Shell-detachable micelles based on disulfide-linked block copolymer as potential carrier for intracellular drug delivery.

Aiming at development of a micellar nanoparticle system for intracellular drug release triggered by glutathione in tumor cells, a disulfide-linked biodegradable diblock copolymer of poly(epsilon-caprolactone) and poly(ethyl ethylene phosphate) was synthesized. It formed biocompatible micelles loaded with doxorubicin in aqueous solution but detached the shell material under glutathione stimulus, resulting in rapid drug release with destruction of micellar structure. These glutathione-sensitive micelles also rapidly released the drug molecules intracellularly and led to enhanced growth inhibition to A549 tumor cells, suggesting that this nanoparticle system may have potential for improving drug delivery efficacy.

Thermoresponsive block copolymers of poly(ethylene glycol) and polyphosphoester: thermo-induced self-assembly, biocompatibility, and hydrolytic degradation.

Novel thermoresponsive block copolymers of poly(ethylene glycol) and polyphosphoester were synthesized, and the thermo-induced self-assembly, biocompatibility, and hydrolytic degradation behavior were studied. The block copolymers with various molecular weights and compositions were synthesized through ring-opening polymerization of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EEP) and 2-isopropoxy-2-oxo-1,3,2-dioxaphospholane (PEP) using poly(ethylene glycol) monomethyl ether (mPEG) as the initiator and stannous octoate as the catalyst. The obtained block polymers exhibited thermo-induced self-assembly behavior, demonstrated by dynamic light scattering and UV-vis measurements using 1,6-diphenyl-1,3,5-hexatriene as the probe. It was found that the critical aggregation temperature (CAT) of the block copolymers shifted to higher temperature with increased molecular weight of mPEG, while copolymerization with more hydrophobic monomer PEP led to lower transition temperature; thus, the CAT can be conveniently adjusted. The block copolymers did not induce significant hemolysis and plasma protein precipitation. In vitro MTT and live/dead staining assays indicated they are biocompatible, and the biocompatibility was further demonstrated in vivo by the absence of local acute inflammatory response in mouse muscle following intramuscular injection. Unlike most frequently studied thermoresponsive poly(N-isopropylacrylamide), polyphosphoesters were hydrolytically degradable in aqueous solution that was proven by gel permeation chromatography and NMR analyses, and the degradation products were proven to be nontoxic to HEK293 cells. Therefore, with good biocompatibility and thermoresponsiveness, these biodegradable block copolymers of mPEG and polyphosphoesters are promising as stimuli-responsive materials for biomedical applications.

Evaluation of polymeric micelles from brush polymer with poly(epsilon-caprolactone)-b-poly(ethylene glycol) side chains as drug carrier.

Brush polymers PHEMA-g-(PCL-b-PEG) with poly(2-hydroxyethyl methacrylate) (PHEMA) as the backbone and poly(epsilon-caprolactone)-b-poly(ethylene glycol) (PCL-b-PEG) block copolymers as side chains were synthesized and evaluated as drug delivery vehicles. Two brush polymers were synthesized, and their structures were confirmed by gel permeation chromatography analyses and (1)H NMR measurements. The brush polymers self-assembled into micelles in aqueous solution, and the critical micellization concentrations of brush polymers were 2-fold lower than that of the linear diblock copolymer PCL-b-PEG with structure similar to that of the grafted side chains of brush polymers, indicating the higher aqueous stability of brush polymer micelles. The micelles were spherical with average diameters below 100 nm. Brush polymer micelles exhibited higher loading doxorubicin capacity compared with micelles from linear PCL-b-PEG block copolymer by the dialysis method, and the burst doxorubicin release from the brush polymer micelles was significantly suppressed. Doxorubicin-loaded brush polymer micelles can be effectively internalized by A549 human lung carcinoma cells and slowly released the encapsulated drug molecules as demonstrated by the drug accumulation in cytoplasm, which was opposite to free doxorubicin, which accumulated rapidly in the cell nuclei.

Self-assembled micelles of biodegradable triblock copolymers based on poly(ethyl ethylene phosphate) and poly(-caprolactone) as drug carriers.

A series of novel amphiphilic triblock copolymers of poly(ethyl ethylene phosphate) and poly(-caprolactone) (PEEP-PCL-PEEP) with various PEEP and PCL block lengths were synthesized and characterized. These triblock copolymers formed micelles composed of a hydrophobic core of poly(-caprolactone) (PCL) and a hydrophilic shell of poly(ethyl ethylene phosphate) (PEEP) in aqueous solution. The micelle morphology was spherical, determined by transmission electron microscopy. It was found that the size and critical micelle concentration values of the micelles depended on both hydrophobic PCL block length and PEEP hydrophilic block length. The in vitro degradation characteristics of the triblock copolymers were investigated in micellar form, showing that these copolymers were completely biodegradable under enzymatic catalysis of Pseudomonas lipase and phosphodiesterase I. These triblock copolymers were used for paclitaxel (PTX) encapsulation to demonstrate the potential in drug delivery. PTX was successfully loaded into the micelles, and the in vitro release profile was found to be correlative to the polymer composition. These biodegradable triblock copolymer micelles are potential as novel carriers for hydrophobic drug delivery.