pH‐responsive polymer core–shell nanospheres for drug delivery

Stimuli‐responsive polymer nanoparticles are playing an increasingly more important role in drug delivery applications. However, limited knowledge has been accumulated about processes which use stimuli‐responsive polymer nanospheres (matrix nanoparticles whose entire mass is solid) to carry and deliver hydrophobic therapeutics in aqueous solution. In this research, pyrene was selected as a model hydrophobic drug and a pyrene‐loaded core‐shell structured nanosphere named poly(DEAEMA)‐poly(PEGMA) was designed as a drug carrier where DEAEMA and PEGMA represent 2‐(diethylamino)ethyl methacrylate and poly(ethylene glycol) methacrylate, respectively. The pyrene‐loaded core‐shell nanospheres were prepared via an in situ two‐step semibatch emulsion polymerization method. The particle size of the core‐shell nanosphere can be well controlled through adjusting the level of surfactant used in the polymerization where an average particle diameter of below 100 nm was readily achieved. The surfactant was removed via a dialysis operation after polymerization. Egg lecithin vesicles (liposome) were prepared to mimic the membrane of a cell and to receive the released pyrene from the nanosphere carriers. The in vitro release profiles of pyrene toward different pH liposome vesicles were recorded as a function of time at 37 °C. It was found that release of pyrene from the core‐shell polymer matrix can be triggered by a change in the environmental pH. In particular the pyrene‐loaded nanospheres are capable of responding to a narrow window of pH change from pH = 5, 6, to 7 and can achieve a significant pyrene release of above 80% within 90 h. The rate of release increased with a decrease in pH. A first‐order kinetic model was proposed to describe the rate of release with respect to the concentration of pyrene in the polymer matrix. The first‐order rate constant of release k was thus determined as 0.049 h^?1 for pH = 5; 0.043 h^?1 for pH = 6; and 0.035 h^?1 for pH = 7 at 37 °C. The release of pyrene was considered to follow a diffusion‐controlled mechanism. The synthesis and encapsulation process developed herein provides a new approach to prepare smart nanoparticles for efficient delivery of hydrophobic drugs. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4440–4450     

Magnetic‐targeted pH‐responsive drug delivery system via layer‐by‐layer self‐assembly of polyelectrolytes onto drug‐containing emulsion droplets and its controlled release

Novel magnetic‐targeted pH‐responsive drug delivery system have been designed by the layer‐by‐layer self‐ assembly of the polyelectrolytes (oligochitosan as the polycation and sodium alginate as the polyanion) via the electrostatic interaction with the oil‐in‐water type hybrid emulsion droplets containing the superparamagnetic ferroferric oxide nanoparticles and drug molecules [dipyridamole (DIP)] as cores. Here the drug molecules were directly encapsulated into the interior of droplets without etching the templates and refilling with the desired guest molecules. The drug‐delivery system showed high encapsulation efficiency of drugs and drug‐loading capacity. The cumulative release ratio of dipyridamole from the oligochitosan/sodium alginate multilayer‐encapsulated magnetic hybrid emulsion droplets (DIP/Fe₃O₄‐OA/OA)@(OCS/SAL)₄ was up to almost 100% after 31 h at pH 1.8. However, the cumulative release ratio was only 3.3% at pH 7.4 even after 48 h. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

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     

Synthesis and characterization of biodegradable pH and reduction dual‐sensitive polymeric micelles for doxorubicin delivery

Novel pH and reduction dual‐sensitive biodegradable polymeric micelles for efficient intracellular delivery of anticancer drugs were prepared based on a block copolymer of methyloxy‐poly(ethylene glycol)‐b‐poly[(benzyl‐l ‐aspartate)‐co‐(N‐(3‐aminopropyl) imidazole‐l ‐aspartamide)] [mPEG‐SS‐P(BLA‐co‐APILA), MPBA] synthesized by a combination of ring‐opening polymerization and side‐chain reaction. The pH/reduction‐responsive behavior of MPBA was observed by both dynamic light scattering and UV–vis experiments. The polymeric micelles and DOX‐loaded micelles could be prepared simply by adjusting the pH of the polymer solution without the use of any organic solvents. The drug release study indicated that the DOX‐loaded micelles showed retarded drug release in phosphate‐buffered saline at pH 7.4 and a rapid release after exposure to weakly acidic or reductive environment. The empty micelles were nontoxic and the DOX‐loaded micelles displayed obvious anticancer activity similar to free DOX against HeLa cells. Confocal microscopy observation demonstrated that the DOX‐loaded MPBA micelles can be quickly internalized into the cells, and effectively deliver the drugs into nuclei. Thus, the pH and reduction dual‐responsive MPBA polymeric micelles are an attractive platform to achieve the fast intracellular release of anticancer drugs. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1771–1780     

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.

     

Synthesis and self‐assembly of multiple‐responsive magnetic nanogels

In this paper, temperature and pH‐sensitive interpenetrating polymer network (IPN) nanogels (NGs) were firstly prepared, and magnetic hybrid NGs were made through in‐situ precipitation of Fe²⁺ and Fe³⁺ into the IPN NGs. Under the optimized condition, the resulting hybrid NG dispersion with up to 17.3 wt% magnetite was stable, while the size distribution of the NGs is broad due to the formation of Fe₃O₄ nanoparticles outside the NGs. In order to synthesize relatively uniform magnetic NGs, magnetite content was reduced to 8.1 wt% magnetite. The NGs with 8.1 wt% magnetite can quickly self‐assemble into colloidal crystals induced by magnet, while such NGs slowly self‐assembled into colloidal crystals without external magnetic field. Furthermore, the reflection wavelength of the self‐assembled magnetic NGs showed red‐shift with increasing pH and temperature.     

Dendritic Polyglycerol‐Derived Nano‐Architectures as Delivery Platforms of Gemcitabine for Pancreatic Cancer

Dendritic polyglycerol‐co‐polycaprolactone (PG‐co‐PCL)‐derived block copolymers are synthesized and explored as nanoscale drug delivery platforms for a chemotherapeutic agent, gemcitabine (GEM), which is the cornerstone of therapy for pancreatic ductal adenocarcinoma (PDAC). Current treatment strategies with GEM result in suboptimal therapeutic outcome owing to microenvironmental resistance and rapid metabolic degradation of GEM. To address these challenges, physicochemical and cell‐biological properties of both covalently conjugated and non‐covalently stabilized variants of GEM‐containing PG‐co‐PCL architectures have been evaluated. Self‐assembly behavior, drug loading and release capacity, cytotoxicity, and cellular uptake properties of these constructs in monolayer and in spheroid cultures of PDAC cells are investigated. To realize the covalently conjugated carrier systems, GEM, in conjunction with a tertiary amine, is attached to the polycarbonate block grafted from the PG‐co‐PCL core. It is observed that pH‐dependent ionization properties of these amine side‐chains direct the formation of self‐assembly of block copolymers in the form of nanoparticles. For non‐covalent encapsulation, a facile “solvent‐shifting” technique is adopted. Fabrication techniques are found to control colloidal and cellular properties of GEM‐loaded nanoconstructs. The feasibility and potential of these newly developed architectures for designing carrier systems for GEM to achieve augmented prognosis for pancreatic cancer are reported.     

Synthesis and characterization of biodegradable amphiphilic ABC Y‐shaped miktoarm terpolymer by click chemistry for drug delivery

Biodegradable amphiphilic ABC Y‐shaped triblock copolymer (MPBC) containing PEG, PBLA, and PCL segments was synthesized via the combination of enzymatic ring‐opening polymerization (ROP) of epsilon‐caprolactone, ROP of BLA‐N‐carboxyanhydride and click chemistry, where PEG, PBLA, and PCL are poly(ethylene glycol), poly(benzyl‐l ‐aspartate), and polycaprolactone, respectively. Propynylamine was employed as ROP initiator for the preparation of alkynyl‐terminated PBLA and methyloxy‐PEG with hydroxyl and azide groups at the chain‐end was used as enzymatic ROP initiator for synthesis of monoazido‐midfunctionalized block copolymer mPEG‐b‐PCL. The subsequent click reaction led to the formation of Y‐shaped asymmetric heteroarm terpolymer MPBC. The polymer structures were characterized by different analyses. The MPBC terpolymer self‐assembled into micelles and physically encapsulated drug doxorubicin (DOX) to form DOX‐loaded micelles, which showed good stability and slow drug release. In vitro cytotoxicity study indicated that the MPBC micelles were nontoxic and the DOX‐loaded micelles displayed obvious anticancer activity similar to free DOX against HeLa cells. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3346–3355     

Biomimetic pH/redox dual stimuli‐responsive zwitterionic polymer block poly(L‐histidine) micelles for intracellular delivery of doxorubicin into tumor cells

A series of pH/redox dual stimuli‐responsive poly(2‐methacryloyloxyethyl phosphorylcholine)₂₅‐block‐poly(l ‐histidine)_n (p[MPC])₂₅‐b‐p[His]_n, n = 20, 35, 50, and 75) copolymers consisting of a pH‐responsive p(His)_n block and a biocompatible phospholipid analog p(MPC) block connected by a redox‐responsive disulfide linker have been synthesized. The block copolymers are self‐assembled into uniform micelles (～100 nm) in which doxorubicin (Dox) is efficiently encapsulated. The in vitro release profile shows an enhanced release of Dox at low pH (5.0) in 10 mM glutathione (GSH). The in vitro cell viability assays performed using various cell lines show that the blank hybrid micelles have no acute or intrinsic toxicity. A pH‐dependent cytotoxicity is observed with the Dox‐loaded micelles, especially at pH 5.0. Moreover, confocal microscopy images and flow cytometry results show the pH‐dependent cellular uptake of Dox‐loaded micelles. Therefore, the Dox‐loaded micelles can be considered a good candidate for cancer therapy. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 2061–2070     

Yoctowell Cavities on Magnetic Silica Nanoparticles for pH Stimuli‐Responsive Controlled Release of Drug Molecules

Drug‐delivery systems that medically transport active molecules to diseased cells, in a controlled manner, have gained much attention in recent years. Yoctowell (1 yL=8 nm³ that is, 10^?24 L volume) cavities on magnetic silica nanoparticles were used for the encapsulation and release of the drug molecule, “mitoxantrone ( MTZ )”, and controlled using naturally occurring stimuli, that is, pH. First, MTZ was encapsulated from a bulk solution under physiological conditions, and then released from the yoctowells, in a controlled manner, by manipulating the pH (7.2–3.0). The sustained release of MTZ , the recovery of active yoctowells after the release process and magnetic properties of nanoparticles provide potential for development of a new generation of drug‐delivery system.     

Synthesis of pH‐responsive photocrosslinked hyaluronic acid‐based hydrogels for drug delivery

Photocrosslinked hyaluronic acid/poly(vinyl alcohol)‐styrylpyridinium (HA/PVA‐SbQ) hydrogels were synthesized for controlled antitumor drug delivery. The photocrosslinking reaction was rapid, and the time required for completely converting into the insoluble hydrogels was less than 500 s on exposure to 5 mW/cm² UV light irradiation. The resulting hydrogels exhibited sensitivity to the pH value of the surrounding environment. Scanning electron microscopic analysis revealed that the morphology and the pore size of the hydrogels could be controlled by changing the ratio of HA and PVA‐SbQ in the formulations. Paclitaxel (PTX)‐loaded hydrogel could also be formed rapidly by UV irradiation of a mixed solution of HA/PVA‐SbQ and PTX. Release profiles of PTX from the hydrogels showed pH‐dependent and sustained manner. Moreover, our data revealed that PTX released from the HA hydrogels remained biologically active and had the capability to kill cancer cells. In contrast, control groups of HA hydrogels without PTX did not exhibit any cytotoxicity. This study demonstrates the feasibility of using HA‐based hydrogels as a potential carrier for chemotherapeutic drugs for cancer treatments. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Novel hepatoma‐targeting micelles based on chemoenzymatic synthesis and self‐assembly of galactose‐functionalized ribavirin‐containing amphiphilic random copolymer

Hepatoma‐targeting micelles were successfully prepared by self‐assembly of galactose‐functionalized ribavirin‐containing amphiphilic random copolymer as novel drug delivery vehicles. The ribavirin‐containing random copolymer with galactose as the targeting ligand was facilely synthesized by combining enzymatic transesterification with radical polymerization and fully characterized by FTIR, NMR, and GPC. The formation of micelle‐type aggregates from the random copolymer was verified by UV–vis and fluorescence spectroscopy using pyrene as the guest molecule. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) experiments revealed that the micelles were well dispersed as spherical nanoparticles in water, whose hydrodynamic diameter was 217 ± 19 nm. Their biological recognition to fluorescein‐labeled peanut agglutinin investigated by confocal laser scanning microscopy (CLSM) proved the existence of hydrophilic galactose targeting moieties on the surface of micelles. Cell cytotoxicity tests and the inhibition experiment of galactose performed by MTT assay showed that the micelles had evident targeting function to hepG2 cells and the galactose moieties on the surface of micelles mediated cellar uptake of micelles. In vitro release studies indicated that ribavirin could be slowly released from the copolymer with pseudo zero‐order kinetics. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2734–2744, 2008     

Synthesis and physicochemical characterization of biodegradable and pH‐responsive hydrogels based on polyphosphoester for protein delivery

In this work, a series of biodegradable and pH‐responsive hydrogels based on polyphosphoester and poly(acrylic acid) are presented. A novel biodegradable macrocrosslinker α‐methacryloyloxyethyl ω‐acryloyl poly(ethyl ethylene phosphate) (HEMA‐PEOP‐Ac) was synthesized by first ring‐opening polymerization of the cyclic monomer 2‐ethoxy‐2‐oxo‐1,3,2‐dioxaphospholane using HEMA as the initiator and Sn(Oct)₂ as catalyst, and subsequent conversion of hydroxyl into vinyl group. The hydrogels were then fabricated by the copolymerization of the macromonomer with acrylic acid, and their swelling/deswelling and degradation behaviors were investigated. The results demonstrated that the crosslinking density and pH values of media strongly influenced both the swelling ratio and the degradation rate of the hydrogels. The rheological properties of these hydrogels were also studied from which the storage modulus (G′) showed clear dependence on the crosslinking density. MTT and “live/dead” assay showed that these hydrogels were compatible to fibroblast cells, not exhibiting apparent cytotoxicity even at high concentrations. Moreover, in vitro bovine serum albumin release from these hydrogels was also investigated, and it could be found that the release profiles showed a burst effect followed by a continuous release phase, and the release rate was inversely proportional to the crosslinking density of hydrogels. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1919–1930, 2010     

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     

Self‐Assembled Micelles Based on PEG‐Polypeptide Hybrid Copolymers for Drug Delivery

A series of amphiphilic poly(L ‐leucine)‐block‐poly(ethylene glycol)‐block‐poly(L ‐leucine) (PLL‐PEG‐PLL) hybrid triblock copolymers have been synthesized. All the blocks in this system have good biocompatibility and low toxicity. The PLL‐PEG‐PLL copolymers could self‐assemble into micelles with PLL blocks as the hydrophobic core and PEG blocks as the hydrophilic shell, which were characterized by FT‐IR, ¹H NMR, and transmission electron microscopy analysis. The critical micellar concentration of the copolymer was 95.0 mg · L⁻¹. The circular dichroism spectrum shows that the PLL segments adopt a unique α‐helical conformation, which is found to play an important role in controlling the drug release rate. The drug release could be effectively sustained by encapsulation in the micelles. The copolymers may have potential applications in drug delivery.

     

Synthesis and self‐assembly of novel amphiphilic copolymers poly(lactic acid)‐block‐poly(ascorbyl acrylate)

In this study, a novel type of amphiphilic block copolymers poly(lactic acid)‐block‐poly(ascorbyl acrylate) (PLA‐block‐PAAA) with biodegradable poly(lactic acid) as hydrophobic block and poly(ascorbyl acrylate) (PAAA) as hydrophilic block was successfully developed by a combination of ring‐opening polymerization and atom transfer radical polymerization, followed by hydrogenation under normal pressure. The chemical structures of the desired copolymers were characterized by ¹H NMR and gel permeation chromatography. The thermal physical properties and crystallinity were investigated by thermogravimetric analysis, differential scanning calorimetry, and wide angle X‐ray diffraction, respectively. Their self‐assembly behavior was monitored by fluorescence‐probe technique and turbidity change using UV–vis spectrometer, and the morphology and size of the nanocarriers via self‐assembly were detected by cryo‐transmission electron microscopy and dynamic light scattering. These polymeric micelles with PAAA shell extending into the aqueous solution have potential abilities to act as promising nanovehicles for targeting drug delivery. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis of chitosan‐based thermo‐ and pH‐responsive porous nanoparticles by temperature‐dependent self‐assembly method and their application in drug release

In this research, thermo‐ and pH‐responsive chitosan‐based porous nanoparticles were prepared by the temperature‐dependent self assembly method. The chitosan‐graft‐poly(N‐isopropylacrylamide) (CS‐g‐PNIPAAm) copolymer solution was prepared through polymerization of N‐isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) solution using cerium ammounium nitrate as the initiator. Then, CS‐g‐PNIPAAm solution was diluted by deionized water and heated to 40 °C for CS‐g‐PNIPAAm self‐assembly. After that, CS‐g‐PNIPAAm assembled to form micelles in which shell layer was CS. Crosslinking agent was used to reinforce the micelle structure to form nanoparticle. The molar ratio of CS/NIPAAm in the feed mixture was changed to investigate its effect on structure, morphology, thermal‐ and pH‐responsive properties of the nanoparticles. TEM images showed that a porous structure of nanoparticles was developed. The synthesized nanoparticles carried positive charges on the surface and 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. These porous particles with environmentally sensitive properties are expected to be utilized in hydrophilic drug delivery system. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5126–5136, 2009