Xiaoshan Fan

Recent development of unimolecular micelles as functional materials and applications

Unimolecular micelles have attracted increasing attention due to their high functionality, encapsulation and site specific confinement capabilities in various applications. Compared to conventional supramolecular micelles, unimolecular micelles possess unique single molecular architectures which can maintain excellent stability when they are subjected to extreme surrounding environment changes such as high dilution and alterations in temperature, pH, ionic strength etc. In this review, the most recent advances in the design strategies of unimolecular micelles are presented with respect to different types of architectural polymers, including dendrimers, and hyperbranched, dendritic, star, brush-like and amphiphilic cyclic polymers. The diverse functions of these sophisticated materials endow a biosignificance in therapeutic agent delivery. And the use of unimolecular micelles as templates for inorganic nanoparticle preparation, catalysis, and energy harvesting are also summarized in this review. Finally, the challenges for the facile fabrication of unimolecular micelles and future perspectives are also discussed.

Conjugation of poly(ethylene glycol) to poly(lactide)-based polyelectrolytes: An effective method to modulate cytotoxicity in gene delivery

Positively charged amphiphilic polymers comprising of poly(N,N-dimethylaminoethyl methacrylate) segments on both sides of a poly(l-lactic acid) segment was conjugated with poly(ethylene glycol) (DMA-PLLA-DMA@PEG). Efficient condensation of plasmid DNA by these polymers was shown. Cell toxicity studies demonstrated that the positively charged polymers with attached PEG exhibited much less cytotoxicity than polymers with no PEG in both HEK293 and Hela cell lines. PEGylation also resulted in polymers with enhanced haemo-compatibility. The positively charged polymers displayed very good DNA plasmid delivery efficiencies in both HEK293 and Hela cells.

“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 of star-like hybrid POSS-(PDMAEMA-b-PDLA)8 copolymer and its stereocomplex properties with PLLA

Although poly(lactide) (PLA), when used as biomaterials, possesses many good properties, its high hydrophobicity and slow degradation may hinder its applications. In this work, a novel star-like oligomeric silsesquioxane-(poly(2-dimethylaminoethyl methacrylate)-b-poly(d-lactide))8 (POSS-(PDMAEMA-b-PDLA)8) was first synthesized through a three-step procedure that involves Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization of DMAEMA initiated by the macroinitiator POSS-8-CTA, and then conversion of the trithiocarbonated end groups on PDMAEMA arms into hydroxyl groups by a combination of aminolysis and Michael addition followed by controlled ring-opening polymerization of D-LA. In the next step, the synthesized hybrid copolymer POSS-(PDMAEMA-b-PDLA)8 was blended with PLLA in solution to form nanocomposites to further modify the thermo-mechanical and degradation properties of PLLA. It was noted that the outer PDLA shell could facilitate POSS-(PDMAEMA-b-PDLA)8 to be well-dispersed in PLLA matrix through stereocomplex (SC) interaction, and the inner PDMAEMA shell endowed PLLA with good hydrophilicity. The SC formation between POSS-(PDMAEMA-b-PDLA)8 and PLLA was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses. The surface wettability of the PLLA was enhanced due to the presence of hydrophilic PDMAEMA segments and the contact angle values decreased with increasing amount of PDMAEMA in the nanocomposites. Meanwhile, controlled degradation of PLLA in a faster pace was achieved when the nanocomposites were incubated in different pH solutions, indicating its potential in specific biomedical applications.

Hierarchically Self-Assembled Supramolecular Host–Guest Delivery System for Drug Resistant Cancer Therapy

In this report, a new star-like copolymer β-CD- g-(PNIPAAm- b-POEGA) x, consisting of a β-CD core, grafted with temperature-responsive poly( N-isopropylacrylamide) (PNIPAAm) and biocompatible poly(oligo(ethylene glycol) acrylate) (POEGA) in a block copolymer of the arms, was used to deliver chemotherapeutics to drug resistant cancer cells and tumors. The first step of the self-assembly process involves the encapsulation of chemotherapeutics through host-guest inclusion complexation between the β-cyclodextrin cavity and the anticancer drug. Next, the chain interaction of the PNIPAAm segment at elevated temperature drives the drug-loaded β-CD- g-(PNIPAAm- b-POEGA) x/PTX inclusion complex to hierarchically self-assemble into nanosized supramolecular assemblies at 37 °C, whereas the presence of poly(ethylene glycol) (PEG) chains in the distal end of the star-like copolymer arms impart enhanced stability to the self-assembled structure. More interestingly, this supramolecular host-guest nanocomplex promoted the enhanced cellular uptake of chemotherapeutics in MDR-1 up-regulated drug resistant cancer cells and exhibited high therapeutic efficacy for suppressing drug resistant tumor growth in an in vivo mouse model, due to the increased stability, improvement in aqueous solubility, enhanced cellular uptake, and partial membrane pump impairment by taking the advantage of PEGylation and supramolecular complex between this star-like copolymer and chemotherapeutics. This work signifies that temperature-sensitive PEGylated supramolecular nanocarriers with good biocompatibility are effective in combating MDR-1 mediated drug resistance in both in vitro and in vivo models, which is of significant importance for the advanced drug delivery platform designed to combat drug resistant cancer.

Cyclodextrin-Based Star-Like Amphiphilic Cationic Polymer as a Potential Pharmaceutical Carrier in Macrophages.

Effective delivery of therapeutic genes or small molecular drugs into macrophages is important for cell based immune therapy, but it remains a challenge due to the intracellular reactive oxygen species and endosomal degradation of therapeutics inside immune cells. In this report, the star-like amphiphilic biocompatible β-cyclodextrin-graft-(poly(ε-caprolactone)-block-poly(2-(dimethylamino) ethyl methacrylate)x (β-CD-g-(PCL-b-PDMAEMA)x ) copolymer, consisting of a biocompatible cyclodextrin core, hydrophobic poly(ε-caprolactone) PCL segments and hydrophilic PDMAEMA blocks with positive charge, is optimized to achieve high efficiency gene transfection with enhanced stability, due to the micelle formation by hydrophobic PCL segments. In comparison with lipofetamine, a currently popular nonviral gene carrier, β-CD-g-(PCL-b-PDMAEMA)x copolymer, shows better transfection efficiency of plasmid desoxyribose nucleic acid in RAW264.7 macrophages. More interestingly, this delivery platform by β-CD-g-(PCL-b-PDMAEMA)x not only shows low toxicity but also better dexamethasone delivery efficiency, which might indicate its great potential in immunotherapy.

Polymeric Janus Nanoparticles: Recent Advances in Synthetic Strategies, Materials Properties, and Applications

Polymeric Janus nanoparticles with two sides of incompatible chemistry have received increasing attention due to their tunable asymmetric structure and unique material characteristics. Recently, with the rapid progress in controlled polymerization combined with novel fabrication techniques, a large array of functional polymeric Janus particles are diversified with sophisticated architecture and applications. In this review, the most recently developed strategies for controlled synthesis of polymeric Janus nanoparticles with well-defined size and complex superstructures are summarized. In addition, the pros and cons of each approach in mediating the anisotropic shapes of polymeric Janus particles as well as their asymmetric spatial distribution of chemical compositions and functionalities are discussed and compared. Finally, these newly developed structural nanoparticles with specific shapes and surface functions orientated applications in different domains are also discussed, followed by the perspectives and challenges faced in the further advancement of polymeric Janus nanoparticles as high performance materials.

Biodegradable polyester unimolecular systems as emerging materials for therapeutic applications

Unimolecular micelles, as a class of single-molecular micelles, are structurally stable regardless of their concentrations or alterations of the outer environment such as pH, temperature, ion strength etc. in comparison with conventional polymeric micelles. Polyester unimolecular micelles are extensively applied in bio-medical fields because of their stability, biocompatibility, biodegradability, structural-controllabilty etc. In this review, the most recent developments in polyester unimolecular micelle designs in terms of Boltorn polymer H40 core, cyclodextrin, dendrimer or dendrimer-like polymer, or polyhedral oligomeric silsesquioxane (POSS) based polyester unimolecular micelles are presented. The significance and application in biomedical fields including drug delivery, bio-imaging and theranostics are also classified in this review. Finally, the remaining challenges and future perspectives for further development of unimolecular micelles as therapeutic materials are also discussed.