The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres

Abstract

Injectable blood persistent particulate carriers have important therapeutic application in site-specific drug delivery or medical imaging. However, injected particles are generally eliminated by the reticuloendothelial system within minutes after administration and accumulate in the liver and spleen. To obtain a coating that might prevent opsonization and subsequent recognition by the macrophages, sterically stabilized nanospheres were developed using amphiphilic diblock or multiblock copolymers. The nanospheres are composed of a hydrophilic polyethylene glycol coating and a biodegradable core in which various drugs were encapsulated. Hydrophobic drugs, such as lidocaine, were entrapped up to 45 wt% and the release kinetics were governed by the polymer physico-chemical characteristics. Plasma protein adsorption was drastically reduced on PEG-coated particles compared to non-coated ones. Relative protein amounts were time-dependent. The nanospheres exhibited increased blood circulation times and reduced liver accumulation, depending on the coating polyethylene glycol molecular weight and surface density. They could be freeze-dried and redispersed in aqueous solutions and possess good shelf stability. It may be possible to tailor "optimal" polymers for given therapeutic applications.

Keywords: Biodegradable polymers; Hydrophilic coating; Intravenous drug administration; Long-circulating nanoparticles; Polyethylene glycol; Reduced liver accumulation.

Fig. 1

Interactions between a protein and a hydrophobic substrate with attached PEG chains (adapted from [68]). 1: hydrophobic attraction between the protein and the substrate; 2: steric repulsion resulting from PEG chain constriction; 3: van der Waals attraction between the protein and the substrate; 4: van der Waals attraction between the protein and the PEG chains.

Fig. 2

Schematic representation of the nanosphere fabrication procedure following an emulsion-solvent evaporation procedure.

Fig. 3

Time course of the polymerization reaction between MPEG and lactide/glycolide followed by gel permeation chromatography (adapted from [25]). Peak P: PEG-PLGA copolymer; peak D: starting monomers (lactide/glycolide).

Fig. 4

DSC thermograms of PEG5K-PLGA copolymers with increased chain length of PLGA. The first run (heating rate 10°C/min) was obtained with purified polymers. The samples were rapidly quenched and a second run (10°C/min) was enregistered.

Fig. 5

Scanning electron microscopy of PLGA40K (A) and PEG5K-PLGA45K (B) nanospheres.

Fig. 6

Freeze-fracture electron microscopy of PLGA40K (A), PEG20K-PLGA180K (B) and lidocaine-loaded (45 wt%) PEG20K-PLGA180K (C) nanospheres.

Fig. 7

Fraction of PEG detached from PEG5K-PLGA45K nanospheres during incubation at 37°C in phosphate buffer solutions (pH 7.4).

Fig. 8

Lidocaine release from PEG20K-PLGA180K nanospheres (10 and 33 wt% loading) (reproduced with permission from [22]).

Fig. 9

Plasma protein adsorption on PLGA40K (A) and PEG5K-PLGA45K (B) nanospheres (sample preparation and 2-D PAGE protocol after [72]). Close-up of the bottom left part of the 2-D PAGE gels. The proteines are separated on the basis of their molecular weights (MW) and isoelectric points (pI). (1) ApoA-IV, (2) ApoJ, (3) ApoE, (4) ApoA-1, (5) ApoC-III, (6) ApoC-II, (7) ApoA-II.

Scheme 1

Chemical structure of some diblock PEG-R and multiblock PEG_n-R_m copolymers used for the preparation of PEG-coated nanospheres.