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     

Synthesis and characterization of stimuli‐responsive porous/hollow nanoparticles by self‐assembly of chitosan‐based graft copolymers and application in drug release

In this research, stimuli‐responsive porous/hollow nanoparticles were prepared by the self‐assembly method. First, chitosan‐graft‐poly(N‐isopropylacrylamide) (CS‐g‐PNIPAAm) copolymers were synthesized through polymerization of N‐isopropylacrylamide (NIPAAm) monomer in the presence of chitosan (CS) solution using ceric ammounium nitrate as the initiator. Then, the CS‐g‐PNIPAAm copolymers were dissolved in the acetic acid aqueous solution and heated to 40 °C to induce their self‐assembly. After CS‐g‐PNIPAAm assembled to form micelles, a cross‐linking agent was used to reinforce the structure to form nanoparticles. The molecular weight of grafted PNIPAAm on CS chains was changed to investigate its effect on the structure, morphology, thermo‐, and pH‐responsive properties of the nanoparticles. TEM images showed that a porous or hollow structure in the interior of nanoparticles was developed, depending on the medium temperature. The synthesized nanoparticles carried positive charges on the surface and exhibited stimuli‐responsive properties, and their mean diameter thus could be manipulated by changing the 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/hollow particles with environmentally sensitive properties are expected to be used in hydrophilic drug delivery system. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2377–2387, 2010     

Dual pH and glucose sensitive gel gated mesoporous silica nanoparticles for drug delivery

A low-molecular-weight gel with dual pH and glucose sensitivity was designed as the gate controller for mesoporous silica nanoparticles (MSNs) to fabricate a smart drug delivery system. The smart gel caped MSNs could control the antidiabetic drug release via the detection of glucose and pH levels.     

Reversible aggregation of gold nanoparticles induced by pH dependent conformational transitions of a self-assembled polypeptide

Controlling the stable structures of metallic nanoparticles on mesoscopic and macroscopic length scales is of great interest in nanotechnology. Here, this task is accomplished using a synthetic biopolymer that is responsive to external stimuli and undergoes changes in secondary structure. Reversible aggregation of gold nanoparticles (GNP) is induced by pH dependent changes in a self-assembled monolayer of disulfide modified poly(L-glutamic acid) (SSPLGA) with M(w) approximately 27000. The disulfide anchoring group drives chemisorption onto the gold nanoparticles and leads to the formation of a self-assembled monolayer. Characterization of the modified GNP and its aggregation behavior is performed using dynamic light scattering (DLS), UV-vis and IR spectroscopy, and transmission electron microscopy (TEM). Experimental results show that decrease in pH near 5.5 leads to aggregation of the modified GNP. The change in aggregation behavior with pH occurs within minutes, is reversible, and happens within a narrow range of pH from about 4.5 to 5.5. Comparison with literature data on molar enthalpy of hydrogen bonding, specific optical rotation, and ionization for the helix-coil transition of PLGA indicates that the aggregation of the SSPLGA modified GNP corresponds to the transition in the secondary structure of the polyacid.     

Triplex DNA Nanostructures: From Basic Properties to Applications

Triplex nucleic acids have recently attracted interest as part of the rich “toolbox” of structures used to develop DNA‐based nanostructures and materials. This Review addresses the use of DNA triplexes to assemble sensing platforms and molecular switches. Furthermore, the pH‐induced, switchable assembly and dissociation of triplex‐DNA‐bridged nanostructures are presented. Specifically, the aggregation/deaggregation of nanoparticles, the reversible oligomerization of origami tiles and DNA circles, and the use of triplex DNA structures as functional units for the assembly of pH‐responsive systems and materials are described. Examples include semiconductor‐loaded DNA‐stabilized microcapsules, DNA‐functionalized dye‐loaded metal–organic frameworks (MOFs), and the pH‐induced release of the loads. Furthermore, the design of stimuli‐responsive DNA‐based hydrogels undergoing reversible pH‐induced hydrogel‐to‐solution transitions using triplex nucleic acids is introduced, and the use of triplex DNA to assemble shape‐memory hydrogels is discussed. An outlook for possible future applications of triplex nucleic acids is also provided.     

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     

Stimuli‐responsive zein‐based nanoparticles as a potential carrier for ellipticine: Synthesis,release, and in vitro delivery

In the present research, we have investigated a drug delivery system based on the pH‐responsive behaviors of zein colloidal nanoparticles coated with sodium caseinate (SC) and poly ethylene imine (PEI). These systematically designed nanoparticles were used as nanocarriers for encapsulation of ellipticine (EPT), as an anticancer drug. SC and PEI coatings were applied through electrostatic adsorption, leading to the increased size and improved polydispersity index of nanoparticles as well as sustained release of drug. Physicochemical characteristics such as hydrodynamic diameter, size distribution, zeta potential and morphology of nanoparticles prepared using different formulations and conditions were also determined. Based on the results, EPT was encapsulated into the prepared nanoparticles with a high drug loading capacity (5.06%) and encapsulation efficiency (94.8%) under optimal conditions. in vitro experiments demonstrated that the release of EPT from zein‐based nanoparticles was pH sensitive. When the pH level decreased from 7.4 to 5.5, the rate of drug release was considerably enhanced. The mechanism of pH‐responsive complexation in the drug encapsulation and release processes was extensively investigated. The pH‐dependent electrostatic interactions and drug state were hypothesized to affect the release profiles. Compared to the EPT‐loaded zein/PEI nanoparticles, the EPT‐loaded zein/SC nanoparticles exhibited a better drug sustained‐release profile, with a smaller initial burst release and longer release period. According to the results of in vitro cytotoxicity experiments, drug‐free nanoparticles were associated with a negligible cytotoxicity, whereas the EPT‐loaded nanoparticles displayed a high toxicity for the cancer cell line, A549. Our findings indicate that these pH‐sensitive protein‐based nanoparticles can be used as novel nanotherapeutic tools and potential antineoplastic drug carriers for cancer chemotherapy with controlled release.     

Stimuli‐Responsive Biomolecule‐Based Hydrogels and Their Applications

This Review presents polysaccharides, oligosaccharides, nucleic acids, peptides, and proteins as functional stimuli‐responsive polymer scaffolds that yield hydrogels with controlled stiffness. Different physical or chemical triggers can be used to structurally reconfigure the crosslinking units and control the stiffness of the hydrogels. The integration of stimuli‐responsive supramolecular complexes and stimuli‐responsive biomolecular units as crosslinkers leads to hybrid hydrogels undergoing reversible triggered transitions across different stiffness states. Different applications of stimuli‐responsive biomolecule‐based hydrogels are discussed. The assembly of stimuli‐responsive biomolecule‐based hydrogel films on surfaces and their applications are discussed. The coating of drug‐loaded nanoparticles with stimuli‐responsive hydrogels for controlled drug release is also presented.     

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     

Reflection of light by metal nanoparticles at electrodes

We present model calculations for the reflection spectrum of an ordered two dimensional array of metallic nanoparticles located near an electrochemical interface. We consider three cases, nanoparticles at: (i) a metal electrode, (ii) a transparent semiconductor electrode, and (iii) an electrified liquid/liquid interface. In the case of a metal electrode, the presence of nanoparticles introduces dips in reflection, whose position and depth are affected by the distance and size of the nanoparticles. For both a transparent semiconductor electrode and a liquid/liquid interface, the presence of nanoparticles enhances reflectivity. The spectra are sensitive to the particle spacing and size. The response from all three systems exhibits a strong dependence on the polarisation of light. The dependence on the angle of incidence reveals shallow dips typical of surface plasmon resonance spectra. These findings suggest diagnostic tools for the detection and characterisation of nanoparticle monolayers on functionalised electrodes, and enable electrovariable optical devices based on the controlled assembly of nanoparticles at interfaces.     

Synthesis and characterization of photo‐responsive magnetic molecularly imprinted microspheres for the detection of sulfonamides in aqueous solution

A dual responsive molecularly imprinted polymer sensitive to both photonic and magnetic stimuli was successfully prepared for the detection of four sulfonamides in aqueous media. The photoresponsive magnetic molecularly imprinted polymer was prepared by surface imprinting polymerization using superparamagnetic Fe₃O₄ nanoparticles functionalized with a silica layer as a support, water‐soluble 4‐[(4‐methacryloyloxy)phenylazo]benzenesulfonic acid as the functional monomer, and sulfadiazine as the template. The magnetic molecularly imprinted polymers showed specific affinity to sulfadiazine and its structural analogs in aqueous media. Upon alternate irradiation at 365 and 440 nm, the quantitative bind and release of the four sulfonamides by magnetic molecularly imprinted polymers occurred. Furthermore, the prepared magnetic molecularly imprinted polymers were used as solid‐phase extraction material selectively extracted the four sulfonamides from water samples with good recoveries. Thus, a simple, convenient, and reliable detection method for sulfonamides in the environment based on responsive magnetic molecularly imprinted polymers was successfully established.     

Ultrasensitive detection and molecular imaging with magnetic nanoparticles

Recent advances in nanotechnology have produced a variety of nanoparticles ranging from semiconductor quantum dots (QDs), magnetic nanoparticles (MNPs), metallic nanoparticles, to polymeric nanoparticles. Their unique electronic, magnetic, and optical properties have enabled a broad spectrum of biomedical applications such as ultrasensitive detection, medical imaging, and specific therapeutics. MNPs made from iron oxide, in particular, have attracted extensive interest and have already been used in clinical studies owing to their capability of deep-tissue imaging, non-immunogenesis, and low toxicity. In this Research Highlight article, we attempt to highlight the recent breakthroughs in MNP synthesis based on a non-hydrolytic approach, nanoparticle (NP) surface engineering, their unique structural and magnetic properties, and current applications in ultrasensitive detection and imaging with a special focus on innovative bioassays. We will also discuss our perspectives on future research directions.     

An Adjustable pH‐Responsive Drug Delivery System Based on Self‐Assembly Polypeptide‐Modified Mesoporous Silica

In this study, an adjustable pH‐responsive drug delivery system using mesoporous silica nanoparticles (MSNs) as the host materials and the modified polypeptides as the nanovalves is reported. Since the polypeptide can self‐assemble via electrostatic interaction at pH 7.4 and be disassembled by pH changes, the modified poly(l ‐lysine) and poly(l ‐glutamate) are utilized for pore blocking and opening in the study. Poly(l ‐lysine)‐MSN (PLL‐MSN) and poly(l ‐glutamate)‐MSN (PLG‐MSN) are synthesized via the ring opening polymerization of N‐carboxyanhydrides onto the surface of mesoporous silica nanoparticles. The successful modification of the polypeptide on MSN is proved by Zeta potential change, X‐ray photoelectron spectroscopy (XPS), solid state NMR, and MALDI‐TOF MS. In vitro simulated dye release studies show that PLL‐MSN and PLG‐MSN can successfully load the dye molecules. The release study shows that the controlled release can be constructed at different pH by adjusting the ratio of PLL‐MSN to PLG‐MSN. Cellular uptake study indicates that the drug is detected in both cytoplasm and nucleus, especially in the nucleus. In vitro cytotoxicity assay indicates that DOX loaded mixture nanoparticles (ratio of PLL‐MSN to PLG‐MSN is 1:1) can be triggered for drug release in HeLa cells, resulting in 88% of cell killing.     

Dual Thermo‐ and pH‐Responsive Zwitterionic Sulfobataine Copolymers for Oral Delivery System

A novel oral delivery system consisting of thermoresponsive zwitterionic poly(sulfobetaine methacrylate) (PSBMA) and pH‐responsive poly(2‐(diisopropylamino)ethyl methacrylate) (PDPA) is synthesized via free radical polymerization. This copolymer can self‐aggregate into nanoparticles via electrostatic attraction between ammonium cation and sulfo‐anion of PSBMA and successfully encapsulate anticancer drug, curcumin (CUR), with highest loading content of 2.6% in the P(SBMA‐co‐DPA) nanoparticles. The stimuli‐responsive phase transition behaviors of P(SBMA‐co‐DPA) copolymers at different pH buffer solution show pH‐dependent upper critical solution temperature (UCST) attributed to the influence of protonation/deprotonation of the pH‐responsive DPA segments. Through the delicate adjustment of the PSBMA/PDPA molar ratios, the stimuli‐responsive phase transition could be suitable for physiological environment. The kinetic drug release profiles demonstrate that P(SBMA‐co‐DPA) nanoparticles have the potential as oral delivery carriers due to their effective release of entrapped drugs in the stimulated intestinal fluid and preventing the deterioration of drug in stimulated gastric fluid.

     

Biomolecular Release Stimulated by Electrochemical Signals at a Very Small Potential Applied

DNA release electrochemically stimulated by applying ?10 mV on the modified electrode was studied. The release process was based on the local (interfacial) pH change produced upon H₂O₂ reduction electrocatalyzed by the immobilized microperoxidase‐11. SiO₂ nanoparticles attached to the electrode surface and functionalized with trigonelline and boronic acid species changed their electrical charge from positive to negative upon the interfacial pH change, thus allowing electrostatic adsorption of negatively charged DNA on the positive interface and then its repulsion/release from the negative interface. The loaded/released DNA molecules were labeled with a fluorescent dye to allow easy detection of the released DNA molecules. The important feature of the developed system is the controlled DNA release upon applying very small electrical potential on the modified electrode.     

Synthesis of multiresponsive β‐cyclodextrin nanocomposite through surface RAFT polymerization for controlled drug delivery

In this study, a unique magnetic, pH, and thermo‐responsive hydrogel nanocomposite was synthesized via surface reversible addition fragmentation chain transfer (RAFT) copolymerization of acrylic acid (AA) and N‐isopropyl acrylamide (NIPAM) in the presence of magnetic β‐cyclodextrin (β‐CD). The nanocomposite demonstrated a pH‐responsiveness behavior at pHs 3 and 9. Moreover, swelling behaviors of nanocomposite were measured in solutions with various temperatures. Furthermore, the nanocomposites exhibited high swelling capacity by applying an external magnetic field because of the presence of Fe₃O₄ nanoparticles in the polymer structure. Besides, the doxorubicin (DOX) loading and releasing behaviors of the hydrogel nanocomposites were studied because of the stimuli‐responsive properties of the synthesized carriers. The adsorption of DOX obeyed a pseudo‐second‐order model and fitted well to the Langmuir isotherm model with the maximum adsorption capacity uptake of 291 mg g^?1. In conclusion, the hydrogel nanocomposites were found to be as potential nanocarriers for use in controlled release applications.     

Multicompartmental Microcapsules with Orthogonal Programmable Two‐Way Sequencing of Hydrophobic and Hydrophilic Cargo Release

Multicompartmental responsive microstructures with the capability for the pre‐programmed sequential release of multiple target molecules of opposite solubility (hydrophobic and hydrophilic) in a controlled manner have been fabricated. Star block copolymers with dual‐responsive blocks (temperature for poly(N‐isopropylacrylamide) chains and pH for poly(acrylic acid) and poly(2‐vinylpyridine) arms) and unimolecular micellar structures serve as nanocarriers for hydrophobic molecules in the microcapsule shell. The interior of the microcapsule can be loaded with water‐soluble hydrophilic macromolecules. For these dual‐loaded microcapsules, a programmable and sequential release of hydrophobic and hydrophilic molecules from the shell and core, respectively, can be triggered independently by temperature and pH variations. These stimuli affect the hydrophobicity and chain conformation of the star block copolymers to initiate out‐of‐shell release (elevated temperature), or change the overall star conformation and interlayer interactions to trigger increased permeability of the shell and out‐of‐core release (pH). Reversing stimulus order completely alters the release process.     

Enzyme‐Controlled Sensing–Actuating Nanomachine Based on Janus Au–Mesoporous Silica Nanoparticles

Novel Janus nanoparticles with Au and mesoporous silica faces on opposite sides were prepared using a Pickering emulsion template with paraffin wax as the oil phase. These anisotropic colloids were employed as integrated sensing–actuating nanomachines for enzyme‐controlled stimuli‐responsive cargo delivery. As a proof of concept, we demonstrated the successful use of the Janus colloids for controlled delivery of tris(2,2’‐bipyridyl) ruthenium(II) chloride from the mesoporous silica face, which was grafted with pH‐sensitive gatelike scaffoldings. The release was mediated by the on‐demand catalytic decomposition of urea by urease, which was covalently immobilized on the Au face.     

Preparation of albumin—PAA nanocapsules and their controlled release behavior for drugs

New kinds of narrowly distributed protein‐based nanoparticles, bovine serum albumin‐Poly (acrylic acid) (BSA/PAA) nanospheres, and nanocapsules were prepared via in situ polymerization, swelling, and re‐aggregation. The structure and morphology of the nanospheres were characterized by UV‐Vis, FT‐IR, DLS, and TEM. The stability of the BSA/PAA nanospheres and nanocapsules was increased when their skeletons were fixed by cross‐linked agents. The nanospheres carried a positive charge and their size was about 80–110 nm. The protein‐based nanocapsules were stimuli‐responsive with pH value and their hydrodynamic diameter varied from 70 to 230 nm with changes of pH. In vitro release experiments of Rhodamine B and Doxorubicin hydrochloride showed that these biopolymer nanoparticles provided a controlled release of the entrapped drugs for 300 hr. Copyright © 2009 John Wiley & Sons, Ltd.     

Drug Encapsulation and Release by Mesoporous Silica Nanoparticles: The Effect of Surface Functional Groups

Mesoporous silica nanoparticles (MSNPs) have been widely used as drug carriers for stimuli‐responsive drug delivery. Herein, a catalysis screening technique was adopted for analyzing the effects of chain length, terminal group, and density of disulfide‐appended functional ligands on the surface of MSNPs on drug‐loading capacity and glutathione‐triggered drug‐release kinetics. The ligand with an intermediate length (5 carbon atoms) and a bulky terminal group (cyclohexyl) that complexes with theβ‐cyclodextrin ring showed the highest drug loading capacity as well as good release kinetics. In addition, decreasing the surface coverage of the functional ligands led to an enhancement in drug release. In vitro drug‐delivery experiments on a melanoma cell line (B16‐F10) by using the functionalized MSNPs further supported the conclusion. The results obtained may serve as a general guide for developing more effective MSNP systems for drug delivery.