Block copolymer micelles with a dual-stimuli-responsive core for fast or slow degradation

We report the design and demonstration of a dual-stimuli-responsive block copolymer (BCP) micelle with increased complexity and control. We have synthesized and studied a new amphiphilic ABA-type triblock copolymer whose hydrophobic middle block contains two types of stimuli-sensitive functionalities regularly and repeatedly positioned in the main chain. Using a two-step click chemistry approach, disulfide and o-nitrobenzyle methyl ester groups are inserted into the main chain, which react to reducing agents and light, respectively. With the end blocks being poly(ethylene oxide), micelles formed by this BCP possess a core that can be disintegrated either rapidly via photocleavage of o-nitrobenzyl methyl esters or slowly through cleavage of disulfide groups by a reducing agent in the micellar solution. This feature makes possible either burst release of an encapsulated hydrophobic species from disintegrated micelles by UV light, or slow release by the action of a reducing agent, or release with combined fast-slow rate profiles using the two stimuli.     

A new design for light-breakable polymer micelles

A new and general design strategy is presented for amphiphilic block copolymers whose micellar aggregates can be dissociated by light. A diblock copolymer composed of hydrophilic poly(ethylene oxide) (PEO) and a hydrophobic polymethacrylate bearing pyrene pendant groups (PPy) was synthesized using ATRP. Upon UV light irradiation of polymer micellar solutions, the photosolvolysis of pyrene moieties results in their detachment from the polymer and converts the hydrophobic PPy block into hydrophilic poly(methacrylic acid). This effect leads to complete dissociation of polymer micelles.     

Near-infrared light-triggered dissociation of block copolymer micelles using upconverting nanoparticles

We demonstrate a novel strategy enabling the use of a continuous-wave diode near-infrared (NIR) laser to disrupt block copolymer (BCP) micelles and trigger the release of their "payloads". By encapsulating NaYF(4):TmYb upconverting nanoparticles (UCNPs) inside micelles of poly(ethylene oxide)-block-poly(4,5-dimethoxy-2-nitrobenzyl methacrylate) and exposing the micellar solution to 980 nm light, photons in the UV region are emitted by the UCNPs, which in turn are absorbed by o-nitrobenzyl groups on the micelle core-forming block, activating the photocleavage reaction and leading to the dissociation of BCP micelles and release of co-loaded hydrophobic species. Our strategy of using UCNPs as an internal UV or visible light source upon NIR light excitation represents a general and efficient method to circumvent the need for UV or visible light excitation that is a common drawback for light-responsive polymeric systems developed for potential biomedical applications.     

Cylindrical micelles from the aqueous self-assembly of an amphiphilic poly(ethylene oxide)-b-poly(ferrocenylsilane) (PEO-b-PFS) block copolymer with a metallo-supramolecular linker at the block junction

A supramolecular AB diblock copolymer has been prepared by the sequential self-assembly of terpyridine end-functionalized polymer blocks by using Ru(III)/Ru(II) chemistry. By this synthetic strategy a hydrophobic poly(ferrocenylsilane) (PFS) was attached to a hydrophilic poly(ethylene oxide) (PEO) block to give an amphiphilic metallo-supramolecular diblock copolymer (PEO/PFS block ratio 6:1). This compound was used to form micelles in water that were characterized by a combination of dynamic and static light scattering, transmission electron microscopy, and atomic force microscopy. These complementary techniques showed that the copolymers investigated form rod-like micelles in water; the micelles have a constant diameter but are rather polydisperse in length, and light scattering measurements indicate that they are flexible. Crystallization of the PFS in these micelles was observed by differential scanning calorimetry, and is thought to be the key behind the formation of rod-like structures. The cylindrical micelles can be cleaved into smaller rods whenever the temperature of the solution is increased or they are exposed to ultrasound.     

Hyperbranched Azopolymer with Quadruple Responsibility

Simply constructing multiple responsive polymers with obvious shape and dimension variations on their assemblies upon different stimuli is still rarely reported. In this study, we report a hyperbranched polymer named HPAzoBAHB-star-PEG9 with quadruple-response to light,temperature, pH and oxidation stimuli. The polymer contains azobenzene chromophore, sulfide, amide and amine groups in its hydrophobic hyperbranched core, and the core is capped with hydrophilic polyethylene glycol(PEG9) arms. HPAzoBAHB-star-PEG9 could assemble into unusual leaf-like lamellar micelles at 25 °C under the guidance of orderly arranged H-aggregate of azobenzene moieties. These leaf-like lamellar micelles can transform into vesicles upon UV irradiation and lower temperature, or convert to smaller spherical micelles in acidic or oxidative environments, respectively, with the destroy of ordered azobenzene arrangements. This quadruple-responsive hyperbranched polymer is suitable to construct multiple stimuli-responsive micro/nanostructures, or accurate delivery and release following subtle stimuli sequences.     

Specific interactions improve the loading capacity of block copolymer micelles in aqueous media

Block copolymer micelles find application in many fields as nanocarriers, especially in drug delivery. We report herein that specific interactions between hydrophobic guest molecules and core-forming segments can significantly improve the loading capacity of polymeric micelles. High loading capacities (>100% weight/weight of polymer (w/wp)) were systematically observed for the encapsulation of probes containing weak carboxylic acid groups by micellar nanoparticles having poly[2-(dialkylamino)ethyl methacrylate] cores (i.e., particles whose cargo space exhibits antagonist weak base functions), as demonstrated by the incorporation of indomethacin (IND), ibuprofen (IBPF), and trans-3,5-bis(trifluoromethyl)cinnamic acid (F-CIN) into either poly(ethylene oxide)-b-poly[2-(diisopropylamino)ethyl methacrylate] (PEO-b-PDPA) or poly(glycerol monomethacrylate)-b-PDPA (PG2MA-b-PDPA) micelles. The esterification of IND yielding to a nonionizable IND ethyl ester derivative (IND-Et) caused an abrupt decrease in the micellar loading capacity down to 10-15% w/wp. Similar results were also obtained when IND was combined with nonionizable block copolymers such as PEO-b-polycaprolactone (PEO-b-PCL) and PEO-b-poly(glycidyl methacrylate) (PEO-b-PGMA). The existence of acid-base interactions between the solubilizate and the weak polybase block forming the micelle core was confirmed by 1H NMR measurements. However, the incorporation of high numbers of hydrophobic guest molecules inside polymeric micelles can provoke not only an increase in the hydrodynamic size (2RH) of the objects but also a substantial change in the morphology (transition from spheres to cylinders). The application of the Higuchi model showed that the probe release followed a diffusion-controlled mechanism, and diffusion coefficients (D) on the order of 10-18-10-17 cm2/s were determined for IND release from 1.0 mg/mL PEO113-b-PDPA50 + 100% w/wp IND. Probe release from micelles with weak polybase-based cores can also be triggered by changes in the solution pH.     

Reduction and pH dual‐responsive block copolymers containing pendent p‐nitrobenzyl carbamate functionalities: Synthesis and self‐assembly behavior

We report on the preparation of reduction‐responsive amphiphilic block copolymers containing pendent p‐nitrobenzyl carbamate (pNBC)‐caged primary amine moieties by reversible addition–fragmentation chain transfer (RAFT) radical polymerization using a poly(ethylene glycol)‐based macro‐RAFT agent. The block copolymers self‐assembled to form micelles or vesicles in water, depending on the length of hydrophobic block. Triggered by a chemical reductant, sodium dithionite, the pNBC moieties decomposed through a cascade 1,6‐elimination and decarboxylation reactions to liberate primary amine groups of the linkages, resulting in the disruption of the assemblies. The reduction sensitivity of assemblies was affected by the length of hydrophobic block and the structure of amino acid‐derived linkers. Using hydrophobic dye Nile red (NR) as a model drug, the polymeric assemblies were used as nanocarriers to evaluate the potential for drug delivery. The NR‐loaded nanoparticles demonstrated a reduction‐triggered release profile. Moreover, the liberation of amine groups converted the reduction‐responsive polymer into a pH‐sensitive polymer with which an accelerated release of NR was observed by simultaneous application of reduction and pH triggers. It is expected that these reduction‐responsive block copolymers can offer a new platform for intracellular drug delivery. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1333–1343     

Nucleobase‐Functionalized Supramolecular Micelles with Tunable Physical Properties for Efficient Controlled Drug Release

Complementary nucleobase‐functionalized polymeric micelles, a combination of adenine‐thymine (A‐U) base pairs and a blend of hydrophilic–hydrophobic polymer pairs, can be used to construct 3D supramolecular polymer networks; these micelles exhibit excellent self‐assembly ability in aqueous solution, rapid pH‐responsiveness, high drug loading capacity, and triggerable drug release. In this study, a multi‐uracil functionalized poly(ε‐caprolactone) (U‐PCL) and adenine end‐capped difunctional oligomeric poly(ethylene glycol) (BA‐PEG) are successfully developed and show high affinity and specific recognition in solution owing to dynamically reversible A‐U‐induced formation of physical cross‐links. The U‐PCL/BA‐PEG blend system produces supramolecular micelles that can be readily adjusted to provide the desired critical micellization concentration, particle size, and stability. Importantly, in vitro release studies show that doxorubicin (DOX)‐loaded micelles exhibit excellent DOX‐encapsulated stability under physiological conditions. When the pH value of the solution is reduced from 7.4 to 5.0, DOX‐loaded micelles can be rapidly triggered to release encapsulated DOX, suggesting these polymeric micelles represent promising candidate pH‐responsive nanocarriers for controlled‐release drug delivery and pharmaceutical applications.

     

Investigation of a new thermosensitive block copolymer micelle: hydrolysis, disruption, and release

Thermosensitive polymer micelles are generally obtained with block copolymers in which one block exhibits a lower critical solution temperature in aqueous solution. We investigate a different design that is based on the use of one block bearing a thermally labile side group, whose hydrolysis upon heating shifts the hydrophilic-hydrophobic balance toward the destabilization of block copolymer micelles. Atom transfer radical polymerization was utilized to synthesize a series of diblock copolymers composed of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(2-tetrahydropyranyl methacrylate) (PTHPMA). We show that micelles of PEO-b-PTHPMA in aqueous solution can be destabilized as a result of the thermosensitive hydrolytic cleavage of tetrahydropyranyl (THP) groups that transforms PTHPMA into hydrophilic poly(methacrylic acid). The three related processes occurring in aqueous solution, namely, hydrolytic cleavage of THP, destabilization of micelles, and release of loaded Nile Red (NR), were investigated simultaneously using 1H NMR, dynamic light scattering, and fluorescence spectroscopy, respectively. At 80 degrees C, the results suggest that the three events proceed with a similar kinetics. Although slower than at elevated temperatures, the disruption of PEO-b-PTHPMA micelles can take place at the body temperature (approximately 37 degrees C), and the release kinetics of NR can be adjusted by changing the relative lengths of the two blocks or the pH of the solution.     

Amphiphilic β‐cyclodextrin‐based star‐like block copolymer unimolecular micelles for facile in situ preparation of gold nanoparticles

Multifunctional polymer unimolecular micelles, which are used as templates to fabricate stable gold nanoparticles (GNPs) in one‐step without external reductant, have been designed and prepared. Amphiphilic 21‐arm star‐like block copolymers β‐cyclodextrin‐{poly(lactide)‐poly(2‐(dimethylamino) ethyl methacrylate)‐poly[oligo(2‐ethyl‐2‐oxazoline)methacrylate]}₂₁ [β‐CD‐(PLA‐PDMAEMA‐PEtOxMA)₂₁] and the precursors are synthesized by the combination of ring‐opening polymerization (ROP) and activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The tertiary amine groups of PDMAEMA block reduce the counterion to zerovalent gold in situ, and these gold atoms combine mutually to form final GNPs. GNPs with relatively small size and narrow size distribution can be obtained in longer DMAEMA block copolymer, larger molar ratio of DMAEMA to HAuCl₄ and smaller absolute concentrations of both polymer and HAuCl₄. These results showed that the unimolecular micelles can be used as templates for preparing and stabilizing GNPs in situ without any external reducing agents and organic solvents, suggesting that the nanocomposite systems are latent nanocarriers for further biomedical application. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 186–196     

Physicochemical characterization of degradable thermosensitive polymeric micelles

Amphiphilic AB block copolymers consisting of thermosensitive poly(N-(2-hydroxypropyl) methacrylamide lactate) and poly(ethylene glycol), pHPMAmDL-b-PEG, were synthesized via a macroinitiator route. Dynamic light scattering measurements showed that these block copolymers form polymeric micelles in water with a size of around 50 nm by heating of an aqueous polymer solution from below to above the critical micelle temperature (cmt). The critical micelle concentration as well as the cmt decreased with increasing pHPMAmDL block lengths, which can be attributed to the greater hydrophobicity of the thermosensitive block with increasing molecular weight. Cryogenic transmission electron microscopy analysis revealed that the micelles have a spherical shape with a narrow size distribution. 1H NMR measurements in D2O showed that the intensity of the peaks of the protons from the pHPMAmDL block significantly decreased above the cmt, indicating that the thermosensitive blocks indeed form the solidlike core of the micelles. Static light scattering measurements demonstrated that pHPMAmDL-b-PEG micelles with relatively large pHPMAmDL blocks possess a highly packed core that is stabilized by a dense layer of swollen PEG chains. FT-IR analysis indicated that dehydration of amide bonds in the pHPMAmDL block occurs when the polymer dissolved in water is heated from below to above its cmt. The micelles were stable when an aqueous solution of micelles was incubated at 37 degrees C and at pH 5.0, where the hydrolysis rate of lactate side groups is minimized. On the other hand, at pH 9.0, where hydrolysis of the lactic acid side groups occurs, the micelles started to swell after 1.5 h of incubation and complete dissolution of micelles was observed after 4 h as a result of hydrophilization of the thermosensitive block. Fluorescence spectroscopy measurements with pyrene loaded in the hydrophobic core of the micelles showed that when these micelles were incubated at pH 8.6 and at 37 degrees C the microenvironment of pyrene became increasingly hydrated in time during this swelling phase. The results demonstrate the potential applicability of pHPMAmDL-b-PEG block copolymer micelles for the controlled delivery of hydrophobic drugs.     

Micelle-encapsulated carbon nanotubes: a route to nanotube composites

We report a general approach toward dispersing single-walled carbon nanotubes (SWNTs) in solvents and polymer materials, by encapsulating SWNTs within cross-linked micelles. Micelles made from polystyrene-block-poly(acrylic acid) (PS-b-PAA), an amphiphilic block copolymer, are first assembled around SWNTs by gradually adding H2O to a suspension of nanotubes in dimethylformamide. The hydrophilic, outer shells of these micelles are then chemically cross-linked with a difunctional linker molecule. Pure encapsulated SWNTs (e-SWNTs) can then be separated from empty cross-linked micelles by consecutive cycles of centrifugation and redispersion. Atomic force and transmission electron microscopies of the resulting nanostructures demonstrate that individual nanotubes (rather than bundles) have been completely encased in polymer shells whose thickness is slightly larger than that of empty micelles. e-SWNTs encapsulated in PS-b-PAA can be permanently redispersed in H2O, in organic solvents, and in both hydrophobic and hydrophilic polymer matrices with minimal sonication. Micelle encapsulation could improve the compositing of SWNTs in a wide variety of polymer materials for structural, electronic, and thermal applications.     

Photo‐responsive amphiphilic poly(α‐hydroxy acids) with pendent o‐nitrobenzyl ester constructed via copper‐catalyzed azide‐alkyne cycloaddition reaction

Photo‐responsive block copolymer mPEG‐b‐poly(Tyr)‐g‐NB was prepared by introduction of o‐nitrobenzyl ester group into the side chain of amphiphilic poly(ethylene glycol)‐b‐poly(α‐hydroxy acids) (mPEG‐b‐poly(Tyr)) containing pendent alkynyl group via copper‐catalyzed azide‐alkyne cycloaddition reaction. The amphiphilic mPEG‐b‐poly(Tyr) was synthesized via the ring‐opening polymerization of O‐carboxyanhydrides, with monomethoxy poly(ethylene glycol) (mPEG) as macroinitiator. The molecular structure, self‐assembly, and photo‐controlled release of the obtained mPEG‐b‐poly(Tyr)‐g‐NB were thoroughly investigated. mPEG‐b‐poly(Tyr)‐g‐NB could self‐assemble into spherical micelles in water and showed disassembly under UV light irradiation, which was demonstrated by means of UV‐vis spectroscopy, scan electron microscopes, and dynamic light scattering measurement. Fluorescence emission measurements demonstrated that Nile red, encapsulated by micelles, can be released upon UV irradiation. This study provides a convenient way to construct smart poly(α‐hydroxy acids)‐based nanocarriers for controlled release of hydrophobic drugs. Copyright © 2015 John Wiley & Sons, Ltd.     

Physicochemical properties of pH-controlled polyion complex (PIC) micelles of poly(acrylic acid)-based double hydrophilic block copolymers and various polyamines

The physicochemical properties of polyion complex (PIC) micelles were investigated in order to characterize the cores constituted of electrostatic complexes of two oppositely charged polyelectrolytes. The pH-sensitive micelles were obtained with double hydrophilic block copolymers containing a poly(acrylic acid) block linked to a modified poly(ethylene oxide) block and various polyamines (polylysine, linear and branched polyethyleneimine, polyvinylpyridine, and polyallylamine). The pH range of micellization in which both components are ionized was determined for each polyamine. The resulting PIC micelles were characterized using dynamic light scattering and small-angle X-ray scattering experiments (SAXS). The PIC micelles presented a core–corona nanostructure with variable polymer density contrasts between the core and the corona, as revealed by the analysis of the SAXS curves. It was shown that PIC micelle cores constituted by polyacrylate chains and polyamines were more or less dense depending on the nature of the polyamine. It was also determined that the density of the cores of the PIC micelles depended strongly on the nature of the polyamine. These homogeneous cores were surrounded by a large hairy corona of hydrated polyethylene oxide block chains. Auramine O (AO) was successfully entrapped in the PIC micelles, and its fluorescence properties were used to get more insight on the core properties. Fluorescence data confirmed that the cores of such micelles are quite compact and that their microviscosity depended on the nature of the polyamine. The results obtained on these core–shell micelles allow contemplating a wide range of applications in which the AO probe would be replaced by various cationic drugs or other similarly charged species to form drug nanocarriers or new functional nanodevices.     

Micelles and reverse micelles with a photo and thermo double‐responsive block copolymer

A novel photo and thermo double‐responsive block copolymer was developed to fabricate micelles and reverse micelles in aqueous solution. The block copolymer was synthesized by ATRP block copolymerization of a spiropyran‐ containing methacrylate (SPMA) with di(ethylene glycol) methyl ether methacrylate (DEGMMA). By facile control of the photo irradiation and solution temperature, PSPMA‐core and PDEGMMA‐core micelles can be obtained, respectively. The thermo‐ and photo‐responsive micelles were used as smart polymeric nanocarriers for controlled encapsulation, triggered release, and re‐encapsulation of model drug coumarin 102. The double‐responsive self‐assembly and disassembly were tracked by dynamic light scattering, transmission electron microscopy, and fluorescence spectroscopy. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2855–2861, 2010     

Finely Tuned Thermo‐Responsive Block Copolymer Micelles for Photothermal Effect‐Triggered Efficient Cellular Internalization

Although biodegradable amphiphilic block copolymer micelles have been widely applied in the clinical applications as drug delivery nanocarriers, low‐efficiency cellular internalization frequently reduces therapeutic efficacy of the loaded drugs. Here, photothermal effect‐promoted cellular internalization of finely tuned thermo‐responsive amphiphilic biodegradable block copolymer nanocarriers via noninvasive stimuli of near‐infrared (NIR) light irradiation is demonstrated. Amphiphilic block copolymers, poly(ε‐caprolactone)‐block‐poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide) (PCL‐b‐P(NIPAM‐co‐DMA)), are prepared with finely tuned compositions of P(NIPAM‐co‐DMA) for desirable lower critical solution temperature of the block copolymer micelles in aqueous solution. The block copolymers are then used to co‐encapsulate doxorubicin and indocyanine green, which show high encapsulation efficiency and significant photothermal effect upon exposure to NIR light irradiation. The photothermal effect‐induced collapse and hydrophilic‐to‐hydrophobic transition of P(NIPAM‐co‐DMA) shells significantly enhance the interactions between drug‐loaded micelles and cell membranes, which dramatically promote the cellular internalization of the micelles and therapeutic efficacy of loaded anticancer drugs.

     

Synthesis,characterization, and temperature‐responsive behaviors of novel hybrid amphiphilic block copolymers containing polyhedral oligomeric silsesquioxane

Organic/inorganic hybrid amphiphilic block copolymer poly(methacrylate isobutyl POSS)‐b‐poly(N‐isopropylacrylamide‐co‐oligo(ethylene glycol) methyl ether methacrylate) (PMAPOSS‐b‐P(NIPAM‐co‐OEGMA)) was synthesized via reversible addition–fragmentation chain transfer polymerization. The self‐assembly behavior of this block copolymer in aqueous solution was investigated by dynamic light scattering (DLS) and transmission electron microscopy. The results indicate that the novel block copolymer can self‐assemble into spherical micelles with PMAPOSS segment as the hydrophobic part and P(NIPAM‐co‐OEGMA) segment as the hydrophilic part. The temperature‐responsive characteristics of the assemblies were tested by UV–Vis spectra and DLS. Some factors such as the concentration, molecular weight, and copolymer generation that may affect the cloud point were studied systematically. The results reveal that this copolymer exhibits a sharp and intensive lower critical solution temperature (LCST). The essentially predetermined LCST can be conveniently achieved by adjusting the content of NIPAM or OEGMA domain. In addition, these novel hybrid micelles can undergo an association/disassociation cycle with the heating and cooling of solution and the degree of reversibility displaying a tremendous concentration dependence, as a novel organic/inorganic hybrid material with distinctive virtues can be potentially used in biological and medical fields, especially in drug nanocarriers for targeted therapy. Copyright © 2014 John Wiley & Sons, Ltd.     

pH responsive surfaces with nanoscale topography

We report the preparation of nanostructured adaptive polymer surfaces by diffusion of an amphihilic block copolymer toward the interface. The surface segregation of a diblock copolymer, polystyrene‐block‐poly(acrylic acid) (PS‐b‐PAA), occurred when blended with high molecular weight polystyrene employed as a matrix. On annealing, the polymer surfaces changed both the chemical composition and the hydrophilicity depending on the environment and pH, respectively. By exposure to either water vapor or air, the surface wettability varied between hydrophilic and hydrophobic. In addition, surface enrichment on diblock copolymer by water vapor annealing led to self‐assembly occurring at the interface. Hence, nanostructured domains can be observed by AFM in liquid media. Moreover, the PAA segments placed at the interface respond to pH and can switch from an extended hydrophilic state at basic pH values to a collapsed hydrophobic state in acidic media. Accordingly, the surface morphology changed from swelled micelles to nanometer size holes. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2982–2990, 2010     

Fine‐Tuning of Charge‐Conversion Polymer Structure for Efficient Endosomal Escape of siRNA‐Loaded Calcium Phosphate Hybrid Micelles

For efficient delivery of siRNA into the cytoplasm, a smart block copolymer of poly(ethylene glycol) and charge‐conversion polymer (PEG‐CCP) is developed by introducing 2‐propionic‐3‐methylmaleic (PMM) amide as an anionic protective group into side chains of an endosome‐disrupting cationic polyaspartamide derivative. The PMM amide moiety is highly susceptible to acid hydrolysis, generating the parent cationic polyaspartamide derivative at endosomal acidic pH 5.5 more rapidly than a previously synthesized cis‐aconitic (ACO) amide control. The PMM‐based polymer is successfully integrated into a calcium phosphate (CaP) nanoparticle with siRNA, constructing PEGylated hybrid micelles (PMM micelles) having a sub‐100 nm size at extracellular neutral pH 7.4. Ultimately, PMM micelles achieve the significantly higher gene silencing efficiency in cultured cancer cells, compared to ACO control micelles, probably due to the efficient endosomal escape of the PMM micelles. Thus, it is demonstrated that fine‐tuning of acid‐labile structures in CCP improves the delivery performance of siRNA‐loaded nanocarriers.