Wen Chung Wu

PH-dependent, thermosensitive polymeric nanocarriers for drug delivery to solid tumors

Polymeric micelles are promising carriers for anti-cancer agents due to their small size, ease of assembly, and versatility for functionalization. A current challenge in the use of polymeric micelles is the sensitive balance that must be achieved between stability during prolonged blood circulation and release of active drug at the tumor site. Stimuli-responsive materials provide a mechanism for triggered drug release in the acidic tumor and intracellular microenvironments. In this work, we synthesized a series of dual pH- and temperature-responsive block copolymers containing a poly(ε-caprolactone) (PCL) hydrophobic block with a poly(triethylene glycol) block that were copolymerized with an amino acid-functionalized monomer. The block copolymers formed micellar structures in aqueous solutions. An optimized polymer that was functionalized with 6-aminocaproic acid (ACA) possessed pH-sensitive phase transitions at mildly acidic pH and body temperature. Doxorubicin-loaded micelles formed from these polymers were stable at blood pH (~7.4) and showed increased drug release at acidic pH. In addition, these micelles displayed more potent anti-cancer activity than free doxorubicin when tested in a tumor xenograft model in mice.

Fluorescent Polymeric Micelles with Aggregation-Induced Emission Properties for Monitoring the Encapsulation of Doxorubicin

A new type of fluorescent polymeric micelles is developed by self-assembly from a series of amphiphilic block copolymers, poly(ethylene glycol)-b-poly[styrene-co-(2-(1,2,3,4,5-pentaphenyl-1H-silol-1-yloxy)ethyl methacrylate)] [PEG-b-P(S-co-PPSEMA)]. Their capability of loading doxorubicin (DOX) is investigated by monitoring the loading content, encapsulation efficiency, and photophysical properties of micelles. Förster resonance energy transfer from PPSEMA to DOX is observed in DOX-loaded micelles, which can serve as an indication of successful encapsulation of DOX in these micelles. The application of this new type of fluorescent polymeric micelles as a fluorescent probe and an anticancer drug carrier simultaneously is explored by studying the intracellular uptake of DOX-loaded micelles.

Utilization of micelles formed from poly(ethylene glycol)-block- poly(ε-caprolactone) block copolymers as nanocarriers to enable hydrophobic red two-photon absorbing emitters for cells imaging

A hydrophobic two-photon absorbing (2PA) red emitter (R) was successfully incorporated into micelles formed from two block copolymers, poly(epsilon-caprolactone)-block-poly(ethylene glycol)s, for imaging and toxicity studies. In micelles, the chromophore R exhibits a 2PA cross-section of 400 GM (1 GM = 1 x 10(-50) cm(4) s photon(-1) molecule(-1)) at 820 nm, which is among the highest values reported for red 2PA emitters. The micelles with a cationic amino moiety-containing poly(ethylene glycol) corona showed an enhancement of cell internalization and delivered the dye into the cytoplasmic regions of the mouse macrophage RAW 264.7 cells. In comparison, the dye in micelles with neutral poly(ethylene glycol) as corona could not be delivered into the cells. Cytotoxicity of the micelle-R constructs was studied using a 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. More than 90% of the cells were viable after they were stained with the dye-containing micelles at different concentrations (dye concentrations of 2-6 muM and polymer concentrations of 0.05-0.15 mg/mL) for 16 h. This is the first reported application of a hydrophobic 2,1,3-benzothiadiazole-containing 2PA red emitter delivered into the cytoplasm of cells for bioimaging and toxicity assessment.

Effects of chain architectures on the surface structures of conjugated rod-coil block copolymer brushes.

Rod-coil block copolymers are of unique and interesting characteristics since their physical properties can be reversibly tuned in response to the external stimuli, such as change in solvent quality. In this study, dissipative particle dynamics is used to investigate the surface structures of rod-coil polymer brushes tethered onto a surface. When immersed in the selective solvent for the coil blocks, rod blocks tend to form aggregates. Our results show that linear and Y-shaped polymer brushes exhibit similar aggregative behavior. However, some of the surface structures can be acquired within experimentally attainable surface grafting density only for Y-shaped polymer brushes. On the other hand, comblike polymer brushes are found to possess more diverse aggregative manners than linear brushes. Surface structures with aggregates taking the forms of cones, cylinders, or layers of spheres are found. By controlling the aggregative structures, it is possible for us to adjust the physical properties, such as optical function, of the material.

Electrospun nanofibers with dual plasmonic-enhanced luminescent solar concentrator effects for high-performance organic photovoltaic cells

We fabricated dual functional electrospun (ES) nanofibers by a coaxial electrospinning technique for enhancing the organic photovoltaic (OPV) device efficiency. The nanofibers contained poly[2,7-(9,9-dihexylfluorene)-alt-4,7-(2,1,3-benzothiadiazole)] (PFBT) nanoparticles as the luminescent solar concentrator (LSC) and Ag nanoparticles for the surface plasmon resonance (SPR) effect. Aligned- and crossed-fiber architecture patterns were fabricated to compare the effects of the architecture on the OPV efficiency. The plasmonic-enhanced LSC ES nanofibers with crosslinked poly(methacrylic acid) could be directly integrated into the conventional OPV configuration without sacrificing the coverage area of the active layer. In addition, the in situ reduction of Ag nanoparticles simultaneously enhanced the exciton generation of PFBT and the active materials with the SPR effect. The dual functional ES nanofibers with a crossed-pattern embedded into OPV devices provided significant light harvesting through down conversion and enhanced exciton generation. They led to PCE values of 4.11 and 7.12% for P3HT (poly(3-hexylthiophene)) : PC61BM ([6,6]-phenyl C61-butyric acid methyl ester) and PTB7 (polythieno[3,4-b]-thiophene-co-benzodithiophene) : PC71BM ([6,6]-phenyl C71-butyric acid methyl ester) ([6,6]-phenyl) photovoltaic cells, respectively, which are 18% enhancements compared to their parent devices. This interface-modification approach using plasmonic-enhanced LSC ES nanofibers provides a new approach for enhancing the OPV device performance.

Fluorescent polymeric micelles containing fluorene derivatives for monitoring drug encapsulation and release

In this study, we demonstrate a new series of fluorescent polymeric micelles self-assembled from two amphiphilic block copolymers, poly(ethylene glycol)-block-poly[styrene-co-[4-tri(9,9-dihexylfluoren-2,7-yl)styrene]] [PEG-b-P(S-co-TFS), P1] and poly(ethylene glycol)-block-poly[styrene-co-[4-(2-(4-benzo-[2,1,3]-thiadiazole)-9,9-dihexylfluoren-7-yl)styrene]] [PEG-b-P(S-co-BTFS), P2], with fluorescent moieties based on two different fluorene derivatives. The weight fraction and the chemical structure of these two fluorene derivatives could be correlated to the nanostructures and photophysical properties of the corresponding polymeric micelles. In particular, facile adjustment on the emission color of micelles enables the delicate design of drug carriers for the drug with specific photophysical properties. Two fluorescent drugs, curcumin (CUM) and doxorubicin (DOX), are chosen as model drugs for P1 and P2 micelles. Due to the spectral overlap between fluorescent micelles and drugs and their close proximity in the core of micelles, Förster resonance energy transfer (FRET) from micelles to drugs is observed for both the CUR-loaded P1-1 micelles and DOX-loaded P2-1 micelles, which could serve as an indication of successful encapsulation of drug in these micelles. Furthermore, the subsequent decrement of FRET resulting from the increasing distance between fluorene moieties and drugs could be used as an optical approach for monitoring the drug release from the drug carriers.

Folate‐Conjugated and Dual Stimuli‐Responsive Mixed Micelles Loading Indocyanine Green for Photothermal and Photodynamic Therapy

A folic acid targeted mixed micelle system based on co-assembly of poly(ε-caprolactone)-b-poly(methoxytri(ethylene glycol) methacrylate-co-N-(2-methacrylamido)ethyl folatic amide) and poly(ε-caprolactone)-b-poly(diethylene glycol monomethyl ether methacrylate) is developed to encapsulate indocyanine green (ICG) for photothermal therapy and photodynamic therapy. In this study, the use of folic acid is not only for specific cancer cell recognition, but also in virtue of the carboxylic acid on folic acid to regulate the pH-dependent thermal phase transition of polymeric micelles for controlled drug release. The prepared ICG-loaded mixed micelles possess several superior properties such as a preferable thermoresponsive behavior, excellent storage stability, and good local hyperthermia and reactive oxygen species generation under near-infrared (NIR) irradiation. The photototoxicity induced by the ICG-loaded micelles has efficiently suppressed the growth of HeLa cells (folate receptor positive cells) under NIR irradiation compared to that of HT-29, which has low folate receptor expression. Hence, this new type of mixed micelles with excellent features could be a promising delivery system for controlled drug release, effective cancer cell targeting, and photoactivated therapy.