Jianzhong Du

Advances and challenges in smart and functional polymer vesicles

Polymer vesicles prepared by self-assembly techniques have attracted increasing scientific interest in recent years. This is as a result of their numerous potential applications such as tunable delivery vehicles, for the templating of biomineralization, as nanoreactors and as scaffolds for biological conjugation. Presented in this review are the recent advances in the preparation and application of ‘smart’ and functional block copolymer vesicles such as those which respond to external stimuli to afford a change in structure, morphology or controlled release event. In this Highlight, we first give an overview of the structure of polymer vesicles, followed by a summary of the methods used for their preparation. We then focus on recently developed intelligent polymer vesicles which can respond to the application of external stimuli such as a change in temperature, pH or redox to afford novel nanomaterials. The potential applications of these materials are explored with specific focus on the functionalization of various domains of the polymer vesicles. Finally, the current limitations in the preparation and application of polymer vesicles are explored as are the challenges facing the development of these nanostructures towards real-world applications.

Anisotropic particles with patchy, multicompartment and Janus architectures: preparation and application

Anisotropic particles, such as patchy, multicompartment and Janus particles, have attracted significant attention in recent years due to their novel morphologies and diverse potential applications. The non-centrosymmetric features of these particles make them a unique class of nano- or micro-colloidal materials. Patchy particles usually have different compositional patches in the corona, whereas multicompartment particles have a multi-phasic anisotropic architecture in the core domain. In contrast, Janus particles, named after the double-faced Roman god, have a strictly biphasic geometry of distinct compositions and properties in the core and/or corona. The term Janus particles, multicompartment particles and patchy particles frequently appears in the literature, however, they are sometimes misused due to their structural similarity. Therefore, in this critical review we classify the key features of these different anisotropic colloidal particles and compare structural properties as well as discuss their preparation and application. This review brings together and highlights the significant advances in the last 2 to 3 years in the fabrication and application of these novel patchy, multicompartment and Janus particles (98 references).

Non-cytotoxic polymer vesicles for rapid and efficient intracellular delivery

We have recently achieved efficient cytosolic delivery by using pH-sensitive poly(2-(methacryloyloxy)ethylphosphorylcholine)-co-poly(2-(diisopropylamino)ethylmethacrylate) (PMPC-PDPA) diblock copolymers that self-assemble to form vesicles, known as polymersomes, in aqueous solution. It is particularly noteworthy that these diblock copolymers form stable polymersomes at physiological pH but rapidly dissociate below pH 6 to give molecularly-dissolved copolymer chains (unimers). These PMPC-PDPA polymersomes are used to encapsulate nucleic acids for efficient intracellular delivery. Confocal laser scanning microscopy and fluorescence flow cytometry are used to quantify cellular uptake and to study the kinetics of this process. Finally, we examine how PMPC-PDPA polymersomes affect the viability of primary human cells (human dermal fibroblasts (HDF)), paying particular regard to whether inflammatory responses are triggered.

Ultrasound and pH Dually Responsive Polymer Vesicles for Anticancer Drug Delivery

Recently, smart polymer vesicles have attracted increasing interest due to their endless potential applications such as tunable delivery vehicles for the treatment of degenerative diseases. However, the evolution of stimuli-responsive vesicles from bench to bedside still seems far away for the limitations of current stimuli forms such as temperature, light, redox, etc. Since ultrasound combined with chemotherapy has been widely used in tumor treatment and the pH in tumor tissues is relatively low, we designed herein a novel polymer vesicle that respond to both physical (ultrasound) and chemical (pH) stimuli based on a PEO-b-P(DEA-stat-TMA) block copolymer, where PEO is short for poly(ethylene oxide), DEA for 2-(diethylamino)ethyl methacrylate and TMA for (2-tetrahydrofuranyloxy)ethyl methacrylate. These dually responsive vesicles show noncytotoxicity below 250 μg/mL and can encapsulate anticancer drugs, exhibiting retarded release profile and controllable release rate when subjected to ultrasound radiation or varying pH in tris buffer at 37°C.

Efficient Encapsulation of Plasmid DNA in pH‐Sensitive PMPC–PDPA Polymersomes: Study of the Effect of PDPA Block Length on Copolymer–DNA Binding Affinity

We report the self-assembly of a series of amphiphilic diblock copolymers comprising a biocompatible, hydrophilic block, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and a pH-sensitive block, poly(2-(diisopropylamino)ethyl methacrylate) (PDPA), into a dispersion of colloidally stable, nanometer-sized polymersomes at physiological pH and salt concentration. The pH-sensitivity of the PDPA block affords the electrostatic interaction of these block copolymers with nucleic acids at endocytic pH, as a result of the protonation of its tertiary amine groups at pH values below its pK(a). Herein we investigate the effect of PDPA block length on the binding affinity of the block copolymer to plasmid DNA.

Multifunctional polymer vesicles for ultrasensitive magnetic resonance imaging and drug delivery

Presented in this article is the synthesis of a new class of block copolymer, poly(ethylene oxide)-block-poly(tert-butyl acrylate-stat-acrylic acid) [PEO-b-P(AA-stat-tBA)], which can self-assemble into polymer vesicles with tuneable sizes at various conditions. The biocompatible and hydrophilic PEO chains form the vesicle coronas, while the PAA-stat-PtBA chains form the membrane. Superparamagnetic iron oxide nanoparticles (SPIONs) were generated in situ within the membrane of the polymer vesicles by nanoprecipitation. 1H NMR, GPC, DLS, TGA, VSM and TEM were employed to characterize the structure and properties of the block copolymer, polymer vesicles and Fe3O4-decorated magnetic polymer vesicles. The water-dispersible, biocompatible, drug deliverable and superparamagnetic polymer vesicles exhibited excellent colloidal stability at a range of pH conditions and very high T2 relaxivity, demonstrating ultra-sensitivity for magnetic resonance imaging and promising potential applications in nanomedicine.

Preparation of Biocompatible Zwitterionic Block Copolymer Vesicles by Direct Dissolution in Water and Subsequent Silicification within Their Membranes

The facile preparation of block copolymer vesicles in pure water and their subsequent stabilization by sol-gel chemistry within the vesicle membrane is described. An amphiphilic biocompatible zwitterionic diblock copolymer, poly(epsilon-caprolactone)-block-poly[2-(methacryloyloxy)ethyl phosphorylcholine], PCL-b-PMPC, was synthesized by (i) ring-opening polymerization of epsilon-caprolactone, (ii) end-group modification by esterification, and (iii) atom transfer radical polymerization (ATRP) of 2-(methacryloyloxy)ethyl phosphorylcholine (MPC). Unusually, block copolymer vesicles were formed instantly upon adding dried copolymer powder into hot water without using organic cosolvents, pH adjustment, or even stirring. This protocol is much more convenient than previously reported methods such as solvent-switching and film rehydration. The PCL vesicle membrane is moderately hydrophobic and fully biodegradable. The highly biocompatible PMPC chains are expressed on both the exterior and interior surface of the membrane. These vesicles can be stabilized by aqueous sol-gel chemistry within the hydrophobic PCL vesicle membrane by using tetramethyl orthosilicate (TMOS) as the silica precursor in the absence of any external catalyst. The water-immiscible TMOS precursor is initially solubilized within the hydrophobic membrane prior to its in situ transformation into silica. The vesicles were characterized by 1H NMR spectroscopy, atomic force microscopy, transmission electron microscopy, and dynamic light scattering.

Asymmetrical Polymer Vesicles with a "Stealthy" Outer Corona and an Endosomal-Escape-Accelerating Inner Corona for Efficient Intracellular Anticancer Drug Delivery

The efficient intracellular drug delivery is an important challenge due to the slow endocytosis and inefficient drug release of traditional delivery vehicles such as symmetrical polymer vesicles, which have the same coronas on both sides of the membrane. Presented in this paper is a noncytotoxic poly(ethylene oxide)-block-poly(caprolactone)-block-poly(acrylic acid) (PEO113-b-PCL132-b-PAA15) triblock copolymer vesicle with an asymmetrical structure. The biocompatible exterior PEO coronas are designed for stealthy drug delivery; The pH-responsive interior PAA chains are designed for rapid endosomal escape and enhanced drug loading efficiency. The hydrophobic PCL vesicle membrane is for biodegradation. Such asymmetrical polymer vesicle showed high doxorubicin (DOX) loading efficiency and good biodegradability under extracellular enzymatic conditions. Compared with three traditional symmetrical vesicles prepared from PEO113-b-PCL110, PEO43-b-PCL98-b-PAA25, and PAA21-b-PCL75 copolymers, the DOX-loaded asymmetrical PEO113-b-PCL132-b-PAA15 polymer vesicles exhibited rapid endocytosis rate and much faster endosomal escape ability, demonstrating promising potential applications in nanomedicine.

Patchy multi-compartment micelles are formed by direct dissolution of an ABC triblock copolymer in water

Patchy multi-compartment micelles are formed on direct dissolution of a primary amine-based triblock copolymer, poly(ethylene oxide)-b-poly(e-caprolactone)-b-poly(2-aminoethyl methacrylate), PEO-b-PCL-b-PAMA, in water, with PCL chains forming the micelle cores and the PEO and PAMA chains forming phase-segregated patchy or hemispherical coronas. By selectively silicifying the PCL cores with tetramethyl orthosilicate (TMOS), the phase-separated character of these micelles is revealed by transmission electron microscopy.

Preparation of primary amine-based block copolymer vesicles by direct dissolution in water and subsequent stabilization by sol-gel chemistry.

A new amphiphilic biocompatible diblock copolymer, poly(epsilon-caprolactone)-block-poly(2-aminoethyl methacrylate), PCL-b-PAMA, was synthesized in three steps by (i) ring-opening polymerization of epsilon-caprolactone, (ii) end-group modification by esterification, and (iii) atom transfer radical polymerization (ATRP) of 2-aminoethyl methacrylate hydrochloride (AMA) in its hydrochloride salt form. This copolymer forms block copolymer vesicles with the hydrophobic PCL block forming the vesicle membrane. Unusually, these vesicles are easily prepared by direct dissolution in water without using organic co-solvents, pH adjustment, or even stirring. These vesicles can be stabilized by aqueous sol-gel chemistry using tetramethyl orthosilicate (TMOS) as the silica precursor. It is well-known that cationic polymers can catalyze silica formation, but in this particular case, it seems that the TMOS precursor is solubilized within the hydrophobic PCL membrane. Thus, the neutral membrane actually directs silica formation, rather than the cationic PAMA chains. The final vesicle morphology and the silica content depend on the silicification conditions. Provided that the TMOS/AMA molar ratio does not exceed 10:1, silicification is solely confined within the PCL membrane. At higher ratios, silica nanoparticles (5-12 nm) are also observed on the outer surface of the silicified vesicles. However, these nanoparticles appear to be only weakly adsorbed, since they can be easily removed by dialysis. The mean hydrodynamic diameter of the silicified vesicles varies from 175 to 205 nm with solution pH due to (de)protonation of the externally expressed PAMA chains. Calcination of the silicified vesicles at 800 degrees C leads to the formation of hollow silica particles. 1H NMR, transmission electron microscopy (TEM), dynamic light scattering (DLS), aqueous electrophoresis, and thermogravimetric analysis (TGA) were employed to characterize the vesicles, both before and after silicification.