Self-assembly of biodegradable copolyester and reactive HPMA-based polymers into nanoparticles as an alternative stealth drug delivery system

Eliézer Jäger; Alessandro Jäger; Tomáš Etrych; Fernando Carlos Giacomelli; Petr Chytil; Alexander Jigounov; Jean-Luc Putaux; Blanka Říhová; Karel Ulbrich; Petr Štěpánek

doi:10.1039/C2SM26150B

Self-assembly of biodegradable copolyester and reactive HPMA-based polymers into nanoparticles as an alternative stealth drug delivery system†

Eliézer Jäger,*^a Alessandro Jäger,^a Tomáš Etrych,^a Fernando Carlos Giacomelli,^b Petr Chytil,^a Alexander Jigounov,^a Jean-Luc Putaux,‡^c Blanka Říhová,^d Karel Ulbrich^a and Petr Štěpánek*^a

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^a Institute of Macromolecular Chemistry v.v.i., Academy of Sciences of the Czech Republic, Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic
E-mail: jager@imc.cas.cz, stepanek@imc.cas.cz
Tel: +420 296 809 322

^b Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, 09210-170 Santo André, Brazil

^c Centre de Recherches sur les Macromolécules Végétales (CERMAV-CNRS), BP 53, 38041 Grenoble Cedex 9, France

^d Institute of Microbiology v.v.i., Academy of Sciences of the Czech Republic, Vídenska 1083, 142 20 Prague 4, Czech Republic

Abstract

The surface modification of nanoparticles by physically anchoring hydrophilic biocompatible polymers is a simple and commercially attractive strategy to produce stealth drug delivery nanocarriers. Herein, we report the preparation, characterization and preliminary evaluation of the biological behaviour of polymeric nanoparticles (NPs) comprising a biodegradable poly(butylene succinate-co-butylene dilinoleate) – PBS/PBDL – copolyester and a non-immunogenic and non-toxic hydrophilic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. Narrowly distributed sub-100 nm polymeric nanoparticles with stealth properties were successfully prepared by using a combination of interfacial nanoprecipitation and self-assembly. The assemblies were characterized by using complementary scattering techniques and cryo-transmission electron microscopy. The dimension of the NPs was found to be in the proper range to avoid fast renal clearance (D_H > 10 nm) and still below the cut-off size of the leaky pathological microvasculature of hypervascular tumours (D_H < 200 nm), thus making them candidates for application in cancer therapy based on the EPR effect. The presence of PHPMA copolymer exposed at the surface of the nanoparticles was confirmed by scattering measurements. The stealth property of the biocompatible and biodegradable NPs is responsible for their remarkable in vitro stability monitored in a simulated physiological environment and increased stability in concentrated NaCl solutions compared to uncoated PBS/PBDL nanoparticles, making them an alternative to PEG-shielded particles. Furthermore, a reproducible, efficient and satisfactory physical entrapment of the antitumoral drug doxorubicin (DOX) was achieved (∼5.0% w_drug/w_NPs). The controlled DOX release is pH-dependent and faster under slightly acidic conditions and the cell viability experiments demonstrated that the drug-free NPs are non-toxic, whereas the DOX-loaded NPs exert in vitro cytostatic efficacy on EL4 T cell lymphoma.

Soft Matter

Self-assembly of biodegradable copolyester and reactive HPMA-based polymers into nanoparticles as an alternative stealth drug delivery system†

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