Baoyan Wang

pH‐Controlled Reversible Formation of a Supramolecular Hyperbranched Polymer Showing Fluorescence Switching

A π-conjugated AB2 monomer 1 with a dibenzo[24]crown-8 (DB24C8) ring and two secondary amine centres has been synthesised. Treatment of a solution of 1 in dichloromethane with trifluoroacetic acid (TFA) leads to protonation of the amine groups, and then the DB24C8 rings are threaded by the dialkylammonium ion centres of other monomer molecules, leading to the formation of a supramolecular hyperbranched polymer, TFA-1. Rather strong π-π stacking interactions between the conjugated cores are evident in this polymer. The supramolecular hyperbranched polymer (SHP) can be completely depolymerised by adding a slight excess of N-tert-butyl-N,N,N,N,N,N-hexamethylphosphorimidic triamide, tetrabutylammonium fluoride, or tetrabutylammonium acetate. The acid-base-controlled process induces a reversible change in the fluorescence intensities of the solutions due to the controllable presence of the π-π stacking interactions between the conjugated cores. This dynamic behaviour is significant with respect to smart supramolecular polymer materials.

Luminescent polymeric hybrids formed by platinum(II) complexes and block copolymers

The incorporation of platinum(II) complexes into block copolymers leads to the formation of luminescent polymeric hybrids with hierarchical nanostructures from spherical, rodlike micelles to vesicles in solvents.

Reversible luminescence switching accompanied by assembly-disassembly of metallosupramolecular amphiphiles based on a platinum(II) complex

The electrostatic self-assembly of anionic surfactants with a cationic platinum(II) complex bearing triethylene glycol leads to the formation of metallosupramolecular amphiphiles with rod- and sheet-like aggregates in aqueous solutions. The resulting solutions show strong luminescence enhancement, which can decrease back to the original emissive intensity of the platinum(II) complex by disassembling the aggregates through host–guest recognition with α-cyclodextrin. Both the self-assembly and disassembly processes are monitored in real time by UV-vis absorption and emission spectra and dynamic light scattering. The critical aggregation concentrations are determined by concentration-dependent measurements of emission spectra and dynamic light scattering. The present study provides an efficient and convenient strategy to fabricate dynamic metallosupramolecular amphiphiles with controllable photophysical properties.

Fabrication of supramolecular star-shaped amphiphilic copolymers for ROS-triggered drug release

Star-shaped copolymers with branched structures can form unimolecular micelles with better stability than the micelles self-assembled from conventional linear copolymers. However, the synthesis of star-shaped copolymers with precisely controlled degree of branching (DB) suffers from complicated sequential polymerizations and multi-step purification procedures, as well as repeated optimizations of polymer compositions. The use of a supramolecular host-guest pair as the block junction would significantly simplify the preparation. Moreover, the star-shaped copolymer-based unimolecular micelle provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy if the association/dissociation of the supramolecular host-guest joint can be triggered by the biologically relevant stimuli. For this purpose, in this study, a panel of supramolecular star-shaped amphiphilic block copolymers with 9, 12, and 18 arms were designed and fabricated by host-guest complexations between the ring-opening polymerization (ROP)-synthesized star-shaped poly(ε-caprolactone) (PCL) with 3, 4, and 6 arms end-capped with ferrocene (Fc) (PCL-Fc) and the atom transfer radical polymerization (ATRP)-produced 3-arm poly(oligo ethylene glycol) methacrylates (POEGMA) with different degrees of polymerization (DPs) of 24, 30, 47 initiated by β-cyclodextrin (β-CD) (3Br-β-CD-POEGMA). The effect of DB and polymer composition on the self-assembled properties of the five star-shaped copolymers was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescence spectrometery. Interestingly, the micelles self-assembled from 12-arm star-shaped copolymers exhibited greater stability than the 9- and 18-arm formulations. The potential of the resulting supramolecular star-shaped amphiphilic copolymers as drug carriers was evaluated by an in vitro drug release study, which confirmed the ROS-triggered accelerated drug release from the doxorubicin (DOX)-loaded supramolecular star-shaped micelles due to the oxidation-induced dissociation of β-CD/Fc pair and the consequent loss of the colloidal stability of the star-shaped micelles. Studies of the delivery efficacy by an in vitro cytotoxicity study further indicated that higher DBs and longer hydrophilic arm compromised the therapeutic efficacy of the DOX-loaded supramolecular star-shaped micelles, resulting in significantly reduced cytotoxicity, as measured by increased IC50 value. Overall, our results revealed that the screening of hydrophilic block by DB and MW for an optimized star-shaped copolymer should balance the stability versus therapeutic efficacy tradeoff for a comprehensive consideration. Therefore, the 12-arm star-shaped copolymer with POEGMA30 is the best formulation tested.

Fabrication of Hyperbranched Block-Statistical Copolymer-Based Prodrug with Dual Sensitivities for Controlled Release

Dendrimer with hyperbranched structure and multivalent surface is regarded as one of the most promising candidates close to the ideal drug delivery systems, but the clinical translation and scale-up production of dendrimer has been hampered significantly by the synthetic difficulties. Therefore, there is considerable scope for the development of novel hyperbranched polymer that can not only address the drawbacks of dendrimer but maintain its advantages. The reversible addition-fragmentation chain transfer self-condensing vinyl polymerization (RAFT-SCVP) technique has enabled facile preparation of segmented hyperbranched polymer (SHP) by using chain transfer monomer (CTM)-based double-head agent during the past decade. Meanwhile, the design and development of block-statistical copolymers has been proven in our recent studies to be a simple yet effective way to address the extracellular stability vs intracellular high delivery efficacy dilemma. To integrate the advantages of both hyperbranched and block-statistical structures, we herein reported the fabrication of hyperbranched block-statistical copolymer-based prodrug with pH and reduction dual sensitivities using RAFT-SCVP and post-polymerization click coupling. The external homo oligo(ethylene glycol methyl ether methacrylate) (OEGMA) block provides sufficient extracellularly colloidal stability for the nanocarriers by steric hindrance, and the interior OEGMA units incorporated by the statistical copolymerization promote intracellular drug release by facilitating the permeation of GSH and H+ for the cleavage of the reduction-responsive disulfide bond and pH-liable carbonate link as well as weakening the hydrophobic encapsulation of drug molecules. The delivery efficacy of the target hyperbranched block-statistical copolymer-based prodrug was evaluated in terms of in vitro drug release and cytotoxicity studies, which confirms both acidic pH and reduction-triggered drug release for inhibiting proliferation of HeLa cells. Interestingly, the simultaneous application of both acidic pH and GSH triggers promoted significantly the cleavage and release of CPT compared to the exertion of single trigger. This study thus developed a facile approach toward hyperbranched polymer-based prodrugs with high therapeutic efficacy for anticancer drug delivery.

Promotion of micelle stability via a cyclic hydrophilic moiety

A novel strategy to promote micelle stability was reported by altering the topological structure of polymer species. Specifically, a cyclic hydrophilic moiety offers greater stability for the self-assembled micelles than a linear analogue. This study thus provides an alternative to enhance micelle stability for drug delivery.

Facile Fabrication of 10-Hydroxycamptothecin-Backboned Amphiphilic Polyprodrug with Precisely Tailored Drug Loading Content for Controlled Release

Polymeric prodrugs with precisely controlled drug loading content (DLC) and rapid intracellular destabilization generally require complicated chemistry that hinders large-scale manufacture. For this purpose, we reported in this study a facile construction of reduction-sensitive amphiphilic polyprodrugs with an anticancer drug, 10-hydroxycamptothecin (HCPT), and a hydrophilic poly(ethylene oxide) (PEG) moiety as the alternating building blocks of the multiblock copolymer using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAc) click coupling between azide-SS-HCPT-SS-azide and alkyne-PEG-alkyne. Adoption of PEGs with two different molecular weights (MWs) of 400 and 1450 Da (PEG400 and PEG1450) afforded two polyprodrugs with different DLCs. Both formulations can self-assemble into spherical micelles with hydrodynamic diameter smaller than 200 nm, and exhibit glutathione (GSH)-triggered degradation for promoted drug release. A further comparison study revealed that the PEG1450-based polyprodrug is a better formulation than the analogue constructed from PEG400 in terms of in vitro drug release behaviors, and cytotoxicity. This work thus provides a facile yet efficient strategy toward polymeric prodrugs with precisely controlled DLC and reduction-triggered degradation for enhanced anticancer drug delivery.

Fabrication of Acidic pH-Cleavable Polymer for Anticancer Drug Delivery Using a Dual Functional Monomer

The preparation of tumor acidic pH-cleavable polymers generally requires tedious postpolymerization modifications, leading to batch-to-batch variation and scale-up complexity. To develop a facile and universal strategy, we reported in this study design and successful synthesis of a dual functional monomer, a-OEGMA that bridges a methacrylate structure and oligo(ethylene glycol) (OEG) units via an acidic pH-cleavable acetal link. Therefore, a-OEGMA integrates (i) the merits of commercially available oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) monomer, i.e., hydrophilicity for extracellular stabilization of particulates and a polymerizable methacrylate for adopting controlled living radical polymerization (CLRP), and (ii) an acidic pH-cleavable acetal link for efficiently intracellular destabilization of polymeric carriers. To demonstrate the advantages of a-OEGMA ( Mn = 500 g/mol) relative to the commercially available OEGMA ( Mn = 300 g/mol) for drug delivery applications, we prepared both acidic pH-cleavable poly(ε-caprolactone)21- b-poly( a-OEGMA)11 (PCL21- b-P( a-OEGMA)11) and pH-insensitive analogues of PCL21- b-P(OEGMA)18 with an almost identical molecular weight (MW) of approximately 5.0 kDa for the hydrophilic blocks by a combination of ring-opening polymerization (ROP) of ε-CL and subsequent atom transfer radical polymerization (ATRP) of a-OEGMA or OEGMA. The pH-responsive micelles self-assembled from PCL21- b-P( a-OEGMA)11 showed sufficient salt stability, but efficient acidic pH-triggered aggregation that was confirmed by the DLS and TEM measurements as well as further characterizations of the products after degradation. In vitro drug release study revealed significantly promoted drug release at pH 5.0 relative to the release profile recorded at pH 7.4 due to the loss of colloidal stability and formation of micelle aggregates. The delivery efficacy evaluated by flow cytometry analyses and an in vitro cytotoxicity study in A549 cells further corroborated greater cellular uptake and cytotoxicity of Dox-loaded pH-sensitive micelles of PCL21- b-P( a-OEGMA)11 relative to the pH-insensitive analogues of PCL21- b-P(OEGMA)18. This study therefore presents a facile and robust means toward tumor acidic pH-responsive polymers as well as providesxa0one solution to the trade-off between extracellular stability and intracellular high therapeutic efficacy of drug delivery systems using a novel monomer of a-OEGMA with dual functionalities.