right: the speakers, coordinator and session co-chair (from left: Prof Stefaan de Smedt, Prof Miquel Refojo, Prof Rocio Herrero Vanrell, Dr Blanca Arango-Gonzalez, Prof Neil Cameron, Dr Mengmeng Zong, Ms Nanda Smits, Dr Eva Ramsay, Dr Sarah Hehir, Prof Uday Kompella).
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Figure 18. Poster presented by Dr Sarah Hehir at IUPAC 10th International Conference on Advanced Polymers via Macromolecular Engineering, Durham University, August 18-22, 2013.
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Figure 19. First page of one article published by the PANOPTES consortium members.
Socio-economic impact Three pieces of potentially exploitable intellectual property were identified at a dedicated
session on exploitation held during the consortium meeting in Nijmegen in November 2013. None of these has progressed yet to the stage of patent filing and so cannot be disclosed here.
Wider societal impact An outward-facing website, containing a summary of the project, list of consortium members,
consortium news, list of publications, vacancies and contact details was created. The site is hosted at www.panoptesfp7.eu (a domain name purchased for and dedicated to the project).
A short article was published in The Parliament Magazine in 2011 highlighting the project and describing its overall aim. The Parliament Magazine is the EU’s publication for MEPs and other professionals engaged with the parliament (https://www.theparliamentmagazine.eu). It is published fortnightly and the digital version has a circulation of over 50,000.
A further general interest article describing the project was published in Projects magazine in 2014 (http://www.projectsmagazine.eu.com). Projects is a European science, technology and innovation magazine that is published 8 times per year and has a readership of over 40,000.
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Articles published by consortium members in the special issue of Macromolecular Bioscience on Peptide-based Materials in Nanomedicine are available open access for the whole of 2015.
Website and Contact DetailsThe public website of the PANOPTES project is www.panoptesfp7.eu. Contact details of the coordinator are:
Professor Neil Cameron, Department of Materials Engineering, Monash University, Clayton 3800, Victoria, Australia; [email protected]. Tel. +61399020074.
ConclusionsThe original objectives of the PANOPTES project, as described in the Description of Work (DoW), were achieved and several new successful drug delivery vehicles were established. The main achievements are as follows:
• Four different peptide-based materials platforms were successfully developed: self-assembling polypeptides; stimulus responsive elastin-like polypeptides (ELPs); polyesteramides (PEAs); and polyester-oxazoline block copolymers.
• The assembly of these polymers into a variety of micro- and nanostructures, including micelles, vesicles, nanoparticles, nanocapsules and microparticles, was achieved.
• The loading and release of various ocular drugs into these micro- and nanostructures was demonstrated.
• Extensive in vitro and ex vivo testing of the biocompatibility of the materials prepared, with and without loaded drugs, was conducted.
• Kinetic ocular modeling was undertaken to predict concentrations of drugs, delivery vehicle components and their breakdown products, in different compartments of the eye, following administration.
• In vivo assays of drug delivery vehicle biocompatibility and impact on retinal function were performed.
• The reproducibility of the processes for manufacturing the drug delivery vehicles was demonstrated.
• Extensive dissemination of the results of the project, to academia, industry and the general public, was undertaken.
• Significant numbers of researchers and samples were exchanged between the consortium partners.
All deliverables were successfully completed and uploaded to the EC online portal. The consortium members have disseminated the research results widely, at scientific conferences, in the open academic literature and in general publications available more widely. Further disseminations are planned in the near future. The project did not quite progress to the commercialization phase, due to slower than anticipated progress in the latter stages, in particular in WP7. However, it is felt within the consortium that we have a solid platform on which to build, and two promising candidate materials for further development towards commercialization. We intend to apply for funding from H2020 for further development of the promising materials generated in the PANOPTES project.
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