Hairy polymeric nanocapsules with ph‐responsive shell and thermoresponsive brushes: Tunable permeability for controlled release of water‐soluble drugs

The hairy poly(methacrylic acid‐co‐divinylbenzene)‐g‐poly(N‐isopropylacrylamide) (P(MAA‐co‐DVB)‐g‐PNIPAm) nanocapsules with pH‐responsive P(MAA‐co‐DVB) inner shell and temperature‐responsive PNIPAm brushes were prepared by combined distillation–precipitation copolymerization and surface thiol‐ene click grafting reaction using 3‐(trimethoxysilyl)propyl methacrylate‐modified silica (SiO₂‐MPS) nanospheres as a sacrificial core material. The well‐defined PNIPAm was synthesized by a reversible addition fragmentation chain transfer (RAFT) polymerization. The chain end was converted to a thiol by chemical reduction. The PNIPAm was integrated into the nanocapsules via thiol‐ene click reaction. The surface thiol‐ene click reaction conduced to tunable grafting density of PNIPAm brushes. The grafting densities decreased from 0.70 chains nm^?2 to 0.15 chains nm^?2 with increasing the molecular weight of grafted PNIPAm chains. Using water soluble doxorubicin hydrochloride (DOX·HCl) as a model molecular, the tunable shell permeability of the nanocapsule was investigated in detail. The permeability constant can be tuned by controlling the thickness of the P(MAA‐co‐DVB) inner shell, the grafting density of PNIPAm brushes, and the environmental pH and temperature. The tunable shell permeability of these nanocapsules results in the release of the loaded guest molecules with manipulable releasing kinetics. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2202–2216     

Bioreducible and core‐crosslinked hybrid micelles from trimethoxysilyl‐ended poly(ε‐caprolactone)‐S‐S‐poly(ethylene oxide) block copolymers: Thiol‐ene click synthesis and properties

Bioreducible and core‐crosslinked hybrid micelles were for the first time fabricated from biodegradable and biocompatible trimethoxysilyl‐terminated and disulfide‐bond‐linked block copolymers poly(ε‐caprolactone)‐S‐S‐poly(ethylene oxide), which were prepared by combining thiol‐ene coupling reaction and ring‐opening polymerization. The molecular structures, physicochemical, self‐assembly, and bioreducible properties of these copolymers were thoroughly characterized by means of FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, wide‐angle X‐ray diffraction, dynamic light scattering (DLS), and transmission electron microscopy. The core‐crosslinking sol‐gel reaction was confirmed by ¹H NMR, and the core‐crosslinked hybrid micelles contained about 3 wt % of silica. The bioreducible property of both uncrosslinked and core‐crosslinked micelles in 10 mM 1,4‐dithiothreitol (DTT) solution was monitored by DLS, which demonstrated that the PEO corona gradually shedded from the PCL core. The anticancer doxorubicin drug‐loaded micelles showed nearly spherical morphology compared with blank micelles, presenting a DTT reduction‐triggered drug‐release profile at 37 °C. Notably, the core‐crosslinked hybrid micelles showed about twofold drug loading capacities and a half drug‐release rate compared with the uncross‐liked counterparts. This work provides a useful platform for the fabrication of bioreducible and core‐crosslinked hybrid micelles potential for anticancer drug delivery system. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

POSS end‐linked peptide‐functionalized poly(ɛ‐caprolactone)s and their inclusion complexes with α‐cyclodextrin

In this report, we have synthesized organic/inorganic hybrid peptide–poly(?‐caprolactone) (PCL) conjugates via ring opening polymerization (ROP) of ?‐caprolactone (CL) in the presence of two sequence defined peptide initiators, namely POSS‐Leu‐Aib‐Leu‐NH₂ (POSS: polyhedral oligomeric silsesquioxane; Leu: Leucine; Aib: α‐aminoisobutyric acid) and OMe‐Leu‐Aib‐Leu‐NH₂. Covalent attachment of peptide segments with the PCLs were examined by ¹H and ²⁹Si NMR spectroscopy, matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF‐MS) and FTIR spectroscopy. Supramolecular inclusion complexations of synthesized peptide‐PCL conjugates with α‐cyclodextrin (α‐CyD) were studied to understand the effect of POSS/OMe‐peptide moieties at the PCL chain ends. Inclusion complexation of peptide‐PCL conjugates with α‐CyD produced linear polypseudorotaxane, confirmed by ¹H NMR, FTIR, powder X‐ray diffraction (PXRD), polarized optical microscopy (POM) and differential scanning calorimetry (DSC). Extent of α‐CyD threading onto the hybrid peptide‐PCL conjugated polymers is less than that of α‐CyD threaded onto the linear PCL. Thus, PCL chains were not fully covered by the host α‐CyD molecules due to the bulky POSS/OMe‐peptide moieties connected with the one edge of the PCL chains. PXRD experiment reveals channel like structures by the synthesized inclusion complexes (ICs). Spherulitic morphologies of POSS/OMe‐peptide‐PCL conjugates were fully destroyed after inclusion complexation with α‐CyD and tiny nanoobjects were produced. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3643–3651.     

Construction of anion‐responsive crosslinked polypseudorotaxane based on molecular recognition of pillar[5]arene

A pillar[5]arene pendant polymer (Poly‐P[5]A) is synthesized via ROMP using Grubb's first‐generation catalyst. GPC analysis of the polymer suggested ~30 pendant pillar[5]arene units in the polymer. Supramolecular polypseudorotaxane assembly is constructed by intermolecularly crosslinking pendant pillar[5]arene units using a bispyridinium guest via host–guest complexation. Formation of the polypseudorotaxane assembly is characterized by 1D/2D NMR techniques and DLS analysis. Moreover, anion‐responsiveness of the polypseudorotaxane assembly is demonstrated by ¹H NMR spectroscopic analysis using chloride anion as external stimulus. Scanning electron microscopic analysis of the poly‐P[5]A showed breath‐figure assembly and upon crosslinking with G.2PF₆ the polymer self‐assemble to give a supramolecular polymer network. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1508–1515     

UV‐triggered CO2‐responsive behavior of nanofibers and their controlled drug release properties

A novel nanofibrous mat featuring an ultraviolet (UV)‐induced CO₂‐responsive behavior was fabricated via electrospinning and used as a controlled drug release system. First, a random copolymer for electrospinning, poly(N,N‐diethylaminoethyl acrylamide‐co‐N‐benzylacrylamide‐co‐N,N‐dimethyl‐N‐(2‐nitrobenzyl)‐ethaneamine acrylamide‐co‐4‐acryloyloxy benzophenone) [P(DEEA‐co‐BA‐co‐DMNOBA‐co‐ABP)], was prepared based on pentafluorophenyl esters via an “active ester‐amine” chemistry reaction. Subsequently, doxorubicin hydrochloride (DOX)‐loaded P(DEEA‐co‐BA‐co‐DMNOBA‐co‐ABP) nanofibers were fabricated, yielding a new drug‐loaded nanofibrous mat as a potential wound dressing. These DOX‐loaded nanofibers can respond to UV irradiation and CO₂ stimulation. Interestingly, without UV irradiation, the fabricated nanofibers cannot exhibit any responsiveness. Therefore, the majority of the DOX was steadily stored in the nanofibers, even in the presence of CO₂. However, upon UV irradiation, the CO₂‐responsive behavior of the nanofibers was activated and the prepared nanofibers swelled slightly, resulting in the release of around 42% DOX from the nanofibers. Upon further purging with CO₂, the release amount of DOX from the nanofibers could reach up to approximately 85%, followed by the morphological transition from a nanofibrous mat to a porous hydrogel film. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1580–1586     

Synthesis and Molecular Recognition of Water‐Soluble S6‐Corona[3]arene[3]pyridazines

We report the efficient and scalable synthesis and molecular‐recognition properties of novel and water‐soluble S₆‐corona[3]arene[3]pyridazines. The synthesis comprises a one‐pot nucleophilic aromatic substitution reaction between diesters of 2,5‐dimercaptoterephthalate and 3,6‐dichlorotetrazine followed by the inverse electron‐demand Diels–Alder reaction of the tetrazine moieties with an enamine and exhaustive saponification of esters. The resulting S₆‐corona[3]arene[3]pyridazines, which adopt a 1,3,5‐alternate conformation in the crystalline state, are able to selectively form stable 1:1 complexes with dicationic guest species in water with association constants ranging from (1.10±0.06)×10³ M ^?1 to (1.18±0.06)×10⁵ M ^?1. The easy availability, large cavity size, strong and selective binding power render the water‐soluble S₆‐corona[3]arene[3]pyridazines useful macrocyclic hosts in various disciplines of supramolecular chemistry.     

Dual‐responsive supramolecular inclusion complexes of block copolymer poly(ethylene glycol)‐block‐poly[(2‐dimethylamino)ethyl methacrylate] with α‐cyclodextrin

A new class of temperature and pH dual‐responsive and injectable supramolecular hydrogel was developed, which was formed from block copolymer poly(ethylene glycol)‐block‐poly[(2‐dimethylamino)ethyl methacrylate] (PEG‐b‐PDMAEMA) and α‐cyclodextrin (α‐CD) inclusion complexes (ICs). The PEG‐b‐PDMAEMA diblock copolymers with different ratio of ethylene glycol (EG) to (2‐dimethylamino)ethyl methacrylate (DMAEMA) (102:46 and 102:96, respectively) were prepared by atom transfer radical polymerization (ATRP). ¹H NMR measurement indicated that the ratio of EG unit to α‐CD in the resulted ICs was higher than 2:1. Thermal analysis showed that thermal stability of ICs was improved. The rheology studies showed that the hydrogels were temperature and pH sensitive. Moreover, the hydrogels were thixotropic and reversible. The self‐assembly morphologies of the ICs in different pH and ionic strength environment were studied by transmission electron microscopy. The formed biocompatible micelles have potential applications as biomedical and stimulus‐responsive material. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2143–2153, 2010     

Preparation of inclusion complex between polyaniline and β‐cyclodextrin in aqueous solution

Two routes have been developed inorder to prepare an inclusion complex of polyaniline (PANI) and β‐cyclodextrin (βCyD). The first route was to in situ polymerize N‐phenyl‐1,4‐phenylenediamine (PPD) which was encapsulated in βCyD in advance. The formation of an inclusion complex was confirmed by UV‐vis, circular dichroism (CD), and NMR spectra. It was found that the synthesized complex was readily dissolved in a range of solvents due to the solubility of βCyD. In these solvents, PANI was well encapsulated by βCyD with some conformation change in the chain of PANI, which was proved by the CD spectra of PANI. The second route involved preparing the inclusion complex by post‐encapsulation of PANI emeraldine base (EB) into βCyD in aqueous solution at room temperature. The encapsulation of EB into βCyD was confirmed by FT‐IR and UV‐vis spectra. The band shift in UV‐vis spectra indicated that the inclusion complexation was a gradual process, and the change in the chain conformation of PANI was also observed after it was encapsulated into βCyD. Copyright © 2003 John Wiley & Sons, Ltd.     

Biocompatible stimuli‐responsive nanogels for controlled antitumor drug delivery

Herein, the synthesis and potential application as cargo delivery systems of thermo‐responsive poly(N‐vinylcaprolactam) (PVCL)‐based, pH‐responsive poly(2‐(diethylamino)ethyl) methacrylate (PDEAEMA)‐based, and thermo‐, and pH‐responsive PDEAEMA/PVCL‐based core–shell nanogels are reported. All the nanogels have been synthesized using different dextran‐methacrylates (Dex‐MAs) as macro‐cross‐linkers. Doxorubicin hydrochloride (DOXO), an anticancer drug, has been effectively loaded into nanogels via hydrogen‐bonding interactions between ? OH groups of DOXO and ? OH groups of Dex‐MA chains. Drug‐release profiles at various pHs, and the cytocompatibility of the DOXO‐loaded nanogels have been assessed in vitro using cervical cancer HeLa and breast cancer MDA‐MB‐231 cell lines. In all the cases, the DOXO release is controlled by Fickian diffusion and case‐II transport, being the diffusional process dominant. In addition, DOXO‐loaded nanogels are efficiently internalized by HeLa and MDA‐MB‐231 cells and DOXO is progressively released in time. Therefore, nanogels synthesized could be suitable and potentially useful as nanocarriers for antitumor drug delivery. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1694–1705     

Synthesis,Structure, and Properties of O6‐Corona[3]arene[3]tetrazines

O₆‐Corona[3]arene[3]tetraazines, a new class of macrocyclic compounds, were synthesized efficiently in a one‐pot reaction from the nucleophilic aromatic substitution reaction between 1,4‐dihydroxybenzene derivatives and 3,6‐dichlorotetrazine in warm acetonitrile. In the crystalline structure, the resulting macrocycles adopt highly symmetric structures of a regular hexagonal cavity with all bridging oxygen atoms and tetrazine rings located on the same plane with phenylene units orthogonally orientated. The constitutional aromatic rings are able to rotate around the macrocyclic annulus, depending on the steric effect of the substituents and temperature, in solution. The electron‐deficient nature revealed by cyclic voltammetry, differential pulse voltammetry, and characteristic absorbances at a visible region show the O₆‐corona[3]arene[3]tetrazines to be suitable macrocyclic receptors for electron‐rich guests.     

Hybrid alginate beads with thermal‐responsive gates for smart drug delivery

Polysaccharide‐based thermo‐responsive material was prepared by grafting PNIPAAm onto hybrid alginate beads, in which a biomineralized polyelectrolyte layer was constructed aiming to enhance the mechanical strength and ensure higher graft efficiency. XPS results demonstrated that the incorporation of PNIPAAm to the hybrid beads was successful, and the PNIPAAm‐grafted beads were more hydrophilic than the ungrafted ones as indicated by their swelling behavior. The drug release behaviors revealed that the grafted beads were both thermo‐ and pH‐sensitive, and the PNIPAAm existed in the pores of the alginate beads acted as the “on–off” gates: the pores of the beads were covered by the stretched PNIPAAm to delay the drug release at 25°C and opened to accelerate the drug release at 37°C because of the shrinking of PNIPAAm molecules. This paper would be a useful example of grafting thermo‐responsive polymers onto biodegradable natural polymer substrate. The obtained beads provide a new mode of behavior for thermo‐responsive “smart” polysaccharide materials, which is highly attractive for targeting drug delivery system and chemical separation. Copyright © 2010 John Wiley & Sons, Ltd.     

Supramolecular Drug Delivery Systems Based on Water‐Soluble Pillar[n]arenes

Supramolecular drug delivery systems (SDDSs), including various kinds of nanostructures that are assembled by reversible noncovalent interactions, have attracted considerable attention as ideal drug carriers owing to their fascinating ability to undergo dynamic switching of structure, morphology, and function in response to various external stimuli, which provides a flexible and robust platform for designing and developing functional and smart supramolecular nano‐drug carriers. Pillar[n]arenes represent a new generation of macrocyclic hosts, which have unique structures and excellent properties in host–guest chemistry. This account describes recent progress in our group to develop pillararene‐based stimuli‐responsive supramolecular nanostructures constructed by reversible host–guest interactions for controllable anticancer drug delivery. The potential applications of these supramolecular drug carriers in cancer treatment and the fundamental questions facing SDDSs are also discussed.

     

Lead‐sensitive PNIPAM microgels modified with crown ether groups

A series of lead‐sensitive poly(N‐isopropylacrylamide) microgels with pendant crown ether groups were prepared. Their cation‐sensitive behaviors were studied by dynamic light scattering. When ionic strength is not controlled, adding salts causes the microgel particles to deswell. However, when the salt effect is ruled out by keeping a constant ionic strength, adding Pb²⁺ results in much larger swelling. The Pb²⁺‐induced swelling was explained by the formation of host–guest complex between Pb²⁺ and the pendant crown ether groups, which increases the hydrophilicity of the polymer and accordingly the degree of swelling. The lead sensitivity of the microgels increases with increasing crown ether content. For the modified microgel with the highest crown ether content, it swells to ～430% of its original volume at [Pb²⁺] = 10 mM. Other cations also increase the swelling degree of the modified microgels. The extent of the cation‐induced swelling mainly depends on their affinity to the pendant crown ether groups. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 4120–4127, 2010     

Complexation Between (O‐Methyl)6‐2,6‐Helic[6]arene and Tertiary Ammonium Salts: Acid/Base‐ or Chloride‐Ion‐Responsive Host–Guest Systems and Synthesis of [2]Rotaxane

Complexation between (O ‐methyl)₆‐2,6‐helic[6]arene and a series of tertiary ammonium salts was described. It was found that the macrocycle could form stable complexes with the tested aromatic and aliphatic tertiary ammonium salts, which were evidenced by ¹H NMR spectra, ESI mass spectra, and DFT calculations. In particular, the binding and release process of the guests in the complexes could be efficiently controlled by acid/base or chloride ions, which represents the first acid/base‐ and chloride‐ion‐responsive host–guest systems based on macrocyclic arenes and protonated tertiary ammonium salts. Moreover, the first 2,6‐helic[6]arene‐based [2]rotaxane was also synthesized from the condensation between the host–guest complex and isocyanate.     

Noncovalently connected micelles based on a β‐cyclodextrin‐containing polymer and adamantane end‐capped poly(ε‐caprolactone) via host–guest interactions

New random copolymers, poly(N‐vinyl‐2‐pyrrolidone‐co‐mono‐6‐deoxy‐6‐methacrylate ethylamino‐β‐cyclodextrin) (PnvpCD) bearing pendent β‐cyclodextrin (CD) groups were synthesized. PnvpCD formed soluble graft‐like polymer complex with adamantane (AD) end‐capped poly(ε‐caprolactone) (PclAD) in their common solvent N‐methyl‐2‐pyrrolidone driven by the inclusion interactions between the CD and AD groups. The formation of the graft complex has been confirmed by viscometry, dynamic light scattering (DLS), and isothermal titration calorimeter. The graft complex self‐assembled further into noncovalently connected micelles in water, which is a selective solvent for the main chain PnvpCD. Transmission electron microscopy, DLS, and atomic force microscopy have been used to investigate the structure and morphology of the resultant micelles. A unique “multicore” structure of the micelles, in which small PclAD domains scattered within the micelles, was obtained under nonequilibrium conditions in the preparation. However, the micelles prepared in a condition close to equilibrium possess an ordinary core‐shell structure. In both cases, the core and shell are believed to be connected by the AD‐CD inclusion complexation. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4267–4278, 2009