Hollow mesoporous silica nanoparticles modified with coumarin‐containing copolymer for photo‐modulated loading and releasing guest molecule

Hollow mesoporous silica nanoparticles (HMSNs) grafted with a photo‐responsive copolymer containing coumarin groups were successfully prepared. With uniform polystyrene nanoparticles and cetyltrimethylammonium bromide correspondingly as the template of core and channel, HMSNs were made from tetraethyloxysilane in alkalic condition. Epoxy groups were introduced onto the outer surface of HMSNs with γ‐(2,3‐epoxypropoxy)propyltrimethoxysilane and converted into azido groups with sodium azide, resulting in azido‐functionalized HMSNs (azido‐HMSNs). Meanwhile, single‐electron transfer‐living radical copolymerization of methyl methacrylate (MMA) and 7‐(2‐methacryloyloxy)‐4‐methylcoumarin (CMA) with propargyl 2‐bromoisobutyrate as the initiator produced alkynyl‐capped P(MMA‐co‐CMA) [alkynyl‐P(MMA‐co‐CMA)]. Finally, photo‐responsive HMSNs grafted with P(MMA‐co‐CMA) [HMSN‐g‐P(MMA‐co‐CMA)] was achieved through the click reaction between azido‐HMSNs and alkynyl‐P(MMA‐co‐CMA). Different techniques such as transmission electron microscopy, Fourier transform infrared spectroscopy, and thermal gravimetric analysis confirmed the successful preparation of the resultant hybrid nanoparticles and their intermediates. Because of its hollow core, mesoporous shell channels and light responsiveness, the coumarin‐modified HMSNs would be an interesting nano‐vehicle for guest molecules. Thus, the loading and release of pyrene with HMSN‐g‐P(MMA‐co‐CMA) was studied. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3791–3799     

Interfacial crosslinking of self‐assembled triblock copolymer nanoparticles via alkoxysilane hydrolysis and condensation

The use of amphiphilic triblock copolymers bearing a reactive alkoxysilane middle block as polymeric stabilizers is reported in this work. A series of poly(ethylene glycol) methyl ether methacrylate‐b‐(3‐trimethoxysilyl)propyl methacrylate‐b‐benzyl methacrylate (PEGMA‐b‐MPS‐b‐BzMA) triblock copolymers were prepared by RAFT solution polymerization and polymerization‐induced self‐assembly (PISA), respectively, where the various block lengths and overall composition were varied. The copolymers prepared by solution polymerization were employed as oil‐in‐water stabilizers where upon application of a catalyst, the 3‐(trimethoxysilyl)propyl methacrylate (MPS) block at the droplet interface was crosslinked to yield capsule‐like structures. The effectiveness of interfacial crosslinking was validated by dynamic light scattering and electron microscopy. In situ self‐assembly by the PISA method resulted in spherical nanoparticles of controllable size that were readily crosslinked by addition of base, with significant enhancement of colloidal stability. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1897–1907     

Behaviors of self‐assembled diblock copolymer with pendant photosensitive azobenzene segments

A novel monomer, ethyl 4‐[4‐(11‐methacryloyloxyundecyloxy)phenyl azobenzoyl‐oxyl] benzoate, containing a photoisomerizable N?N group was synthesized. The monomer was further diblock copolymerized with methyl methacrylate. Amphiphilic diblock copolymer poly(methyl methacrylate‐block‐ethyl 4‐[4‐(11‐methacryloyloxyundecyloxy)phenyl azobenzoyl‐oxyl] benzoate ( PMMA ‐ b ‐ PAzoMA ) was synthesized using atom transfer radical polymerization. The reverse micelles with spherical construction were obtained with 2 wt % of the diblock copolymer in a THF/H₂O mixture of 1:2. Under alternating UV and visible light illumination, reversible changes in micellar structure between sphere and rod‐like particles took place as a result of the reversible E‐Z photoisomerization of azobenzene segments in PMMA ‐ b ‐ PAzoMA . Microphase separation of the amphiphilic diblock copolymer in thin films was achieved through thermal and solvent aligning methods. The microphases of the annealed thin films were investigated using atom force microscopy topology and scanning electron microscopy analyses. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1142–1148, 2010     

Polyaspartamide-graft-polymethacrylate nanoparticles for doxorubicin delivery

A new PHEA‐IB‐PMANa⁺ copolymer has been synthesized and its pH‐induced self‐assembly has been investigated in an aqueous medium. PHEA‐IB‐PMANa⁺ formed nanoparticles with diameters from 25 to 50 nm upon protonation of the carboxylic acid moieties dislocated along the grafted polymethacrylate sodium salt side chains. The physico‐chemical characterization of the nanoparticles was performed using light scattering, zeta‐potential measurements, SEM, and AFM. Doxorubicin‐loaded nanoparticles were prepared and drug release profiles were evaluated under conditions mimicking physiological media. A biological characterization was carried out by testing the cytotoxicity on Caco‐2 cells, and cellular uptake on mouse monocyte macrophage (J774 A.1) and Caco‐2 cells.

     

Block copolymer nanoparticles of controlled sizes via ring‐opening metathesis polymerization

This article describes the formation and characterization of self‐assembled nanoparticles of controlled sizes based on amphiphilic block copolymers synthesized by ring‐opening metathesis polymerization. We synthesized a novel hydrophobic derivative of norbornene; this monomer could be polymerized using Grubbs' catalyst [Cl₂Ru(CHPh)(PCy₃)₂] forming polymers of controlled molecular weight. We synthesized amphiphilic block copolymers of controlled composition and showed that they assemble into nanoparticles of controlled size. The nanoparticles were characterized using dynamic light scattering and transmission electron microscopy. Tuning the composition of the block copolymer enables the tuning of the diameters of the nanoparticles in the 30‐ to 80‐nm range. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 3352–3359, 2004     

pH‐responsive near‐infrared emitting conjugated polymer nanoparticles for cellular imaging and controlled‐drug delivery

In this article, pH‐responsive near‐infrared emitting conjugated polymer nanoparticles (CPNs) are prepared, characterized, and their stabilities are investigated under various conditions. These nanoparticles have capacity to be loaded with water insoluble, anticancer drug, camptothecin (CPT), with around 10% drug loading efficiency. The in vitro release studies demonstrate that the release of CPTs from CPNs is pH‐dependent such that significantly faster drug release at mildly acidic pH of 5.0 compared with physiological pH 7.4 is observed. Time and dose‐dependent in vitro cytotoxicity tests of blank and CPT‐loaded nanoparticles are performed by real‐time cell electronic sensing (RT‐CES) assay with hepatocellular carcinoma cells (Huh7). The results indicate that CPNs can be effectively utilized as vehicles for pH‐triggered release of anticancer drugs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 114–122     

Co‐delivery of 10‐Hydroxycamptothecin with Doxorubicin Conjugated Prodrugs for Enhanced Anticancer Efficacy

Well‐defined amphiphilic linear‐dendritic prodrugs (MPEG‐b‐PAMAM‐DOX) are synthesized by conjugating doxorubicin (DOX), to MPEG‐b‐PAMAM through the acid‐labile hydrazone bond. The amphiphilic prodrugs form self‐assembled nanoparticles in deionized water and encapsulate the hydrophobic anticancer drug 10‐hydroxycamptothecin (HCPT) with a high drug loading efficiency. Studies on drug release and cellular uptake of the co‐delivery system reveal that both drugs are released in a pH‐dependent manner and effectively taken up by MCF‐7 cells. In vitro methyl thiazolyl tetrazolium (MTT) assays and drug‐induced apoptosis tests demonstrate the HCPT‐loaded nanoparticles suppress cancer cell growth more efficiently than the MPEG‐b‐PAMAM‐DOX prodrugs, free HCPT, and physical mixtures of MPEG‐b‐PAMAM‐DOX and HCPT at equivalent DOX or HCPT doses.

     

PEG‐b‐PtBA‐b‐PHEMA well‐defined amphiphilic triblock copolymer: Synthesis,self‐assembly,and application in drug delivery

A series of well‐defined amphiphilic triblock copolymers, poly(ethylene glycol)‐b‐poly(tert‐butyl acrylate)‐b‐poly(2‐hydroxyethyl methacrylate) (PEG‐b‐PtBA‐b‐PHEMA), were synthesized via successive atom transfer radical polymerization (ATRP). ATRP of tBA was first initiated by PEG‐Br macroinitiator using CuBr/N,N,N′,N″,N′″‐pentamethyldiethylenetriamine as catalytic system to give PEG‐b‐PtBA diblock copolymer. This copolymer was then used as macroinitiator to initiate ATRP of HEMA, which afforded the target triblock copolymer, PEG‐b‐PtBA‐b‐PHEMA. The critical micelle concentrations of obtained amphiphilic triblock copolymers were determined by fluorescence spectroscopy using N‐phenyl‐1‐naphthylamine as probe. The morphology and size of formed aggregates were investigated by transmission electron microscopy and dynamic light scattering, respectively. Finally, an acid‐sensitive PEG‐b‐PtBA‐b‐P(HEMA‐CAD) prodrug via cis‐aconityl linkage between doxorubicin and hydroxyls of triblock copolymers with a high drug loading content up to 38%, was prepared to preliminarily explore the application of triblock copolymer in drug delivery. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Optimization of bioreducible micelles self‐assembled from amphiphilic hyperbranched block copolymers for drug delivery

Dendritic polymers‐based unimolecular micelles with enhanced stability are attractive carriers. However, the preparation of dendrimers or dendrons with higher generation remains substantially synthetic challenge due to the increased steric hindrance, multistep and tedious preparation, and low yields. The adoption of Boltorn H40, a commercially available dendritic polymer of Boltorn family containing multiple hydroxyl groups with various functionalities as a dendrimer‐based starting core template for the generation of hyperbranched polymers, offers a straightforward solution to address this problem. To develop universal strategies toward H40‐based amphiphilic block copolymers, the “grafting from” and “grafting to” approaches were both applied in this study. The reduction‐insensitive block copolymers, H40‐b‐poly(ɛ‐caprolactone)‐b‐poly(oligo(ethylene glycol) monomethyl ether methacrylate) (H40‐b‐PCL‐b‐POEGMA), were synthesized by “grafting from” including sequential ring‐opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The core structure and the polymer composition of the nonreducible amphiphilic hyperbranched block copolymers were optimized toward better properties and performance for drug delivery applications, and H40‐PCL₁₅‐b‐POEGMA₂₃ was screened as the best polymer construct relative to H20‐PCL₁₅‐b‐POEGMA₂₃ and H40‐PCL₁₅‐b‐POEGMA₃₂ in terms of micelle stability and drug loading capacity. Therefore, the reducible H40‐b‐PCL‐SS‐POEGMA with an identical core and polymer composition to that of H40‐PCL₁₅‐b‐POEGMA₂₃ was further prepared by “grafting to” using click coupling between H40‐PCL‐azide and P(OEGMA)‐alkyne. The delivery efficacy evaluated by an in vitro cytotoxicity study revealed that the resulting DOX‐loaded reducible micelles of H40‐PCL₁₅‐SS‐POEGMA₂₃ produced greater cytotoxicity in cancer cells than in normal cells and macrophages, therefore, are promising carriers for anticancer drug delivery. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1383–1394     

Block copolymer micelles conjugated with anti‐EGFR antibody for targeted delivery of anticancer drug

Antiepidermal growth factor receptor antibody (anti‐EGFR antibody) was conjugated with the block copolymer micelle based on poly(ethylene glycol) (PEG) and poly(ε‐caprolactone) (PCL) for active targeting to EGFR overexpressing cancer cells. Doxorubicin (DOX) was encapsulated in the core of the block copolymer (MePEG‐b‐PCL) micelle (DOX‐micelle). The mean diameters of the DOX‐micelle and the anti‐EGFR‐PEG‐b‐PCL copolymer micelles loaded with DOX (DOX‐anti‐EGFR‐micelle) were about 25 and 31 nm, respectively. The RKO human colorectal cancer cells expressing moderate degree of EGFR were incubated with free DOX, DOX‐micelle, or DOX‐anti‐EGFR‐micelle to study the distribution of DOX in the cells. When cells were incubated with free DOX, moderate degree of DOX fluorescence was observed in the nuclei. In the cells treated with DOX‐micelle, the DOX fluorescence intensity in the cytoplasm was much greater than that in the nuclei. On the other hand, the nuclei of the cells treated with DOX‐anti‐EGFR‐micelle exhibited DOX fluorescence intensity similar to that in the cytoplasm. The cytotoxicity of DOX‐anti‐EGFR‐micelle to induce apoptosis in RKO cells was significantly greater than that of free DOX or DOX‐micelle. These results demonstrated that the presence of anti‐EGFR antibody on the DOX‐micelle surface (DOX‐anti‐EGFR‐micelle) increased the internalization of the DOX‐micelle and nuclear accumulation of DOX, and enhanced the DOX‐induced cell death. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7321–7331, 2008     

New Design of Thiol‐Responsive Degradable Polylactide‐Based Block Copolymer Micelles

A new design to synthesize thiol‐responsive degradable polylactide (PLA)‐based micelles having a disulfide linkage in the middle of triblock copolymers is reported. They were synthesized by a new method that centers on the use of a disulfide‐labeled diol as an initiator for ring‐opening polymerization, followed by controlled radical polymerization. These well‐controlled copolymers with monomodal and narrow molecular weight distribution (M _w/M _n < 1.15) self‐assembled to form aqueous micellar aggregates with disulfide‐containing PLA cores, which is not toxic to cells. Central disulfide linkages were cleaved in response to thiols; such thiol‐triggered degradation enhanced the release of encapsulated anticancer drugs.     

The Interaction of CORM‐2 with Block Copolymers Containing Poly(4‐vinylpyridine): Macromolecular Scaffolds for Carbon Monoxide Delivery in Biological Systems

CORM‐2, tricarbonyldichlororuthenium(II) dimer (Ru₂Cl₄(CO)₆), is a common carbon monoxide releasing molecule (CORM) studied both in vitro and in vivo, but this compound possesses poor water solubility and a short half‐life, which hinders its clinical development. Herein, for the first time the conjugation of CORM‐2 is reported with a copolymer containing poly(4‐vinylpyridine) to yield water‐soluble CO‐releasing polymeric nanoparticles. CORM‐2 is rapidly conjugated to copolymers through pyridine groups as confirmed by inductively coupled plasma‐optical emission spectroscopy and infrared spectroscopy. In comparison with free CORM‐2, the copolymers functionalized with CORM‐2 display better water solubility and the CO release from the polymer‐based CORM is slow and sustained. This study paves the way for the potential use of a copolymer encapsulating CORM‐2 as a therapeutic agent.

     

PNVCL‐PEGMA nanohydrogels with tailored transition temperature for controlled delivery of 5‐fluorouracil

Sensitive nanohydrogels were prepared via surfactant free emulsion copolymerization of N‐vinylcaprolactam and poly(ethylene glycol) methyl ether methacrylate, and either N‐vinylpyrrolidone (VP) or 2‐methacryloyloxybenzoic acid (2MBA) to adjust the transition temperature (T_tr). The crosslinker ethylene glycol dimethacrylate was used for the polymer network construction. The resulting nanohydrogel sizes are between 120 and 300 nm. ρ‐Parameter, obtained from light scattering studies, suggests that core‐sell nanogels of flexible chains were obtained. T_tr increases with increasing comonomer content (VP or 2MBA) and decreases with decreasing pH for 2MBA containing nanohydrogels. Nanohydrogels containing 15.5% of 2MBA exhibit T_tr close to 38 °C. Nanogels are able to control the release of the loaded antineoplastic drug 5‐fluorouracil. For the prepared T/pH‐sensitive nanogels, the release is slower at pH 7.4 and 37 °C than at tumor conditions: pH 6 and 40 °C. Mathematical models were applied to evaluate the kinetics of drug release; Peppas model fitted best indicating a Fickian diffusion trough a sphere. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2662–2672     

Synthesis of Imatinib‐loaded chitosan‐modified magnetic nanoparticles as an anti‐cancer agent for pH responsive targeted drug delivery

Targeted drug delivery is a promising approach to overcome the limitations of classical chemotherapy. In this respect, Imatinib‐loaded chitosan‐modified magnetic nanoparticles were prepared as a pH sensitive system for targeted delivery of drug to tumor sites by applying a magnetic field. The proposed magnetic nanoparticles were prepared through modification of magnetic Fe₃O₄ nanoparticles with chitosan and Imatinib. The structural, morphological and physicochemical properties of the synthesized nanoparticles were determined by different analytical techniques including energy‐dispersive X‐ray spectroscopy (EDS), field emission scanning electron microscopy (FESEM), Fourier‐transform infrared (FTIR) spectroscopy, high resolution transmission electron microscopy (HR‐TEM), vibrating sample magnetometry (VSM), X‐ray diffraction (XRD) and X‐ray photoelectron spectroscopy (XPS). UV/visible spectrophotometry was used to measure the Imatinib contents. Thermal stability of the prepared particles was investigated and their efficiency of drug loading and release profile were evaluated. The results demonstrated that Fe₃O₄@CS acts as a pH responsive nanocarrier in releasing the loaded Imatinib molecules. Furthermore, the Fe₃O₄@CS/Imatinib nanoparticles displayed cytotoxic effect against MCF‐7 breast cancer cells. Results of this study can provide new insights in the development of pH responsive targeted drug delivery systems to overcome the side effects of conventional chemotherapy.     

Optically active core/shell nanoparticles prepared using self‐assembled polymer micelle as reactive nanoreactor

This article reports on optically active core/shell nanoparticles constituted by chiral helical polymers and prepared by a novel approach: using self‐assembled polymer micelles as reactive nanoreactors. Such core/shell nanoparticles were composed of optically active helical‐substituted polyacetylene as the core and thermosensitive poly(N‐isopropylacrylamide) as the shell. The synthetic procedure is divided into three major steps: (1) synthesis of amphiphilic diblock copolymer bearing polymerizable C[tbond]C bonds via atom transfer radical polymerization, followed by (2) self‐assembly of the diblock copolymer to form polymer micelles; and (3) catalytic emulsion polymerization of substituted acetylene monomer conducted using the polymer micelles as reactive nanoreactors leading to the core/shell nanoparticles. The core/shell nanoparticles simultaneously exhibited remarkable optical activity and thermosensitivity. The facile, versatile synthesis methodology opens new approach toward preparing novel multifunctional core/shell nanoparticles.© 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis and properties of chitosan‐based thermo‐ and pH‐responsive nanoparticles and application in drug release

In this research, thermo‐ and pH‐responsive nanoparticles with an average diameter of about 50–200 nm were synthesized via the surfactant‐free emulsion polymerization. The thermal/pH dual responsive properties of these nanoparticles were designed by the addition of a pH sensitive monomer, acrylic acid (AA), to be copolymerized with N‐isopropylacrylamide (NIPAAm) in a chitosan (CS) solution. The molar ratio of CS/AA/NIPAAm in the feed was changed to investigate its effect on structure, morphology, thermal‐ and pH‐responsive properties of the nanoparticles. It was found that CS‐PAA‐PNIPAAm nanoparticles could be well dispersed in the aqueous solution and carried positive charges on the surface. The addition of thermal‐sensitive NIPAAm monomer affected the polymerization mechanism and interactions between CS and AA. The particle size of the nanoparticles was found to be varied with the composition of NIPAAm monomer in the feed. The synthesized nanoparticles exhibited stimuli‐responsive properties, and their mean diameter thus could be manipulated by changing pH value and temperature of the environment. The nanoparticles showed a continuous release of the encapsulated doxycycline hyclate up to 10 days during an in vitro release experiment. The environmentally responsive nanoparticles are expected to be used in many fields such as drug delivery system. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2798–2810, 2009     

Facile Generation of Tumor‐pH‐Labile Linkage‐Bridged Block Copolymers for Chemotherapeutic Delivery

Successful bench‐to‐bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor‐pH‐labile linkage‐bridged copolymers of clinically validated poly(d,l ‐lactide) and poly(ethylene glycol) (PEG‐Dlink_m‐PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG‐Dlink_m‐PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1 % in comparison to 47.8 % of the non‐responsive control. Furthermore, PEG‐Dlink_m‐PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG‐b‐PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.     

Hyperbranched poly (amine‐ester)‐poly (lactide‐co‐glycolide) copolymer and their nanoparticles as paclitaxel delivery system

A new hyperbranched poly (amine‐ester)‐poly (lactide‐co‐glycolide) copolymer (HPAE‐co‐PLGA) was synthesized by ring‐opening polymerization of D , L ‐lactide (DLLA) glycolid and branched poly (amine‐ester) (HPAE‐OHs) with Sn(Oct)₂ as catalyst. The chemical structures of copolymers were determined by FT‐IR, ¹H‐NMR(¹³C NMR), TGA and their molecular weights were determined by gel permeation chromatography (GPC). Paclitaxel‐loaded copolymer nanoparticles were prepared by the nanoprecipitation method. Their physicochemical characteristics, e.g. morphology and nanoparticles size distribution were then evaluated by means of fluorescence spectroscopy, environmental scanning electron microscopy (ESEM), and dynamic light scattering (DLS). Paclitaxel‐loaded nanoparticles assumed a spherical shape and have unimodal size distribution. It was found that the chemical composition of the nanoparticles was a key factor in controlling nanoparticles size, drug‐loading content, and drug release behavior. As the molar ratio of DL ‐lactide/glycolide to HPAE increased, the nanoparticles size and drug‐loading content increased, and the drug release rate decreased. The antitumor activity of the paclitaxel‐loaded HPAE‐co‐PLGA nanoparticles against human liver cancer H7402 cells was evaluated by 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) method. The paclitaxel‐loaded HPAE‐co‐PLGA nanoparticles showed comparable anticancer efficacy with the free drug. Copyright © 2010 John Wiley & Sons, Ltd.