New PhD Project Offers
2012-04-LF Polypeptide-based multifunctional nano-assemblies for biomedical imaging and drug delivery (UCL-IMCN, UB1-LCPO)
It is now demonstrated that nano-assemblies such as micelles and vesicles hold great promises in the field of nano-medicine for applications such as targeted drug delivery or probes for imaging [1]. While both these applications have known tremendous development over the last years, there is still ample space for improvement and innovation, especially in the field of an integrated approach combining these two aspects into a single system (so-called theranostic systems). In this context, block copolymers are particularly interesting building blocks since their chemistry can be easily tuned, they can form stable nano-assemblies of various shapes and sizes with long circulation life-times, they can respond to many different stimuli, they can easily encapsulate hydrophobic or hydrophilic drugs and therapeutic biomolecules (peptide, protein, DNA/RNA…).
The objective of this PhD proposal is to develop block copolymer based multifunctional micelles/vesicles acting both as multimodal imaging probes and as drug delivery carriers. The targeted imaging techniques are MRI and fluorescence imaging. During this PhD, most of the efforts will be devoted to the synthesis and self-assembly behavior of the block copolymers, but in vitro tests will be also realized.
The first step will be the synthesis of the block copolymers. Polypeptide based copolymers, either di-polypeptide or hybrid (i.e. one block is a polypeptide, the other is a “classical” polymer such as a polyester segment or poly(ethylene oxide)), will be used, since they are particularly interesting for the construction of micelles/vesicles to be used in biological applications [2]. Moreover, they can respond to a variety of biologically relevant stimuli such as pH, temperature, and ionic strength. Strategies to functionalize these copolymers at the desired location (chain-end or side groups) with squaraine rotaxanes will be developed, based mainly on the CuAAc “click” reaction and peptidic coupling. These newly discovered rotaxanes are ideally suited for our targeted application since they exhibit strong fluorescence in the deep-red/near-infrared region, chemiluminescence in the near-IR region, and can act as a source of singlet oxygen [3]. The copolymers could be designed as to either expose the rotaxanes in the corona of the micelles/vesicles or in their core depending on the specific need. The second step will be the study of the self-assembly of those copolymers in aqueous solutions into micelles or vesicles. Those nano-assemblies will be prepared by nano-precipitation to allow the incorporation of drugs and/or magnetic particles into them, and will be characterized mainly by light scattering (static and dynamic), SAXS/SANS and TEM/AFM. The magnetic particles will act as contrast agent for MRI but can also be used to induce a burst release of the encapsulated drug by hyperthermia as already reported by the Bordeaux partner [4]. Finally, the multifunctional nano-assemblies will be tested in vitro in experiments such as uptake by cells, cytotoxicity,…
The strategy proposed in this project will ultimately lead to an integrated platform exploiting a unique combination of multimodal imaging, drug release capacity, and stimuli responsive behavior. This kind of approach will for example allow the tracking of the administered dose by the most adapted imaging technique, and apply the drug release stimulus only when it has reached its target, helping to strongly decrease side effects.
References
[1] a) W.J.M. Mulder, G.J. Strijkers, G.A.F. Van Tilborg, D.P. Cormode, Z.A. Fayad, K. Nicolay, Acc. Chem. Res. 2009, 42, 904 ; b) C. Oerlemans, W. Bult, M. Bos, G. Storm, J.F.W. Nijsen, W.E. Hennink, Pharm. Res. 2010, 27, 2569.
[2] A. Carlsen, S. Lecommandoux, Curr. Opin. Colloid Interface Sci. 2009, 14, 329.
[3] a) J.J. Gassensmith, J.M. Baumes, B.D. Smith, Chem. Commun. 2009, 6329 ; b) J.M. Baumes, J.J. Gassensmith, J. Giblin, J.J. Lee, A.G. White, W.J. Culligan, W.M. Leevy, M. Kuno, B.D. Smith, Nature Chem. 2010, 2, 1025.
[4] C. Sanson, O. Diou, J. Thevenot, E. Ibarboure, A. Soum, A. Brulet, S. Miraux, E. Thiaudiere, S. Tan, A. Brisson, V. Dupuis, O. Sandre, S. Lecommandoux, ACS Nano 2011, 5, 1122
Project Partners
UCL-IMCN, Louvain-la-Neuve: Squaraine rotaxane synthesis, photophysics properties, chemi-luminescence measurements, supramolecular self-assembly, singlet oxygen generation.
UB1-LCPO, Bordeaux: polypeptide-based block copolymer synthesis and self-assembly, nanostructure characterization (light scattering, small angle neutrons scattering, TEM and AFM imaging), magnetic nanoparticles synthesis and properties, hyperthermia.
SERVIER, DRD Galénique, France: pharmaceutical formulation, toxicity assays
