Zhiguo Hu

Facile synthesis of RGD-conjugated unimolecular micelles based on a polyester dendrimer for targeting drug delivery

Arginyl-glycyl-aspartic acid (RGD)-conjugated core-shell amphiphilic copolymers consisting of a polyester dendrimer poly(propargyl alcohol-4-mercaptobutyric acid) (PPMA) core and hydrophilic poly(ethylene glycol) (PEG) shells (PPMA-MPEG/PEG-RGD) were synthesized as unimolecular micelles for targeted drug delivery. During the synthesis, the PPMA core was firstly constructed at the end of a polystyrene (PS) support via the combination of a highly efficient thio-yne click reaction and esterification. The presence of PS segments in l-PS-PPMA hybrid copolymers facilitated the easy separation of the product from the excessive unreacted monomers by simple precipitation. After five reaction cycles, the fifth-generation PPMA with 64 terminal carboxylic acid groups (PPMAG5-64-COOH) was formed, in which the characteristic alkoxyamine linker between PS and PPMA segments was easily cleaved at an elevated temperature. The resultant PPMA-64-COOH was further coupled with MPEG/MAPEG followed by functionalization with RGD-SH to produce the targeted copolymer PPMA-MPEG/PEG-RGD. Due to the unique single molecular core-shell architecture, PPMA-MPEG/PEG-RGD copolymers exist as stable unimolecular micelles in aqueous solution. In addition, the hydrophobic core in PPMA-MPEG/PEG-RGD unimolecular micelles exhibited strong capability for the encapsulation of hydrophobic anticancer drugs, and it showed the pH-dependent controlled release behavior of the payload. Furthermore, in vitro cytotoxicity assay revealed the good biocompatibility of PPMA-MPEG/PEG-RGD unimolecular micelles. These results indicated that as-developed unimolecular micelles are promising candidates as tumor-targeted drug delivery nanocarriers.

“Y”-shape armed amphiphilic star-like copolymers: design, synthesis and dual-responsive unimolecular micelle formation for controlled drug delivery

In this study, a novel amphiphilic star-like CD-PCL-SS-PEG(PNIPAM) copolymer with a disulfide linkage at the junction points of the “Y”-shaped arms is designed and further fabricated into dual temperature and redox-responsive unimolecular micelles for controlled drug delivery in cancer therapy. During the synthesis, the end-alkyne functionalized hydrophobic star-like core CD-PCL-SS-alkyne was first synthesized by ring-opening polymerization (ROP) of e-CL using β-CD as an initiator, followed by a two-step end group transformation reaction. Then, CD-PCL-SS-alkyne was coupled with α,α′-azide, hydroxyl-PEG (PEG-N3(OH)) via “click” chemistry to obtain PCL-SS-(OH)PEG copolymers with reactive –OH at the junction point. Furthermore, esterification between the –OH on PCL-SS-(OH)PEG and S-1-dodecyl-S′-(α,α′-dimethyl-α′′-acetic acid)trithiocarbonate (DDAT) was carried out to afford the CD-PCL-b-(CTA)PEG copolymer, followed by reversible addition–fragmentation chain-transfer polymerization (RAFT) of N-isopropylacrylamide to obtain the desired star-like CD-PCL-SS-PEG(PNIPAM) copolymer. The targeted copolymer and its intermediates were characterized by 1H NMR and gel permeation chromatography (GPC). The unimolecular micelles formed from the CD-PCL-SS-PEG(PNIPAM) copolymer were studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM) techniques. Drug release studies from CD-PCL-SS-PEG(PNIPAM) micelles exhibited sustained release profiles and the rate of release can be tuned by variation of temperature and glutathione (GSH). Cellular uptake and in vitro stimuli-mediated intracellular DOX release were investigated by flow cytometry and confocal laser scanning microscopy (CLSM) measurements, demonstrating high cellular uptake efficiency and significant intracellular drug release from doxorubicin (DOX) loaded CD-PCL-SS-PEG(PNIPAM) micelles via controlling temperature and reduction. Together with the excellent cell biocompatibility, the new star-like CD-PCL-SS-PEG(PNIPAM) copolymer reported in this paper could potentially be used as intelligent nanocarriers for controlled drug delivery.

Synthesis and unimolecular micelles of amphiphilic copolymer with dendritic poly(L-lactide) core and poly(ethylene oxide) shell for drug delivery

A novel type of amphiphilic copolymer POSS-(G3-PLLA-b-PEO-COOH)8 with a hydrophobic third-generation dendritic PLLA core and a functionalized hydrophilic PEO shell with surface carboxylic groups was synthesized as a carrier for drug delivery. The POSS-(G3-PLLA-OH)8 core was first synthesized by the combination of repetitive ring-opening polymerization (ROP) of L-lactide and branching reactions. Second, the amphiphilic copolymer POSS-(G3-PLLA-b-PEO-COOH)8 was obtained by esterification coupling between allyl-PEO-COOH chains and POSS-(G3-PLLA-OH)8, followed by the peripheral allyl groups reacting with 3-mercaptopropionic acid (MPA). In aqueous solution, this amphiphilic copolymer exists as stable unimolecular micelles with a unique core–shell structure and uniform size distribution (99.9–102.5 nm), as detected by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Doxorubicin (DOX), an anticancer drug, was encapsulated into POSS-(G3-PLLA-b-PEO-COOH)8 micelles to evaluate the drug release profile. The result showed that the DOX-loaded micelles, with a loading content 18.5 ± 2.3 w/w%, exhibited controlled release of up to 39% loaded drug over a time period of 80 h. In addition, the surface carboxylic groups provide the opportunity for further conjugating targeting molecules, fluorescence dye or even drugs. These results indicated that the structurally stable unimolecular micelles from POSS-(G3-PLLA-b-PEO-COOH)8 hold potential applications as controlled drug delivery nanocarriers.

Temperature-responsive hairy particle-supported proline for direct asymmetric aldol reaction in water

In this paper, three kinds of hairy particles with different brush structures were prepared and evaluated as chiral catalysts in the direct asymmetric aldol reaction. Compared to other hairy particles, hairy particle (1) grafted with amphiphilic copolymer chains showed a good conversion rate and an outstanding enantioselectivity in pure water. The copolymer brush on the surface of hairy particle (1) contained temperature responsive poly(N-isopropylacrylamide) which underwent a coil-to-globule transition at a lower critical solution temperature (LCST). The brush formed a hydrophobic nanocavity for the organic substrates, and it provided a suitable reaction microenvironment below and above the LCST of PNIPAM. The aldol reaction was promoted by the catalytic system and it showed stable reactivity from 25 °C to 50 °C. The significant advantages of the hairy particle supported catalytic system were that it was more efficient than the corresponding homogeneous polymer supported proline, and it can be recycled five times while maintaining activity and selectivity.

Carboxymethylpullulan promoted Cu2O-catalyzed Huisgen-click reaction

A combination of carboxymethylpullulan (CMP) and Cu2O has been developed as a highly efficient catalytic system for the Huisgen-click reaction. Our results indicate that the acidic CMP could be used for 6 cycles without decreasing the activating efficiency for Cu2O.

Combining RAFT precipitation polymerization and surface-initiated RAFT polymerization: an efficient approach to prepare hairy particles—supported proline

In this paper, a simple and efficient approach for obtaining hairy particles supported proline system is described. The catalysts were synthesized by the modification of polymer microspheres via surface-initiated RAFT polymerization. Microspheres containing either carboxyl or ester groups were synthesized by RAFT precipitation copolymerization, and the functional groups influenced the yield and asymmetric selectivity of chiral product in different DMF–H2O solvents during a representative aldol reaction. Compared with hairy particles 2 with ester groups, hairy particles 1 with carboxyl groups exhibited better catalytic activity and asymmetric selectivity, providing more suitable microenvironments for the aldol reaction. Importantly, the hairy particles 1, as catalyst, can be easily recovered and recycled, and show no significant loss of activity and selectivity after 6 cycles. The application of RAFT precipitation polymerization together with the facile surface-grafting approach provides a general and promising way for chiral catalyst load.

Nanoparticle Based on Poly(Ionic Liquid) as an Efficient Solid Immobilization Catalyst for Aldol Reaction and Multicomponent Reaction in Water

An environmentally friendly nanoparticle-supported catalyst was successfully prepared via in situ ionic complexation between imidazolium-based polymer ionic liquid (PIL) and poly(l-prolinamide-co-MAA). The physical and chemical properties of the obtained nanoparticles were characterized by TEM, FTIR, XPS, and static water contact angle experiments. The surface properties of the nanoparticle were found to significantly affect the catalytic performance. The nanoparticle with PIL outer facilitated the adsorption of reaction substrate in it. As a result, the catalytic system catalyzed the asymmetric Aldol reaction and multicomponent reaction in pure water efficiently. The catalytic system was able to be reused and recycled five times, and with no discernible loss in catalytic activity and enantioselectivity. These findings suggest that nanoparticles based on PIL may provide a new approach for preparing high performance supported catalysts for organic reactions in water. This technology also addresses issues associated with mass transfer in pure water reactions.

Stable stereocomplex micelles from Y-shaped amphiphilic copolymers MPEG–(scPLA)2: preparation and characteristics

Four new Y-shaped miktoarm amphiphilic copolymers were synthesized by ring-opening polymerization (ROP) and click chemistry. The structure of these copolymers was determined by nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR) and gel permeation chromatography (GPC). The stereocomplexes were prepared by an evaporation method and confirmed by FT-IR, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Further the aggregation behaviors of these synthesized polymers and their stereocomplexes were studied by fluorescence spectroscopy (PL), transmission electron microscopy (TEM) and light scattering (LS). Their critical micelle concentrations (CMC) obtained by PL were 0.005 mg mL−1 for MPEG1.9k–(scPLA4.5k)2 and 0.039 mg mL−1 for MPEG5k–(scPLA4.5k)2. The aggregation morphologies of homochiral copolymers were worm-like aggregates, while for the stereocomplexes, the spherical micelles were visually observed. The biocompatibility of these copolymers and their stereocomplexes was evaluated with relatively lower cytotoxicity. Finally, the release of doxorubicin (DOX) encapsulated into the micelles in buffer at pH 5.4 was faster than that at pH 7.4. This study demonstrates that the DOX-loaded stereocomplex micelles could be a potential carrier for cancer treatments.

Facile synthesis of hairy microparticle-/nanoparticle-supported MacMillan and its application to Diels–Alder reaction in water

AbstractHerein, a series of hairy microparticle-/nanoparticle-supported MacMillan was successfully synthesized by RAFT precipitation polymerization combination with surface-initiated RAFT polymerization. The research’s interest was aimed at achieving a significant enhancement of the catalytic performance which was achieved due to the changes of the polymer particle size, the molecular weight of the grafting polymer brushes, as well as the grafting polymer structure. The results showed that nanoeffect was the key to affect the catalytic activity and selectivity of catalyst system. The hairy nanoparticle had good dispersion in the reaction media and exhibited better catalytic activity and selectivity than hairy microspheres. In addition, the brush structure can be modified by grafting copolymerization with acrylamide which had the synergistic effect to effectively promote the catalyst reaction. The more significant advantages of the hairy nanoparticle-supported MacMillan were that it can effectively catalyze a representative asymmetric Diels–Alder reaction between cyclopentadiene and cinnamaldehyde in pure water and can be recycled five times while maintaining activity and selectivity. Graphical abstract

Preparation and characterization of stereocomplex aggregates based on PLA–P188–PLA

Novel dumbbell-shaped amphiphilic copolymers ((PLLA)2–G1–P188–G1–(PLLA)2 and (PDLA)2–G1–P188–G1–(PDLA)2) and linear-shaped amphiphilic copolymers (PLLA–P188–PLLA and PDLA–P188–PDLA) were synthesized by click chemistry and ring opening polymerization (ROP). The stereocomplexes (scPLA)2–G1–P188–G1–(scPLA)2 and scPLA–P188–scPLA were prepared and confirmed by X-ray diffraction (XRD). The stereocomplex interaction between PLLA and PDLA was firstly analyzed using microscale thermophoresis (MST) technology and the dissociation constant (Kd) was obtained as 342 μM. The aggregation behaviors of these stereocomplexes were studied using fluorescence spectroscopy, transmission electron microscopy (TEM) and light scattering (LS). The critical aggregate concentration (CAC) obtained from fluorescence measurements was 0.021 mg mL−1 for (scPLA)2–G1–P188–G1–(scPLA)2 and 0.042 mg mL−1 for scPLA–P188–scPLA. These stereocomplexes can self-associate in aqueous solution into spherical aggregates with a diameter of 181 nm for (scPLA)2–G1–P188–G1–(scPLA)2 and 222 nm for scPLA–P188–scPLA. Furthermore, the biocompatibility of the stereocomplexes was evaluated with a relatively lower cytotoxicity. Finally, DOX was encapsulated into the stereocomplex aggregates to evaluate the drug release ability in phosphate buffer at a pH value of 7.4 or 5.4. The drug loading content and the encapsulation efficiency of the aggregates are 9.8%, 54% for (scPLA)2–G1–P188–G1–(scPLA)2 and 8.2%, 45% for scPLA–P188–scPLA. The release of DOX at pH 5.4 is faster than that at pH 7.4. The pH value has a greater effect on the release rate of DOX from dumbbell-shaped stereocomplex aggregates than that from the linear-shaped ones, which ensures the long blood circulation and the higher DOX-release surrounding the tumor site.