Chengdong Xiong

Colloidal stability and drug incorporation aspects of micellar-like PLA–PEG nanoparticles

Abstract The drug delivery properties of a series of poly(lactic acid)–poly(ethylene glycol) (PLA–PEG) micellar-like nanoparticles have been assessed in terms of their colloidal stability and their ability to incorporate a water soluble drug. These studies have focused on a range of PLA–PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3–110 kDa). In aqueous media, these copolymers formed micellar-like assemblies following precipitation from water miscible solvents. There was a controlled increase in the particle size as the molecular weight of the PLA block was increased. The characteristics of the PEG corona were also highly dependent on the PLA moiety. Copolymers with a low molecular weight PLA block (3–15 kDa) formed highly colloidally stable dispersions, with a complete PEG surface coverage. However, increasing the molecular weight of the PLA block resulted in significantly less colloidally stable nanoparticle dispersions, which flocculated in solvents that were significantly better than θ-solvents for the stabilising PEG chains. This can be attributed to a reduced PEG surface coverage and the probable presence of naked PLA ‘patches’ on the particle surface. These larger PLA–PEG nanoparticles (30:5–110:5) were found to be stabilised in the presence of serum components, which are thought to adsorb into the gaps on the particle surface and prevent flocculation. All of the dispersions were found to be stable under physiological conditions and therefore suitable for in vivo administration. A reasonable loading (3.1% w/w) of the micellar-like PLA–PEG 30:5 nanoparticles with the water soluble drug procaine hydrochloride was achieved. The incorporated drug was found to have no effect on the nanoparticle structure or recovery, which can be attributed to the micellar character of these assemblies and the presence of the stabilising PEG chains.

Miscibility, crystallization and morphology of poly(β-hydroxybutyrate)/poly(d,l-lactide) blends

The miscibility, crystallization and morphology of poly(β-hydroxybutyrate) (PHB)/poly(d,l-lactide) (PLA) blends were investigated by means of differential scanning calorimetry, polarizing optical microscopy and scanning electron microscopy studies. The results indicated that PHB/PLA blends prepared by casting a film from a common solvent at room temperature were immiscible over the range of compositions studied, while the melt-blended sample prepared at high temperature showed some evidence of greater miscibility. The crystallization of PHB in the blends was affected by the level of addition of PLA. The thermal history caused a depression of the melting point and a decrease in the crystallinity of PHB in the blends. Compared with plain PHB, the blends exhibited a certain improvement in mechanical properties.

Optimization of preparative conditions for poly-DL-lactide- polyethylene glycol microspheres with entrapped Vibrio cholera antigens.

Poly-dl-lactide-polyethylene glycol (PELA) with different contents of polyethylene glycol(PEG) were synthesized and the PEG content was estimated according to the integral height of hydrogen shown in 1H-NMR. PELA microspheres containing V. cholera antigen, outer membrane protein (OMP) were prepared by a water-in-oil-in-water (W/O/W) based on solvent evaporation procedure. Antigen microspheres with smooth surface, suitable size for oral administration (0.5-5 microm), high loading efficiency (about 60%) and low level of residual solvent (lower than 20ppm) were obtained. Microspheres prepared from PELA with PEG content of about 10% achieved the highest loading efficiency among PELA copolymers and poly-dl-lactide (PLA) homopolymer, which suggested that microspheres size, morphology and the precipitation rate of polymer showed considerable relations with OMP loading efficiency. The regulation of the solvent components of the oil phase contributes to a stable emulsion W/O, and it is concluded that the stable emulsion W/O plays a significant role in improving the protein loading efficiency of obtained microspheres. The addition of stabilizer, such as gelatin and polyvinyl alcohol, into the internal water phase before emulsification produced no significant difference in OMP entrapment and microspheres size. A higher OMP loading efficiency was achieved by adding NaCl or adjusting the pH at the iso-electric point of OMP in the external water phase. It was indicated in vitro that PELA microspheres with smaller size showed larger extent of initial release and higher release rate, whereas microspheres with the diameter of 2.17 microm showed no apparent burst effect.

Investigation on process parameters involved in preparation of poly-dl-lactide-poly(ethylene glycol) microspheres containing Leptospira Interrogans antigens

Block copolymer, poly-DL-lactide-poly(ethylene glycol) (PELA) with 11.5% of poly(ethylene glycol) (PEG) content was prepared by bulk ring-opening polymerization using stannous chloride as initiator. PELA microspheres with entrapped Leptospira Interrogans antigens, outer membrane protein (OMP) were elaborated by solvent extraction method based on the formation of multiple w/o/w emulsion, and the resulting microspheres were characterized with respect to particle size, OMP entrapment and morphology characteristics. The purpose of the present study is to perform the optimization of preparative parameters for OMP-loaded PELA micropsheres to control particle size and improve the OMP encapsulation efficiency. Of all the parameters investigated, the polymer concentration of organic phase and the external aqueous phase volume play major roles on particle size, while the organic phase volume, internal aqueous phase volume and the addition of surfactant into the internal aqueous phase display considerable effects on OMP loading efficiency. A small volume of internal aqueous phase and intermediate volumes of organic phase and external aqueous phase were favorable to achieve micropsheres with a size of 1-2 microns and high antigen encapsulation efficiency (70-80%). In vitro OMP release profiles from PELA microspheres consist of a small burst release followed by a gradual release phase. The OMP release rate shows some relations with the porous and water-swollen inner structure of the microspheres matrix. The presence of surfactant in microspheres accelerates OMP release, but the OMP entrapment within microspheres shows limited effects on the release profile.

In vitro degradation and release profiles of poly‐DL‐lactide‐poly(ethylene glycol) microspheres with entrapped proteins

Poly-DL-lactide (PLA) and poly-DL-lactide-poly(ethylene glycol) (PELA) were produced by bulk ring-opening polymerization using stannous chloride as initiator. PLA, PELA microspheres, and PELA microspheres containing the outer membrane protein (OMP) of Leptospira interrogans with the size of 1.5–2 μm were prepared by a solvent evaporation process. In vitro degradation and release tests of PLA, PELA, and OMP-loaded PELA microspheres were performed in pH 7.4 buffer solution at 37°C. Quantitatively, the degree of degradation was monitored by detecting the molecular weight reduction, by evaluating the mass loss and the apparent degradation rate constant, and by determining the intrinsic viscosity and poly(ethylene glycol) content of retrieved polymer, while the release profile was assessed by measuring the amount of protein presented in the release medium at various intervals. Qualitatively, the morphological changes of microspheres were observed with scanning electron micrography. The observed relative rates of mass loss versus molecular weight reduction are consistent with a bulk erosion process rather than surface erosion for PELA microspheres. The introduction of hydrophilic poly(ethylene glycol) domains in copolymer PELA and the presence of OMP within microspheres show critical influences on the degradation profile. The OMP-loaded PELA microspheres present triphasic release profile and a close correlation is observed between the polymer degradation and the OMP release profiles. It is suggested that the polymer degradation rate, protein diffusion coefficient, and the water-swollen structure of microspheres matrix commonly contribute to the OMP release from PELA microspheres.

Drug-polyionic block copolymer interactions for micelle formation: physicochemical characterisation.

While covalent attachment of small drug molecules to AB copolymers for the formation of polymeric micelles for drug delivery has been investigated, few studies have focused on non-covalent interactions. The aim of this study was therefore to explore the potential of non-covalent interactions between an AB copolymer, Poly(aspartic acid)-poly(ethylene glycol) (Pasp-PEG), with anionic pendant groups and diminazene aceturate, a small molecular weight cationic drug. Micelles were prepared by mixing solutions of Pasp-PEG and diminazene in 25 mM Tris-HCl buffer. At all Pasp-PEG concentrations studied, the micelles appeared to be water soluble with a unimodal size distribution and ranged in size from approximately 22 to 60 nm. The polyionic micelles also displayed similar and small absolute zeta potential values at various drug:monomer molar ratios which confirmed stabilisation by the PEG corona. The scattering intensity was maximal and remained unchanged, while particle size increased slightly at pH range from 3.4 to 7.2. At this pH range both the polymer and drug would be ionised and ionic interactions possible to drive micellar formation. An increase in size and scattering intensity with addition of NaCl to the micelles was attributed to dehydration of the PEG corona which may have led to aggregation of the micelles. The absence of micellar dissociation upon addition of salt was attributed to the dominance of hydrogen bonding between Pasp and diminazene aceturate, as assessed by isothermal titration microcalorimetry. Morphological evaluation of these constructs showed them to be discrete and fairly uniform in size and shape. This study was therefore successful in confirming the potential of non-covalent interactions using an AB copolymer to form polyionic micelles for drug delivery.

Synthesis and characterization of biodegradable block copolymers of ?-caprolactone and D,L-lactide initiated by potassium poly(ethylene glycol)ate

Poly(D,L-lactide)–poly(ϵ-caprolactone)–poly(ethylene glycol)–poly(ϵ-caprolactone)–poly(D,L-lactide) block copolymer (PLA–PCL–PEG–PCL–PLA) was prepared by copolymerization of ϵ-caprolactone (ϵ-CL) and D,L-lactide (D,L-LA) initiated by potassium poly(ethylene glycol)ate in THF at 25°C. The copolymers with different composition were synthesized by adjusting the mole ratio of reaction mixture. The resulted copolymers were characterized by 1H-NMR, 13C-NMR, IR, DSC, and GPC. Efforts to prepare copolymers with the corresponding structure of PCL–PLA–PEG–PLA–PCL and D,L-lactide/ϵ-caprolactone random copolymers were not successful.

Polymerization of lactides and lactones. IV. Ring‐opening polymerization of ε‐caprolactone by rare earth phenyl compounds

Ring-opening polymerization of e-caprolactone (CL) has been initiated with rare earth phenyl compounds in both bulk and solution. These rare earth phenyl initiators can give polycaprolactone (PCL) with high yield and high molecular weight. The polymerization mechanism is through a coordination-deprotonation-insertion process, by which the monomer inserts on the Ln-O bond of rare earth enolate. The efficiency of rare earth phenyl compounds for CL is high. The effects of reaction conditions, such as reaction time, reaction temperature, and monomer/initiator molar ratio, on the polymerization are discussed. The polymer was characterized by FTIR, 1 H-NMR.

Tissue anti-adhesion potential of biodegradable PELA electrospun membranes

The most commonly used anti-adhesion device for separation and isolation of wounded tissues after surgery is the polymeric membrane. In this study, a new anti-adhesion membrane from polylactide-polyethylene glycol tri-block copolymer (PELA) has been synthesized. The synthesized copolymers were characterized by gel permeation chromatography and (1)H nuclear magnetic resonance spectroscopy. PELA membrane was prepared by electrospun. The prepared copolymer membranes were more flexible than the control poly-d-l-lactic acid (PDLLA) membrane, as investigated by the measurements of glass transition temperature. Its biocompatibility and anti-adhesion capabilities were also evaluated. In vitro cell adhesions on the PELA copolymer membrane and PDLLA membrane were compared by the culture of mouse fibroblasts L929 on the surfaces. For in vivo evaluation of tissue anti-adhesion potential, the PDLLA and PELA copolymer membranes were implanted between cecum and peritoneal wall defects of rats and their tissue adhesion extents were compared. It was observed that the PELA copolymer membrane was very effective in preventing cell or tissue adhesion on the membrane surface, probably owing to the effects of hydrophilic polyethylene glycol.

Synthesis of heterobifunctional poly(ethylene glycol) with a primary amino group at one end and a carboxylate group at the other end

Abstract A novel synthetic route to heterobifunctional poly(ethylene glycol) containing both amino and carboxylate terminal groups was established via anionic polymerization of ethylene oxide using (cyanomethyl)potassium as the initiator, followed by the successive conversion of the end-hydroxyl group to a primary amino group, and hydrolysis of the cyano group to a carboxylate group.