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FP7

TRANS-INT Report Summary

Project ID: 281035
Funded under: FP7-NMP
Country: Spain

Periodic Report Summary 3 - TRANS-INT (New Oral Nanomedicines: Transporting Therapeutic Macromolecules across the Intestinal Barrier)

Project Context and Objectives:
Marketed injected peptide and protein therapeutics have a great impact on the treatment of important systemic diseases, however, so far they cannot be administered in the fashion that has the highest patient compliance: the oral route. The reasons for this are clear: the gastrointestinal tract is specialised in degrading peptides and does not allow their transport across the intestinal mucosa. The availability of an oral form for the administration of peptides could lead to substantial improvement in the treatment of important chronic pathologies, such as diabetes. A successful oral delivery technology needs to fulfil key tasks: to protect the macromolecules from degradation and to facilitate their transport across the intestinal epithelium in a safe, cost-effective and efficient fashion. For this, we propose the use of nanocarriers specifically tailored to deal with the GI environment.

The concept behind TRANS-INT is the rational design of these oral nanomedicines based on integrative knowledge, networking intelligence and creativity. This design should be driven by:
i) Biopharmaceutical mechanistic criteria (we need to know more about the interaction of nanomaterials with the GI mucosa)
ii) Safety criteria (we will mainly use biomaterials which are already accepted by regulatory agencies or are in clinical evaluation)
iii) Materials bioengineering criteria (we will formulate biomaterials in order to produce nanocarriers with the required functionalities: protection of the peptide, efficient drug transport across the intestinal mucosa, and adequate and controlled drug release)
iv) Pharmaceutical technology criteria (we will make sure that the production technology is scalable and allows an adequate payload and that the final nanomedicine has adequate stability).

While these criteria are logical and rational, the reality is that up until now the design of nanocarriers for more than two decades now has been mostly based on traditional knowledge of biological barriers using a “trial and error” approach. In order to make significant advances, it is crucial to understand the mechanistic behaviour of nanocarriers in the biological system in a systematic and in-depth fashion. Thus, the TRANS-INT motto is: “Understand the barrier; understand the carrier”.

The overall objective of TRANS-INT is to develop new oral nanocarriers and new potential oral nanomedicines for the treatment of high economic and social impact diseases, as well as to contribute to the generation of new knowledge regarding the interaction of nanomaterials with the gastrointestinal barrier.

To address this overall objective, TRANS-INT research activity has been organised in different work packages (WP), whose main activities are indicated below:

WP1 and WP2 cover the initial nanocarrier design, development and characterisation before peptide drug candidates are formulated in WP2.

WP3 and WP4 investigate in vitro and in vivo mechanistic and toxicity studies, respectively in cell cultures and isolated tissue, whilst WP4 looks at in vivo mechanistic and preliminary toxicity studies.

WP5 and WP6 cover in vivo pharmacokinetic/pharmacological evaluation of selected nanomedicines, including extensive preclinical efficacy, toxicology and immunology for lead candidates.

These WPs are related to the scientific and technical activities and are supported by a number of transversal WPs, namely those associated with training and education (WP7), exploitation and dissemination activities (WP8), and the global management of the project (WP9).
Project Results:
WP1: NANOCARRIER DESIGN, DEVELOPMENT AND CHARACTERISATION
WP2: FORMULATION OF PEPTIDE DRUG CANDIDATES
The overall effort in this WP has led to information about thousands of prototypes and the optimization of the 13 prototype families, each of them representing a variety of prototypes prepared with the same technology. The delivery platforms have been classified into 3 categories, nanocapsules, nanoparticles and nanocomplexes.

The delivery platforms were adapted to the formulation of 5 antidiabetic peptides (human insulin, glulisine, lola, exenatide and liraglutide), as well as an anti-pain peptide. The formulations were screened according to the following ranking of properties: size and surface charge -> peptide association efficiency -> shelf stability -> stability in simulated intestinal fluids and in cell culture media -> in vitro release profile -> proteolysis -> mucodiffusion.

WP3: IN VITRO MECHANISTIC AND TOXICITY STUDIES
WP4: PRELIMINARY IN VIVO MECHANISTIC AND TOXICITY STUDIES
Twelve prototype families underwent toxicity evaluation in the Caco-2 monolayers and 6 of them were evaluated for their toxicity in the human intestine. Nine prototype families were investigated for their capacity to modify the TEER and to be internalized by the Caco-2 monolayers and 6 prototype families were also evaluated for their capacity to cross-isolated human intestinal tissue. The results indicated that the interactions of the prototypes with the intestinal mucosa were highly dependent on the size and composition of the prototype. Prototypes 6 and 12 were those showing the greatest internalization by the intestinal tissue.

In vivo fluorescent imaging studies were performed for 6 prototypes using in-situ instillation and in vivo oral administration to rats/mice. PK/PD analysis was also performed for 6 prototypes using rat in situ intestinal instillations under anaesthesia. The conclusion was that only one prototype (12) led to a satisfactory PK/PD profile in the in-situ model.

WP5: IN VIVO PHARMACOKINETIC/PHARMACOLOGICAL EVALUATION OF NANOMEDICINES
WP6: PRECLINICAL EFFICACY, TOXICOLOGICAL, IMMUNOLOGICAL EVALUATION
Seven prototype families were tested for their efficacy in normoglycemic rats, and one of them was tested in hyperglycemic rats, using the intra-intestinal injection model. The conclusion was that 4 out of 7 prototypes led to a modest response in normoglycemic rats, and this response was much more notorious in the diabetic rat model.

Currently, 4 prototypes are being considered for their feasibility according to the “Target Product Profile (TPP) document” defined by what would be needed to support early clinical trials. Two-three different products will be selected for the WP6 studies.

WP7: TRAINING AND EDUCATION
The education and training programme included:
- Scientific sessions on peptide drugs and oral drug delivery, including debates on the current literature and a session on intellectual property and presentation skills.
- Twenty researchers visited partner labs for up to 12 month periods, including one-day open lab.

WP8: EXPLOITATION AND DISSEMINATION
The project website has contributed successfully towards exchanging information within the consortium and with outside stakeholders. The implemented e-tools (e-brochure, e-poster, e-newsletter) are being disseminated through the website and email.

The project has so far resulted in 3 patent applications, 25 publications in scientific journals and 130 presentations in conferences. A monographic issue including TRANS-INT partners has been published in the ADDR journal.

A joint conference between ALEXANDER, COMPACT and TRANS-INT EC projects was held in Dresden, Germany, on the 9-11 November 2015.

WP9: MANAGEMENT
Partners and, notably young researchers, have been highly involved in the management of TRANSINT based on a clearly defined decision making process. An active external scientific board and the executive committee are being critical in accelerating this process.

Potential Impact:
WP1: NANOCARRIER DESIGN, DEVELOPMENT AND CHARACTERISATION
WP2: FORMULATION OF PEPTIDE DRUG CANDIDATES
The final result from these WPs will be a variety of nanocarriers rationally designed in order to overcome the gastrointestinal barriers, and endowed with the capacity to load and control the release of peptides. Major impacts will be: (i) provision of nanotechnology approaches to combine therapeutic peptides with biomaterials and to engineer specific properties for the said combinations; (ii) provision of robust assays with standard operating procedures (SOPs) to assess proteolysis, stability in complex simulated intestinal media, peptide release and proteolysis, and mucodiffusion of the loaded nanocarriers.

WP3: IN VITRO MECHANISTIC AND TOXICITY STUDIES
WP4: PRELIMINARY IN VIVO MECHANISTIC AND TOXICITY STUDIES
The final result will be a comparative analysis of different nanocarriers in terms of their toxicity and mechanism of interaction with the intestinal barriers using model cell lines (Caco-2), isolated human intestinal tissue and mouse/rat in models. An effort will be made to relate the composition, physicochemical properties (size, zeta potential) and muco-diffusion properties of the prototypes with their capacity to overcome the epithelial and mucosal barriers. This information will have a major impact on the rational design of nanomedicines and, notably, on the understanding of the co-relation between the in-vitro (Caco-2 and human intestine)/in-vivo (mice/rats) data. Altogether, WP3-WP4, will provide key information on fundamental preclinical mechanistic studies to be used for the selection of candidates for advanced preclinical development.

WP5: IN VIVO PHARMACOKINETIC/PHARMACOLOGICAL EVALUATION OF NANOMEDICINES
WP6: PRECLINICAL EFFICACY, TOXICOLOGICAL, IMMUNOLOGICAL EVALUATION
The final result from these WPs will be a comparative analysis of different nanocarriers in terms of their capacity to enhance the absorption of the associated peptides. This work will culminate with an understanding of the basis for the formulation of oral peptide drugs and, possibly, the delivery of one preclinical candidate.

Currently, 4 prototypes are being considered for their feasibility according to the “Target Product Profile document” defined by what would be needed to support early clinical trials. Two-three different products will be selected for the WP6 studies involving exploratory toxicology studies and efficacy studies in large-size animal models (dogs and pigs).

WP7: TRAINING AND EDUCATION
The final result will be 30 PhD students / post-docs trained in a cross-disciplinary environment and acquiring relevant knowledge regarding the development of medicines and the translation challenges associated with it. The special skills of these young researchers are already having an impact in their professional career, noted by the fact that those leaving the consortium are already working in academia or industry and some of them have become entrepreneurs.

WP8: EXPLOITATION AND DISSEMINATION
TRANS-INT is having an impact in the world-wide industry/academy research activity in the field. A monographic issue in oral peptide delivery has been published in the Advanced Drug Delivery Reviews journal. A joint conference was organised by the ALEXANDER, COMPACT and TRANS-INT EC projects. A number of background patents are under use and a new patent application from the USC and Sanofi has been issued.

WP9: MANAGEMENT
The management structure has involved all partners, including young researchers, who have been highly involved in a well-defined decision making process. The management training is expected to have an impact in other consortia as well as in the organization of the partner’s laboratories.

Overall, the scientific and technical knowledge generated regarding the characterization of nanomaterials and their interaction with the gastro-intestinal barriers is expected to have a very high impact in the development of peptide-based oral nanomedicines.
List of Websites:
www.trans-int.eu

Contact

Martin Cacheiro Martinez, (R&D Assistant Manager)
Tel.: +34 881 816233
Fax: +34 881 816263
E-mail
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