Albumin particles for intra-articular delivery of celecoxib to treat osteoarthritic inflammation.

Informations projet

IA-NANO

N° de convention de subvention: 840874

DOI

10.3030/840874

Projet clôturé

Date de signature de la CE 11 Avril 2019

Date de début 1 Août 2019

Date de fin 31 Juillet 2021

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 196 590,72

Contribution de l’UE

€ 196 590,72

Coordonné par

UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Ireland

Periodic Reporting for period 1 - IA-NANO (Albumin particles for intra-articular delivery of celecoxib to treat osteoarthritic inflammation.)

Période du rapport: 2019-08-01 au 2021-07-31

Résumé du contexte et des objectifs généraux du projet

Osteoarthritis (OA) is the most common form of arthritis. There is no cure for it and the current treatments only manage symptomatic pain and inflammation. Among all the treatments available, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed. There are 2 types of NSAIDs – non-selective cyclooxygenase (COX) inhibitors and selective COX-2 inhibitors. Selective COX-2 inhibitors are preferred as they cause less side-effects compared to non-selective COX inhibitors. Only one COX-2 inhibitor (Celebrex®, Pfizer, CT, USA) has been approved by both FDA and EMA. This approval is despite the fact that Celebrex (having the celecoxib as active pharmaceutical ingredient) has a black box warning concerning possible side-effects for cardiovascular events and gastrointestinal bleeding following oral administration. Injecting the drug directly into the OA joint via intra articular (IA) injection could be an efficient way to reduce or eliminate these side effects. However, the free celecoxib (Cel) molecules are likely to be removed from knee joints within a few hours due to their low molecular weight, thus decreasing the local bioavailability and efficacy. The only way to increase the retention time of Cel is to load the drug in a biocompatible nanoparticle (NP) and inject the drug-loaded NP to the inflamed joint through IA injection.

This project is important because it will attempt to reduce the side-effects that are associated with the commonly used medicine for OA i.e. Cel. Moreover, it will increase the bioavailability of the drug which will decrease the overall treatment cost. The NP that was developed in this project could potentially be loaded with drugs used for other indications like cancer and could have similar benefits of increased bioavailability, more efficacy, low side-effects, and reduced treatment cost.

The main objective of this project was to develop a Cel-loaded biocompatible NP and demonstrate its application for IA drug delivery of Cel to treat OA.

The other objectives of the project were:

1. To enhance the knowledge of the researcher in terms of technical, transferable, and complementary skills.

2. To enhance the host supervisor capacity in delivering nanomedicine projects.

3. To disseminate, communicate and exploit the results of the project.

In summary, the biocompatible Cel-loaded human serum albumin (HSA) NPs were successfully synthesised and characterised. The NPs reduced markers associated with inflammation in an activated human monocytic cell line (THP-1) and in primary chondrocytes from the knee joints of OA patients.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The work performed during the project is explained below in terms of work packages (WPs) originally proposed in the project.

WP1: Management

The project was started by listing out and placing orders for all the chemicals and equipment required. As multiple institutes and departments were involved in the project, meetings were organised to discuss the project and its requirements, researcher training and access. IP management, ethics management and a data management plan were discussed and finalised with the respective institutes/departments.

WP2: Training and Knowledge Transfer

Many trainings were provided to the researcher to enhance her technical, complementary and transferrable skills. The researcher also transferred her knowledge on development and characterisation of NPs as outlined in the project proposal.

WP3: Development and characterisation of Cel-loaded HSA particles

The Cel-loaded HSA NPs of 2 different average sizes (~66 nm and ~351 nm) were synthesised and characterised using different spectroscopic, microscopic, and scattering techniques.

WP4: Cytotoxicity and anti-inflammatory efficacy study in vitro

The cell viability and anti-inflammatory efficacy of Cel-loaded HSA NPs of ~66 nm were assessed in activated THP-1 cells and in primary chondrocytes from OA patients.

WP5: Anti-inflammatory efficacy study using an ex vivo explant culture model

The anti-inflammatory efficacy of Cel-loaded HSA NPs of ~66 nm was assessed in ex vivo cartilage from the knee of OA patient.

WP6 – Dissemination, Exploitation and Communication

The possibility of filing a patent for the NP made in this project was discussed with NovaUCD and an external patent consultant. The researcher participated in the Commercialisation Bootcamp organised by NovaUCD. An invention disclosure form was submitted to NovaUCD. As a part of dissemination and communication activities, presentations were given on the project and the project results to groups at UCD and in the SFI-CURAM Centre. An article was published in ‘News Rheum’ Newsletter (7th edition). General awareness about the projects and the scholarship funded by EU was posted and tweeted in LinkedIn and Twitter respectively.

In summary, we synthesised Cel-loaded HSA NPs in a novel process without using cross-linking agents, high temperature, polymer coatings, oils and Class II solvents. The NPs were spherical, and the surface was smooth. The NPs also had a narrow size distribution and a low polydispersity index. The NPs showed sustained release of Cel in phosphate buffer. The NPs of size ~66 nm was found to be stable at both room temperature (RT) and 4 C. Moreover, the NPs (~66 nm in diameter) did not reduce cell viability in activated THP-1 cells or in primary chondrocytes from OA patients. The Cel-loaded HSA NPs also decreased the inflammatory markers produced in activated THP-1 cells line and in OA chondrocytes. The ex vivo studies indicated through imaging that the NPs were able to penetrate the dense collagen matrix of cartilage to target chondrocytes.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

In arthritic joints, the NPs of less than 100 nm are known to penetrate the dense collagen matrix of cartilage to target chondrocytes. HSA NPs of size less than 100 nm have been reported in the literature, however, they were developed using either (a) cross-linking agents, (b) high temperature, (c) polymer coatings, or (d) oils/Class II solvents, all of which have their own drawbacks. In this project, we were able to synthesise HSA NPs of size less than 100 nm without using any of these conditions. Moreover, this method will allow the loading of temperature-sensitive drugs including some small molecules and biologics.

The HSA NPs of size less than 100 nm developed within this project may also be utilised to load anti-cancer drugs and can be used for passive targeting of cancer through the enhanced permeation and retention (EPR) effect.

OA and cancer are two of the twenty-four priority diseases quoted in the WHO report on ‘Priority Medicines for Europe and the World Update Report, 2013’ and finding a more effective treatment for these diseases are in line with ‘EU’s Horizon 2020 Programme focus area - Health, Demographic Change and Wellbeing and UN Sustainable Development goal - Good Health and Well-Being’.

The Cel-loaded HSA NPs developed in this project have the potential to be used for IA knee delivery of Cel for targeted OA treatment, which may have the potential for commercialisation and thus can be expected to reduce the total drug cost and adverse side effects, which in turn will decrease the economic burden and increase the good health and well-being.

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