Functionalized nano-objects based on amphiphilic biocompatiblesmectic block copolymers

Lin Jia1, Birgit Oberleitner, Sylvie Coscoy, Aurélie Di Cicco,Vincent Semetey, Min-Hui Li⁎

Institut Curie, CNRS, Université Pierre & Marie Curie, LaboratoirePhysico-Chimie Curie, UMR168, Paris 75248, France1Current address: Department of Chemistry, University of Toronto, 80 St.George Street, Toronto M5S 3H6, Canada.E-mail addresses: jlsioc@hotmail.com (L. Jia),min-hui.li@curie.fr (M.-H. Li).

Micellar nanostructures (vesicles, cylindrical or spherical micellesetc.) based on amphiphilic block copolymers are attractive candi-dates for applications such as encapsulation, drug delivery and nano-reactors [1]. The introduction of responsive properties (actuator) andthe engineering of targeted adhesion and of molecular recognition inthese nanostructures are two critical issues that should be addressedfor their applications. This work will focus on the second issue anddiscuss the functionalization of polymer nano-objects.

In our group, we developed polymer nano-nanostructures self-assembled by amphiphilic block copolymers which are composedof a PEG hydrophilic block and a cholesterol-based liquid crystalpolymer block (PAChol) [2,3]. This biocompatible cholesterol blockleads to the formation of fascinating morphologies, includingpolymersomes, nanofibers and nanotubes, under different physicalchemical conditions due to its smectic liquid crystalline property[3]. We introduce here different functional groups (amine, biotin,benzophenone and gold nanoparticle) to the PEG terminal of thecholesterol-based block copolymers. Nano-objects with differentmorphologies (nanofibers, vesicles and nanotubes) and differentfunctional groups were then obtained by controlled self-assembly inaqueous solution (Fig. 1). Cell uptake and cytotoxicity of these nano-objects were also studied. We aim to explore the application of thesepolymer nano-objects in the targeted and controlled intracellulardrug delivery.

Fig. 1. (a) Flow cytometry test of functionalized nanofibers (Biotin-PEG-b-PAChol)bonding with fluorescent-streptavidin. (b) Nanofibers and (c) vesicles functionalizedwith Au-nanoparticles. Scale bar: 100 nm.

Keywords: Functionalization, Self-assembly, Cholesterol, Smecticliquid crystalline polymer

References[1] D.E. Discher, F. Ahmed, Polymersomes, Annu. Rev. Biomed. Eng. 8 (2006)

323–341.[2] L. Jia, A.M. Cao, D. Lévy, B. Xu, P.-A. Albouy, X.-J. Xing, M.J. Bowick, M.-H. Li,

Smectic polymer vesicles, Soft Matter 5 (2009) 3446–3451.[3] L. Jia, D. Lévy, D. Durand, M. Impéror-Clerc, A.M. Cao, M.-H. Li, Smectic polymer

micellar aggregates with temperature-controlledmorphologies, Soft Matter 7 (2011)7395–7403.

doi:10.1016/j.jconrel.2013.08.106

Radioimmunoconjugate based on metal-chelating polymers andherceptin fragment for in (111) delivery into breast cancer cells

Peng Liua, Yijie Lua, Amanda J. Boyleb, Lin Jiaa,Raymond M. Reillyb, Mitchell A. Winnika,⁎aDepartment of Chemistry, University of Toronto, 80 St. George St.,Toronto M5S 3H6, CanadabDepartment of Pharmaceutical Sciences, University of Toronto,Toronto M5S 3M2, CanadaE-mail addresses: raymond.reilly@utoronto.ca (R.M. Reilly),mwinnik@chem.utoronto.ca (M.A. Winnik).

Radioimmunotherapy is an emerging strategy for cancer treatment[1]. Radioimmunoconjugates (RICs) based onmetal-chelating polymers[MCPs] can increase the specific activity (SA) of RICs [2]. We developednovel MCPs in which the pendant groups can be radio-labeled and theend group is available for bioconjugation to antibodies (Abs). We wantto use MCPs containing diethylenetriaminepentaacetic acid (DTPA) tochelate 111In, an Auger emitting radionuclide, and conjugate it withtrastuzumab. Trastuzumab is a widely used antibody for breast cancertreatment due to its specific targeting ability towards human epidermalgrowth factor receptor-2 (HER2)which is overexpressed on some typesof breast cancer cells. The strategy of labeling trastuzumab with MCPsshould improve radio-labeling efficiency and the SA, and thereforeincrease the therapeutic efficiency.

In our work, the Fab fragment of the trastuzumab (tmFab) wascovalently conjugated to streptavidin (SAv). The MCPs contain biotinchain ends which were complexed with Fab–SAv through the strongaffinity between biotin and streptavidin. These polymer–proteincomplexes were subsequently radio-labeled with 111In to form theRICs. We used four types of polymers with different compositions toform the RICs. These RICs show different pharmacokinetic profiles ina Balb/c mice models but similar immunoreactivities toward HER2on the SKOV3 cell lines [3]. These in vivo and in vitro studies showthat these polymer–protein complexes retain HER2 specific targetingability. In the next generation experiments, we will look at MCPcopolymers containing polyethylene glycol (PEG) pendant groups aswell as DTPA, with the idea that the PEG groups will confer stealth tothe polymers, improve the biodistribution, and reduce the amount ofnon-specific binding to cancer cells.

Fig. 1. Illustrative scheme of tmFab–MCPs and MicroSPECT imaging in balb/c mice.

Keywords: Metal-chelating polymer, Fab-polymer conjugate,Trastuzumab, Radioimmunoconjugate

References[1] D.L. Costantini, K. Bateman, K. McLarty, K.A. Vallis, R.M. Reilly, Trastuzumab-

resistant breast cancer cells remain sensitive to the auger electron–emittingradiotherapeutic agent 111In-NLS-Trastuzumab and are radiosensitized by meth-otrexate, J. Nucl. Med. 49 (2008) 1498–1505.

[2] V.P. Torchilin, Biotin-conjugated polychelating agent, Bioconjug. Chem. 10 (1999)146–149.

[3] A.J. Boyle, P. Liu, Y. Lu, D. Weinrich, A.D. Scollard, G.N.N. Mbong, M.A. Winnik,R.M. Reilly, The effect of metal-chelating polymers (MCPs) for 111In complex via

Abstracts / Journal of Controlled Release 172 (2013) e14–e97 e51