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     

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     

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     

Preparation of chitosan functionalized end‐capped Ag‐NPs and composited with Fe3O4‐NPs: Controlled release to pH‐responsive delivery of progesterone and antibacterial activity against pseudomonas aeruginosa (PAO‐1)

In this work, functionalized chitosan end‐capped Ag nanoparticles (NPs) and composited with Fe₃O₄‐NPs was prepared as pH‐responsive controlled release carrier for gastric‐specific drug delivery. The structure of prepared material was characterized by FE‐SEM, XRD, EDS and FT‐IR analysis. The loading behavior of the progesterone onto this novel material was studied in aqueous medium at 25°C and their release was followed spectrophotometrically at 37°C in seven different buffer solutions (pH 1.2, 2.2, 3.2, 4.2, 5.2, 6.2 and 7.2) to simulate intestine and gastric media which experimental results reveal more release rate in pH 1.2 (gastric medium) with respect to other buffers. This observation is attributed to dependency of the CS‐IMBDO‐Ag‐Fe₃O₄‐NPs and progesterone structure with buffer pH that candidate this new material as prospective pH‐sensitive carrier for gastric‐targeted drug delivery. On the other hand, the antibacterial properties of this material against gram‐negative bacterium pseudomonas aeruginosa (PAO‐1) in agar plates was studied and accordingly based on broth micro dilution the minimum bactericidal concentration (MBC) and minimum inhibitory concentration (MIC) with respect to standard CLSI in different concentrations of CS‐IMBDO‐Ag‐Fe₃O₄‐NPs was calculated. The results reveal that MIC and MBC values are 50 and 1250 μg/mL, respectively. In addition, extracts of Portulaca oleracea leaves was prepared and its antibacterial activity in single and binary system with CS‐IMBDO‐Ag‐Fe₃O₄‐NPs as synergies effect against PAO‐1 was tested and results shown that these materials have significant synergistic effect for each other.     

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.     

Synthesis and characterization of folic acid‐modified carboxymethyl chitosan‐ursolic acid targeted nano‐drug carrier for the delivery of ursolic acid and 10‐hydroxycamptothecin

Carboxymethyl chitosan (CMCS), as a water‐soluble, biocompatible, and biodegradable polymer, is an excellent carrier for a sustained drug delivery system. In this study, a amphiphilic carboxymethyl chitosan‐ursolic acid nano‐drug carrier modified by folic acid (FPCU) were prepared, and then the nano‐drug carrier wrapped another anticancer drug 10‐hydroxycamptothecin were self‐assembled into nanoparticles (FPCU/HCPT NPs). The FPCU/HCPT NPs had a suitable size, high drug loading efficiency of ursolic acid (6.4%) and 10‐hydroxycamptothecin (14.1%). The drug release study in vitro indicated that the nanoparticles have obviously sustained effect and pH sensitive behaviors, the drug release amount was higher at pH 5.5 than at pH 7.4. in vitro and in vivo study showed that the nanoparticles displayed a high antitumor efficiency to tumor cells compared with free drug. The nano delivery system as a carrier for ursolic acid (UA) and 10‐hydroxycamptothecin (HCPT) has good application prospects in cancer treatment.     

Metallo‐Supramolecular Nanogels for Intracellular pH‐Responsive Drug Release

A simple process is developed to fabricate metallo‐supramolecular nanogels (MSNs) by the metallo‐supramolecular‐coordinated interaction between histidine and iron‐meso‐tetraphenylporphin. MSNs are composed of histidine‐modified dextran (DH) and iron‐meso‐tetraphenylporphin (Fe–Por) and exhibit excellent biocompatibility and stability. MSNs show pH responsiveness in the intracellular mildly acidic environment, which has great potential for acid‐triggered drug release delivery. In vitro drug release profiles demonstrate that the pH‐dependent disassembly of MSNs to histidine and Por results in a quicker release rate of loaded‐DOX at pH 5.3, while at pH 7.4 MSNs could hinder the release of loaded‐DOX due to the enhanced stability of MSNs.

     

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.     

Core‐shell structure microcapsules with dual pH‐responsive drug release function

We report dual pH‐responsive microcapsules manufactured by combining electrostatic droplets (ESD) and microfluidic droplets (MFD) techniques to produce monodisperse core (alginate)‐shell (chitosan) structure with dual pH‐responsive drug release function. The fabricated core‐shell microcapsules were size controllable by tuning the synthesis parameters of the ESD and MFD systems, and were responsive in both acidic and alkaline environment, We used two model drugs (ampicillin loaded in the chitosan shell and diclofenac loaded in the alginate core) for drug delivery study. The results show that core‐shell structure microcapsules have better drug release efficiency than respective core or shell particles. A biocompatibility test showed that the core‐shell structure microcapsules presented positive cell viability (above 80%) when evaluated by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The results indicate that the synthesized core‐shell microcapsules were a potential candidate of dual‐drug carriers.     

Continuous Detection of pH‐responsive Drug Delivery System in Cells in situ by Confocal Laser Scanning Microscopy

Mesoporous silica nanoparticles (MSN) were coated by pH‐responsive polymer chitosan‐poly (methacrylic acid) (CS‐PMAA). This nano drug delivery system showed good application prospects and the polymer‐coated microspheres were promising site‐specific anticancer drug delivery carriers in biomedical field. A continuous detection of pH‐responsive drug delivery system in cells in situ, utilizing MSN/CS‐PMAA composite microspheres, was proposed. Two kinds of different cell lines, tumor cell line (Hela) and normal somatic cells (293T), were used to investigate the behaviours of the drug loaded system in the cells. Conclusions could be drawn from the fluorescent images obtained by confocal laser scanning microscopy (CLSM), modified drug‐loaded microspheres (MSN/CS‐PMAA) were ingested into cells more easily, the uptake of DOX@FITC‐MSN/CS‐PMAA by HeLa/293T cells were performed at pH 7.4/pH 6.8, DOX was released during the ingestion process, fluorescence intensity decreased with time because of efflux transport and photo‐bleaching. Fluoresence detection by flow cytometry was performed as comparison. The continuous fluorescent observation in situ could be widely used in the pH‐responsive releasing process of drug delivery system in the cells.     

A pH‐Responsive Hydrogel Based on a Tumor‐Targeting Mesoporous Silica Nanocomposite for Sustained Cancer Labeling and Therapy

A facile strategy is presented to synthesize hyaluronic acid (HA) and a fluorescein isothiocyanate (FITC)‐conjugated mesoporous silica nanocomposite (MSN) with multiple functions of fluorescence, tumor‐cell targeting, pH‐triggered gelation, and enzyme‐responsive drug release. This injectable nanocomposite is able to indicate the entire tumor location and provides a microenvironment with rich anticancer drugs in and around tumor tissue for a long time, to avoid recrudescence. In this design, the mesoporous silica serves as the drug container, the FITC serves as a fluorescent probe, and the anchored HA plays multiple roles as drug‐release cap, tumor‐targeting points, and responsive gel matrix. Owing to the specific affinity between the HA on MSNs and the CD44 antigen over‐expressed on tumor cells, the MSNs can selectively attach to tumor cells. The nanocomposites then exploit the pH‐responsive interactions (hydrogen bonds) among the HA to self‐assemble in situ into a hydrogel around the tumor tissue. The resulting hydrogel gradually releases its payload (doxorubicin, anticancer drugs)‐loaded MSNs upon HA degradation in the presence of hyaluronidase‐1 (Hyal‐1), followed by endocytosis and intracellular drug release. All these properties have distinct benefits for tumor treatment, demonstrating that this device is a promising candidate for oncotherapy applications.

     

Cationic Vesicles Based on Amphiphilic Pillar[5]arene Capped with Ferrocenium: A Redox‐Responsive System for Drug/siRNA Co‐Delivery

A novel ferrocenium capped amphiphilic pillar[5]arene (FCAP) was synthesized and self‐assembled to cationic vesicles in aqueous solution. The cationic vesicles, displaying low cytotoxicity and significant redox‐responsive behavior due to the redox equilibrium between ferrocenium cations and ferrocenyl groups, allow building an ideal glutathione (GSH)‐responsive drug/siRNA co‐delivery system for rapid drug release and gene transfection in cancer cells in which higher GSH concentration exists. This is the first report of redox‐responsive vesicles assembled from pillararenes for drug/siRNA co‐delivery; besides enhancing the bioavailability of drugs for cancer cells and reducing the adverse side effects for normal cells, these systems can also overcome the drug resistance of cancer cells. This work presents a good example of rational design for an effective stimuli‐responsive drug/siRNA co‐delivery system.     

Facile Solvothermal Synthesis of Mesostructured Fe3O4/Chitosan Nanoparticles as Delivery Vehicles for pH‐Responsive Drug Delivery and Magnetic Resonance Imaging Contrast Agents

We report a facile fabrication of a host–metal–guest coordination‐bonding system in a mesostructured Fe₃O₄/chitosan nanoparticle that can act as a pH‐responsive drug‐delivery system. The mesostructured Fe₃O₄/chitosan was synthesized by a solvothermal approach with iron(III) chloride hexahydrate as a precursor, ethylene glycol as a reducing agent, ammonium acetate as a porogen, and chitosan as a surface‐modification agent. Subsequently, doxorubicin (DOX), acting as a model drug (guest), was loaded onto the mesostructured Fe₃O₄/chitosan nanoparticles, with chitosan acting as a host molecule to form the NH₂? Zn^II? DOX coordination architecture. The release of DOX can be achieved through the cleavage of coordination bonds that are sensitive to variations in external pH under weakly acidic conditions. The pH‐responsive nature of the nanoparticles was confirmed by in vitro releases and cell assay tests. Furthermore, the relaxation efficiency of the nanoparticles as high‐performance magnetic resonance imaging contrast agents was also investigated. Experimental results confirm that the synthesized mesostructured Fe₃O₄/chitosan is a smart nanovehicle for drug delivery owing to both its pH‐responsive nature and relaxation efficiency.     

pH‐sensitive carbon quantum dots−doxorubicin nanoparticles for tumor cellular targeted drug delivery

A kind of pH‐responsive carbon quantum dots?doxorubicin nanoparticles drug delivery platform (D‐Biotin/DOX‐loaded mPEG‐OAL/N‐CQDs) was designed and synthesized. The system consists of fluorescent carbon dots as cross‐linkers, and D‐Biotin worked as targeting groups, which made the system have a pH correspondence, doxorubicin hydrochloride (DOX) as the target drug, oxidized sodium alginate (OAL) as carrier materials. Ultraviolet (UV)‐Vis spectrum showed that the drug‐loading rate of DOX is 10.5%, and the drug release in vitro suggested that the system had a pH response and tumor cellular targeted, the drug release rate is 65.6% at the value of pH is 5.0, which is much higher than that at the value of pH is 7.4. The cytotoxicity test and laser confocal fluorescence imaging showed that the synthesized drug delivery system has high cytotoxicity to cancer cells, and the drug‐loaded nanoparticles could enter the cells through endocytosis.     

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.     

Dual‐Cargo Selectively Controlled Release Based on a pH‐Responsive Mesoporous Silica System

A pH‐controlled delivery system based on mesoporous silica nanoparticles (MSNs) was constructed for dual‐cargo selective release. To achieve a better controlled‐release effect, a modified sol–gel method was employed to obtain MSNs with tunable particle and pore sizes. The systems selectively released different kinds of cargo when stimulated by different pH values. At the lower pH value (pH 2.0) only one kind of cargo was released from the MSNs, whereas at a higher pH value (pH 7.0) only the other kind of cargo was released from the MSNs. The multi‐cargo delivery system has brought the concept of selective release to new advances in the field of functional nanodevices and allows more accurate and controllable delivery of specific cargoes, which is expected to have promising applications in nanomedicine.     

Multi‐Stimuli‐Responsive Polymeric Prodrug for Enhanced Cancer Treatment

Accomplishing efficient delivery of a nanomedicine to the tumor site will encounter two contradictions as follows: 1) a contradiction between prolonged circulation time and endocytosis by cancer cells; 2) a dilemma between the stability of nanomedicine during blood circulation and intracellular drug release. While developing a nanomedicine which can solve the above two contradictions simultaneously is still a challenge, here, a multi‐stimuli‐responsive polymeric prodrug (PLys‐co‐(PLys‐DA)‐co‐(PLys‐SS‐PTX))‐b‐PLGLAG‐mPEG (P‐PEP‐SS‐PTX‐DA) is synthesized which is multi‐sensitive to overexpressed matrix metalloproteinase‐2 (MMP‐2), low pH, and high concentration of glutathione in tumors. The P‐PEP‐SS‐PTX‐DA can be dePEGylated and reversed from negative at normal physiological pH to positive charge at tumor extracellular microenvironment; in this way, it can solve the contradiction between prolonged circulation time and endocytosis by cancer cells. Owing to the high reductive conditions in cancer cells, P‐PEP‐SS‐PTX‐DA is ruptured to release paclitaxel (PTX) intracellular efficiently; therefore, it can resolve the dilemma between the stability of nanomedicine during blood circulation and intracellular drug release. These indicate that the multi‐stimuli‐responsive polymeric prodrug has potential application prospects in drug delivery and cancer therapy.     

Differential Effects of Polymer‐Surface Decoration on Drug Delivery,Cellular Retention,and Action Mechanisms of Functionalized Mesoporous Silica Nanoparticles

Polymer‐surface decoration has been found to be an effective strategy to enhance the biological activities of nanomedicine. Herein, three different types of polymers with a cancer‐targeting ligand Arg‐Gly‐Asp peptide (RGD) have been used to decorate mesoporous silica nanoparticles (MSNs) and the functionalized nanosystems were used as drug carriers of oxaliplatin (OXA). The results showed that polymer‐surface decoration of the MSNs nanosystem by poly(ethylene glycol) (PEG) and polyethyleneimine (PEI) significantly enhanced the anticancer efficacy of OXA, which was much higher than that of chitosan (CTS). This effect was closely related to the enhancement of the cellular uptake and cellular drug retention. Moreover, PEI@MSNs‐OXA possessed excellent advantages in penetrating ability and inhibitory effects on SW480 spheroids that were used to simulate the in vivo tumor environments. Therefore, this study provides useful information for the rational design of a cancer‐targeted MSNs nanosystem with polymer‐surface decoration.     

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.     

Mussel‐Inspired Protein Nanoparticles Containing Iron(III)–DOPA Complexes for pH‐Responsive Drug Delivery

A novel bioinspired strategy for protein nanoparticle (NP) synthesis to achieve pH‐responsive drug release exploits the pH‐dependent changes in the coordination stoichiometry of iron(III)–3,4‐dihydroxyphenylalanine (DOPA) complexes, which play a major cross‐linking role in mussel byssal threads. Doxorubicin‐loaded polymeric NPs that are based on Fe^III–DOPA complexation were thus synthesized with a DOPA‐modified recombinant mussel adhesive protein through a co‐electrospraying process. The release of doxorubicin was found to be predominantly governed by a change in the structure of the Fe^III–DOPA complexes induced by an acidic pH value. It was also demonstrated that the fabricated NPs exhibited effective cytotoxicity towards cancer cells through efficient cellular uptake and cytosolic release. Therefore, it is anticipated that Fe^III–DOPA complexation can be successfully utilized as a new design principle for pH‐responsive NPs for diverse controlled drug‐delivery applications.