Detailed WP Objectives

Detailled Objectives :
Atherothrombosis in humans is characterized by a high degree of neovascularization, leukocyte extravasation, inflammation and intraplaque haemorrhages, leading to plaque rupture and eventually thrombotic obstruction of the arterial lumen. By using nanotherapeutic diagnostic and therapeutic platforms, NanoAthero sets out to a) image vulnerable lesions at an earlier stage and b) target and ‘treat’ key processes within the plaque contributing to plaque vulnerability.

NanoAthero proposes five nanosystems that will be elaborated for two clinical situations (thrombus and plaque), with each, imaging and therapeutic treatment for human. Due to the unique features of nanosystems, preliminary data and extensive expertise within the consortium, NanoAthero has the opportunity to deal with both diagnosis and therapy that will be addressed in pivotal interrelated projects:

Thrombus:      1) Complete a phase I trial for the imaging of thrombus with nuclear imaging
2) Design a nanosystem for effective and safe thrombolytic therapy in stroke
Plaque:             3) Design a nanosystem for plaque imaging
4) Provide the proof-of-concept for the local delivery of nanoparticles in atherosclerotic patients
5) Launch a phase I trial assessing the safety and efficacy of a nanosystem for anti-inflammatory treatment of vulnerable plaques

For imaging of vulnerable atherosclerotic plaques, existing imaging techniques will be employed using nanosystems targeting key pathological events such as thrombus generation, increased inflammatory activity or proteolytic activity. For treatment of vulnerable atherosclerotic plaques, anti-inflammatory and anti- thrombotic/thrombolytic nanosystems will be pursued to decrease plaque inflammation, or decrease pro-thrombotic activity all the way up to dissolving established blood clots, respectively.

Two nanosystems have preclinical validations. They can enter GMP production, regulatory and clinical phase at the start of the project with the corresponding partners. Three other nanosystems will be elaborated by the whole consortium, as a global effort from the chemical design to the patient.
One preclinically-validated nanosystem will be used for imaging of thrombus, with 99mTc for SPECT, and fucoidan as a macromolecular targeting agent. Phase I is expected to be completed at the end of NanoAthero project.

– The consortium will design one innovative nanosystem for thrombus treatment. A thrombolytic nanotherapy will be developed with an existing drug (tPA; tissue plasminogen activator) to increase its efficacy, in order to prevent neurological damage by dissolving clots and improving blood flow. For this nanosystem, all the steps of elaboration (WP1), preclinical evaluation (WP2), GMP production (WP3), and the beginning of toxicology files (WP4) will be taken.

– Another preclinically-validated nanosystem will give important information for drug delivery to the plaque based on passive targeting. A GMP-liposomal formulation containing a glucocorticoid (prednisone phosphate) as an anti-inflammatory drug for plaque treatment, for which Institutional Review Board-approval has been obtained, will be tested in patients with advanced atherosclerotic lesions to evaluate local delivery. At the same time, this study also serves to improve clinical evaluation protocols for novel lead compounds developed in WP1-WP2.

– In parallel, the consortium will elaborate one optimized nanosystem for imaging and one for treatment of plaque with assembly of existing and proprietary carriers and novel targeting components.

Risk assessment and ethics at all steps will be rigorously defined (WP6).

Target

Clinical use

Components

Actual status

Goal within the project

Thrombus

Diagnostic

Targeting nanostructure
(fucoidan)
+ imaging agent for nuclear medicine (99mTc)

Patented targeting,
Complete preclinically validation
=> Ready for GMP, regulatory and then clinical trials

Molecular imaging of thrombus by
SPECT
=> to complete Phase I

Treatment

Nanocarrier
+ targeting moiety
+ drug (tPA)

Drug approved, Partial preclinical evaluation
=> Assembly & Preclinical testing required

Thrombolytic treatment for stroke
=> to prepare toxicological files on nanosystem

Plaque

Diagnostic

Nanocarrier
+ targeting
+ imaging agent

Published/patented ligands, Published/patented GLP carriers, industrial development of imaging agents by partners
=> Assembly & Preclinical testing required

Molecular imaging of plaque
=> to obtain all documents necessary for the start of phase I

Treatment

Nanocarrier (liposome)
+ drug (prednisolone)

Preclinically validated and GMP- ready, drug in humans
=> Ready for a preliminary clinical trial

Delivery of drug in plaque with passive targeting
=> to obtain clinical proof of concept of delivery in humans

Nanocarrier
+ targeting
+ drug

Assembly & Preclinical testing required

Therapeutic treatment of human plaque
=> to launch Phase I