Abstract
Research concerning new targeting delivery systems for pharmacologically active molecules and genetic material is of great importance. The aim of the present study was to investigate the potential of fourth generation (P4) cationic phosphorus-containing dendrimers to bind fluorescent probe 8-anilino-1-naphthalenesulfonate (ANS), anti-neoplastic drug cisplatin, anti-HIV siRNA siP24 and its capability to deliver green fluorescent protein gene (pGFP) into cells. The interaction between P4 and ANS (as the model drug) was investigated. The binding constant and the number of binding centers per one molecule of P4 were determined. In addition, the dendriplex between P4 and anti-HIV siRNA siP24 was characterized using circular dichroism, fluorescence polarization and zeta-potential methods; the average hydrodynamic diameter of the dendriplex was calculated using zeta-size measurements. The efficiency of transfection of pGFP using P4 was determined in HEK293 cells and human mesenchymal stem cells, and the cytotoxicity of the P4-pGFP dendriplex was studied. Furthermore, enhancement of the toxic action of the anti-neoplastic drug cisplatin by P4 dendrimers was estimated. Based on the results, the fourth generation cationic phosphorus-containing dendrimers seem to be a good drug and gene delivery carrier candidate.
Highlights
Dendrimers are a new class of polymers with a well-defined molecular structure [1,2,3,4,5,6] that combine defined composition and monodispersity with high molecular mass, resulting in numerous interesting physical and chemical properties
As part of the current research, the possibility of P4 phosphorus-containing dendrimers binding to the anionic fluorescent probe ANS was investigated
If the binding centers of albumin are occupied by ligands the capacity of albumin to bind the fluorescent probe decreases
Summary
Dendrimers are a new class of polymers with a well-defined molecular structure [1,2,3,4,5,6] that combine defined composition and monodispersity with high molecular mass, resulting in numerous interesting physical and chemical properties. The dendrimer characteristics are as follow: they possess several functional end groups, which are responsible for high solubility and reactivity, and empty internal cavities [1,2]. These properties contribute to the suitability of dendrimers for targeting drugs, nucleic acids and short oligodeoxynucleotides (ODN). Phosphorus-containing fourth generation dendrimers were synthesized in the Laboratoire de Chimie de Coordination du CNRS [3,4] They are characterized by the presence of aminothiophosphates at each branching point along the backbone (Figure 1), which may enhance biocompatibility [3]; P4, C1296H2256N375Cl96O90P93S90 (generation 4, 96 surface cationic end groups, Mw: 33,702; diameter: 5 nm) [4]. Human monocytes can be activated by acid phosphoniccapped, phosphorus-containing dendrimers, as indicated by morphological and phenotypic modifications to the cells, together with an increase in phagocytosis and survival [6,7]
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