Ren-Shen Lee

Synthesis and characterization of thermo- responsive and photo-cleavable block copolymers as nanocarriers

In this study, we synthesized thermo-responsive and photo-cleavable amphiphilic block copolymers containing photodegradable linkers as junction points between hydrophilic and hydrophobic chains. We synthesized PNiPAAm-ONB-PXCL block copolymers by using a combination of ring-opening polymerization and nucleophilic substitution reactions using 5-hydroxy-2-nitrobenzyl alcohol as a difunctional photo-responsive initiator. These PNiPAAm-ONB-PXCL copolymers consisting of soft domains of amorphous PNiPAAm and PXCL exhibited amorphous Tg. The polymer micelles exhibited dual responsiveness to heat and light. The lower critical solution temperature of PNiPAAm20-ONB-PMCL49 was 39.3 °C, which is approximately the temperature of tumor tissue. When we exposed the polymer solutions to ultraviolet (UV) irradiation, we observed major changes in the structure and morphology of the particles. Fluorescence emission measurements indicated the release of Nile red (NR), a hydrophobic dye, encapsulated by the PNiPAAm-ONB-PXCL micelles, in response to irradiation because of disruption of the micelles. Release of indomethacin (IMC) was rapid under UV irradiation at 42 °C and approximately 90% of the encapsulate IMC was released in a sustained manner during the first 7 h. The nanoparticles were associated with nonsignificant toxicity at concentrations <100 μg mL−1. Doxorubicin (DOX)-loaded micelles facilitated the uptake of DOX by HeLa cells within 30 min of treatment, and were predominantly retained in the cytoplasm. The DOX-loaded micelles were associated with low cytotoxicity against HeLa cells.

Synthesis and characterization of amphiphilic photocleavable polymers based on dextran and substituted-ɛ-caprolactone

In this study, we synthesized photocleavable amphiphilic block copolymers containing photodegradable linkers, 5-hydroxy-2-nitrobenzyl alcohol, as junction points between hydrophilic dextran (or maltodextrin) and hydrophobic poly(4-substituted-ɛ-caprolactone) chains, by using a combination of ring-opening polymerization and nucleophilic substitution reactions. When the polymer solutions were exposed to ultraviolet (UV) irradiation, major structural and morphological changes were observed in the particles. The copolymers were biodegradable and biocompatible, and they can self-assemble into spherical photoresponsive micelles. Fluorescence emission measurements indicated the release of Nile red, a hydrophobic dye, encapsulated by the Dex-ONB-PXCL micelles, in response to irradiation caused by the disruption of the micelles. Light-triggered bursts were observed for indomethacin (IMC)-loaded Dex-ONB-PXCL micelles during the first 5 h. The nanoparticles were associated with nonsignificant toxicity at concentrations of less than 100 μg mL(-1). The confocal microscopy and flow cytometry results showed that the uptake of DOX-loaded micelles by HeLa cells was slightly less than that of free DOX, and it was predominantly retained in the cytoplasm.

Pseudopoly(amino acid)s: Copolymerization of trans-4-hydroxy-L-proline and α-hydroxy acids

A series of novel copolymers of trans-4-hydroxy-L-proline (Hpr) and α- hydroxy acids [D,L-mandelic acid (DLMA) and D,L-lactic acid (DLLA)] were synthesized via direct melt copolymerization with stannous octoate as a catalyst. These new copolymers had pendant amine functional groups along the polymer backbone chain. The optimal reaction conditions for the synthesis of the copolymers were obtained with 4 wt % stannous octoate at 140 °C under vacuum for 16 h. The synthesized copolymers were characterized by IR spectrophotometry, proton nuclear magnetic resonance, differential scanning calorimetry, and Ubbelohde viscometry. The effects of the kinds of comonomers and the comonomer molar ratio on the polycondensation and glass-transition temperature (Tg) were investigated. The Tgs of the copolymers shifted to lower temperatures with an increasing comonomer molar ratio. As expected, the Tgs of the N-Z-Hpr/DLMA copolymers were higher than the N-Z-Hpr/DLLA copolymers, the pendant groups on the monomers (N-Z-Hpr) became larger and more flexible, and the Tgs of the resulting polymers declined.

Amphiphilic photocleavable block copolymers based on monomethyl poly(ethylene glycol) and poly(4-substituted-ε-caprolactone): synthesis, characterization, and cellular uptake

This paper presents the synthesis of a novel amphiphilic block copolymer containing photodegradable linkers as junction points between hydrophilic and hydrophobic chains. MPEG-ONB-PXCL block copolymers were synthesized by a combination of ROP and “clicks” from a difunctional photoresponsive initiator (ONB). The copolymers are biodegradable and biocompatible, and can self-assemble into photoresponsive micelles. When polymer solutions were exposed to UV, we observed significant changes in the structure and morphology of particles. Fluorescence emission measurements showed that Nile red (NR), a hydrophobic dye, encapsulated by the MPEG-ONB-PXCL micelles, is released upon irradiation because of disruption of the micelles. Light-triggered bursts were observed for Indomethacin (IMC)-loaded MPEG-ONB-PXCL micelles upon at 30 min of light irradiation. No significant toxicity of these nanoparticles was found, at concentrations up to 1000 μg mL−1, before or after light irradiation. The doxorubicin (DOX)-loaded micelles facilitated improved uptake of DOX by HeLa cells within 60 min, and were retained primarily in the cytoplasm.

Synthesis oftrans-4-hydroxy-L-proline-based telechelic prepolymers and poly(ester-urethane)

The synthesis of hydroxyproline-based telechelic prepolymers by the condensation polymerization of trans-4-hydroxy-N-benzyloxycarbonyl-L-proline methyl ester was investigated. All the polymerizations were carried out in the melt with stannous octoate as the catalyst and with different diols. The products were characterized by differential scanning calorimetry, proton nuclear magnetic resonance, infrared spectrophotometry, and inherent viscosity (ηinh). According to the analytic results, the ηinh value of the prepolymers depended on the kind and amount of diols that were added. With an increase in the 1,6-hexanediol feed from 2 to 10 mol %, there was a decrease in ηinh from 0.78 to 0.41 along with a decrease in the glass-transition temperature (Tg ) from 63 to 42 °C. When 2 mol % of different kinds of diols were used, ηinh ranged from 0.78 to 0.21, and Tg varied from 70 to 43 °C. These new prepolymers could be linked to poly(ester-urethane) by the chain extender 1,6-hexamethylene diisocyanate. The poly(ester-urethane) was amorphous, and the Tg was 76 °C.

Temperature, ultrasound and redox triple-responsive poly(N-isopropylacrylamide) block copolymer: synthesis, characterization and controlled release

Triple stimuli-responsive polymers PNiPAAm-S-S-PXCL containing a disulfide (–S–S–) bond as a junction point between hydrophilic and hydrophobic chains were synthesized through ring-opening polymerization (ROP) and nucleophilic substitution. When the polymer solutions were treated with reducing agents and exposed to ultrasound, significant hydrolysis of the amide bonds was observed. The morphology of the particles and the changes in the fluorescence intensity of Nile red revealed that the copolymers underwent micellization or dissociation transitions in water in response to temperature variation, reducing agent treatment, and ultrasound. The release rate could be greatly increased and adjusted remotely under high intensity focused ultrasound in the presence of dithiothreitol. The nanoparticles exhibited slight toxicity against HeLa cells in the concentration range 10–1000 μg mL−1. The DOX-loaded PNiPAAm21-S-S-PMCL25 micelles effectively inhibited the proliferation of HeLa cells with a half-maximal inhibitory concentration of 2.33 μg mL−1. The multiple stimuli-responsive polymeric nanoparticles show promising potential as new nanocarriers for controlled release.

Thermoresponsive and acid-cleavable amphiphilic copolymer micelles for controlled drug delivery

ABSTRACT Thermoresponsive and acid-cleavable amphiphilic block copolymers poly(N-isopropylacrylamide)-acetal-poly(4-substituted-ε-caprolactones) (PNiPAAm-a-PXCLs) containing an acidic-cleavable acetal linkage at the junction between the temperature-sensitive hydrophilic PNiPAAm and the degradable hydrophobic block PXCL were synthesized through ring-opening polymerization and electrophilic addition reactions. These polymer solutions showed reversible changes in optical properties and a lower critical solution temperature in the range of 32.0–46.4°C. The copolymers formed micelles in aqueous solution with critical micelle concentrations in the range of 0.83–15.95 mg L−1 had hydrodynamic sizes of <200 nm and were spherical. Under the combined stimulation of temperature and pH, the micellar nanoparticles could be dissociated; the loaded molecules could be released from the assemblies more efficiently than that under only one stimulus or without stimulus. In addition, the nanoparticles exhibited low toxicity against human cervical cancer (HeLa) cells at concentrations ≤1000 µg mL−1. Doxorubicin-loaded PNiPAAm11-a-PCL28 micelles also effectively inhibited the proliferation of HeLa cells with a half-maximal inhibitory concentration (IC50) of 1.60 µg mL−1. GRAPHICAL ABSTRACT

Dual-stimuli-responsive glycopolymer bearing a reductive and photo-cleavable unit at block junction

New dual-stimuli-responsive and bio-recognizable glycopolymers (Glyco-ONB-s-s-PXCL) containing a photodegradable 5-hydroxy-2-nitrobenzyl alcohol (ONB), and a redox-cleavable disulfide (-s-s-) as junction point between bio-recognizable hydrophilic sugar molecule (Glyco) and hydrophobic poly(4-substituted-e-caprolactone) (PXCL) chains were synthesized using a combination of ring-opening polymerization and nucleophilic substitution reactions. When the polymer solution was exposed to ultraviolet (UV) irradiation and/or the reducing agent DL-dithiothreitol (DTT), substantial structural and morphological changes were observed in the particles. The polymers formed micelles in the aqueous solution, had hydrodynamic sizes ≤200 nm, and were spherical. Under the combined stimulation of UV irradiation and DTT, the micellar nanoparticles dissociated and the loaded molecules could be released from the assemblies more efficiently than under the stimulation of only one of the two stimuli. Selective lectin binding experiments confirmed that glucosylated Gluco-ONB-s-s-PXCL can be used for bio-recognition. The nanoparticles exhibited nonsignificant toxicity against HeLa cells at concentrations of ≤300 μg mL−1. The DOX-loaded Gluco-ONB-s-s-PMCL20 micelles effectively inhibited the proliferation of HeLa cells with a half-maximal inhibitory concentration (IC50) of 1.5 μg mL−1.

Synthesis, Characterization, and Degradation of Copolymer from Trans-4-hydroxy-L-proline and L-lactide

A series of novel copolymers of trans-4-hydroxy-L-proline (Hpr) and L-lactide (LLA) were synthesized by ring opening copolymerization, using stannous octoate as a catalyst. These new copolymers have pendant amino functional groups along the polymer backbone chain. Various techniques, including 1H NMR, IR, DSC, and the use of a Ubbelohde viscometer, were used to elucidate structural characteristics, thermal properties, and degradation behavior of the resulting copolymers. Data showed that the optimal reaction condition for the synthesis of the copolymers was obtained using 3 wt% stannous octoate at 140 ○C for 24 h. The DSC analysis demonstrated amorphous structure for most of the copolymers. The glass transition temperatures (Tg) of the copolymers shift to a higher temperature with increasing Hpr/LLA molar ratio. In vitro degradation of these poly(N-CBz-Hpr-co-L-LA) was evaluated by weight loss measurements.