Core–Shell Hollow Microspheres of Magnetic Iron Oxide@Amorphous Calcium Phosphate: Synthesis Using Adenosine 5′‐Triphosphate and Application in pH‐Responsive Drug Delivery

Drug nanocarriers with magnetic targeting and pH‐responsive drug‐release behavior are promising for applications in controlled drug delivery. Magnetic iron oxides show excellent magnetism, but their application in drug delivery is limited by low drug‐loading capacity and poor control over drug release. Herein, core–shell hollow microspheres of magnetic iron oxide@amorphous calcium phosphate (MIO@ACP) were prepared and investigated as magnetic, pH‐responsive drug nanocarriers. Hollow microspheres of magnetic iron oxide (HMIOs) were prepared by etching solid MIO microspheres in hydrochloric acid/ethanol solution. After loading a drug into the HMIOs, the drug‐loaded HMIOs were coated with a protective layer of ACP by using adenosine 5′‐triphosphate (ATP) disodium salt (Na₂ATP) as stabilizer, and drug‐loaded core–shell hollow microspheres of MIO@ACP (HMIOs/drug/ACP) were obtained. The as‐prepared HMIOs/drug/ACP drug‐delivery system exhibits superparamagnetism and pH‐responsive drug‐release behavior. In a medium with pH 7.4, drug release was slow, but it was significantly accelerated at pH 4.5 due to dissolution of the ACP shell. Docetaxel‐loaded core–shell hollow microspheres of MIO@ACP exhibited high anticancer activity.     

Tragacanth gum‐based pH‐responsive magnetic hydrogels for “smart” chemo/hyperthermia therapy of solid tumors

The drug delivery performances of pH‐responsive magnetic hydrogels (MHs) composed of tragacanth gum (TG), poly(acrylic acid) (PAA), and Fe₃O₄ nanoparticles (NPs) were investigated in terms of physicochemical as well as biological features. The fabricated drug delivery systems (DDSs) were analyzed using Fourier transform infrared spectroscopy, X‐ray diffraction, vibrating sample magnetometer, scanning electron microscopy, and transmission electron microscopy. The synthesized MHs were loaded with doxorubicin hydrochloride (Dox) as a universal model anti‐cancer drug. The MHs showed excellent Dox loading and encapsulation efficiencies, mainly due to strong hydrogen bonding and electrostatic interaction between the drug and polymeric matrix, as well as porous micro‐structures of the fabricated MHs. The drug‐loaded MHs showed negligible drug release values in physiological condition. In contrast, in cancerous condition (pH 5.0), both MHs exhibited highest drug release values that qualified them as “smart” DDSs. The cytocompatibilities of the MHs as well as the cytotoxicity of the Dox‐loaded MHs were investigated against human epidermoid‐like carcinoma (Hela) cells through MTT assay. In addition, hyperthermia therapy induced by Fe₃O₄ NPs was applied to locally raise temperature inside the Hela cells at 45 ± 3°C to promote cell death. As a result, the Dox‐loaded MHs can be considered as potential DDSs for chemo/hyperthermia therapy of solid tumors.     

pH‐ and β‐cyclodextrin‐responsive micelles based on polyaspartamide derivatives as drug carrier

A novel kind of graft polymer poly(aspartic acid)‐ethanediamine‐g‐adamantane/methyloxy polyethylene glycol (Pasp‐EDA‐g‐Ad/mPEG) was designed and synthesized for drug delivery in this study. The chemical structure of the prepared polymer was confirmed by proton NMR. The obtained polymer can self‐assemble into micelles which were stable under a physiological environment and displayed pH‐ and β‐cyclodextrin (β‐CD)‐responsive behaviors because of the acid‐labile benzoic imine linkage and hydrophobic adamantine groups in the side chains of the polymer. The doxorubicin (Dox)‐loaded micelles showed a slow release under physiological conditions and a rapid release after exposure to weakly acidic or β‐CD environment. The in vitro cytotoxicity results suggested that the polymer was good at biocompatibility and could remain Dox biologically active. Hence, the Pasp‐EDA‐g‐Ad/mPEG micelles may be applied as promising controlled drug delivery system for hydrophobic antitumor drugs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1387–1395     

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.     

Mesoporous γ‐Iron Oxide Nanoparticles for Magnetically Triggered Release of Doxorubicin and Hyperthermia Treatment

Mesoporous iron‐oxide nanoparticles (mNPs) were prepared by using a modified nanocasting approach with mesoporous carbon as a hard template. mNPs were first loaded with doxorubicin (Dox), an anticancer drug, and then coated with the thermosensitive polymer Pluronic F108 to prevent the leakage of Dox molecules from the pores that would otherwise occur under physiological conditions. The Dox‐loaded, Pluronic F108‐coated system (Dox@F108‐mNPs) was stable at room temperature and physiological pH and released its Dox cargo slowly under acidic conditions or in a sudden burst with magnetic heating. No significant toxicity was observed in vitro when Dox@F108‐mNPs were incubated with noncancerous cells, a result consistent with the minimal internalization of the particles that occurs with normal cells. On the other hand, the drug‐loaded particles significantly reduced the viability of cervical cancer cells (HeLa, IC₅₀=0.70 μm ), wild‐type ovarian cancer cells (A2780, IC₅₀=0.50 μm ) and Dox‐resistant ovarian cancer cells (A2780/AD, IC₅₀=0.53 μm ). In addition, the treatment of HeLa cells with both Dox@F108‐mNPs and subsequent alternating magnetic‐field‐induced hyperthermia was significantly more effective at reducing cell viability than either Dox or Dox@F108‐mNP treatment alone. Thus, Dox@F108‐mNPs constitute a novel soft/hard hybrid nanocarrier system that is highly stable under physiological conditions, temperature‐responsive, and has chemo‐ and thermotherapeutic modes of action.     

pH‐Triggered Sustained Drug Delivery from a Polymer Micelle having the β‐Thiopropionate Linkage

The synthesis, micellar aggregation, and pH‐triggered intracellular drug delivery ability of an amphiphilic statistical copolymer (P2) are studied. Two methacrylate derivatives, one containing a hydrophilic pendant and the other containing a hydrophobic pendant chain, are copolymerized to produce P2. The hydrophobic pendant chain is linked to the polymer backbone by a β‐thiopropionate linkage, known to undergo slow hydrolysis at mild acidic pH. P2 forms a multimicellar cluster in water with a critical aggregation concentration of 0.02 mg mL⁻¹ and encapsulates a hydrophobic guest such as pyrene, Nile red, or the anti‐cancer drug doxorubicin (Dox). Sustained release of the entrapped Dox (80% after 100 h) is noticed at pH 5.2, while release is significantly slower (35% after 100 h) at pH 7.4. Acidic hydrolysis of the β‐thiopropionate linkage leading to the reduction of the hydrophobicity is established as the cause for micellar disassembly and triggered drug release. Cell‐culture studies with the human breast cancer cell line, MCF‐7, reveal biocompatibility of P2 (below 150 μg mL⁻¹). It is further tested for intracellular delivery of Dox. MCF‐7 cells remain healthy at pH 7.4 but become unhealthy at pH 5.2 when treated with a Dox‐loaded P2 micelles.

     

pH‐Responsive Drug‐Delivery Systems

In many biomedical applications, drugs need to be delivered in response to the pH value in the body. In fact, it is desirable if the drugs can be administered in a controlled manner that precisely matches physiological needs at targeted sites and at predetermined release rates for predefined periods of time. Different organs, tissues, and cellular compartments have different pH values, which makes the pH value a suitable stimulus for controlled drug release. pH‐Responsive drug‐delivery systems have attracted more and more interest as “smart” drug‐delivery systems for overcoming the shortcomings of conventional drug formulations because they are able to deliver drugs in a controlled manner at a specific site and time, which results in high therapeutic efficacy. This focus review is not intended to offer a comprehensive review on the research devoted to pH‐responsive drug‐delivery systems; instead, it presents some recent progress obtained for pH‐responsive drug‐delivery systems and future perspectives. There are a large number of publications available on this topic, but only a selection of examples will be discussed.     

Enzyme‐Responsive Multifunctional Magnetic Nanoparticles for Tumor Intracellular Drug Delivery and Imaging

Enzyme‐responsive, hybrid, magnetic silica nanoparticles have been employed for multifunctional applications in selective drug delivery and intracellular tumor imaging. In this study, doxorubicin (Dox)‐conjugated, enzyme‐cleavable peptide precursors were covalently tethered onto the surface of uniform silica‐coated magnetic nanoparticles through click chemistry. This enzyme‐responsive nanoparticle conjugate demonstrated highly efficient Dox release upon specific enzyme interactions in vitro. It also exhibits multiple functions in selective tumor intracellular drug delivery and imaging in the tumor cells with high cathepsin B expression, whereas it exhibited lower cytotoxicity towards other cells without enzyme expression.     

Integrated Hollow Mesoporous Silica Nanoparticles for Target Drug/siRNA Co‐Delivery

A hollow mesoporous silica nanoparticle (HMSNP) based drug/siRNA co‐delivery system was designed and fabricated, aiming at overcoming multidrug resistance (MDR) in cancer cells for targeted cancer therapy. The as‐prepared HMSNPs have perpendicular nanochannels connecting to the internal hollow cores, thereby facilitating drug loading and release. The extra volume of the hollow core enhances the drug loading capacity by two folds as compared with conventional mesoporous silica nanoparticles (MSNPs). Folic acid conjugated polyethyleneimine (PEI‐FA) was coated on the HMSNP surfaces under neutral conditions through electrostatic interactions between the partially charged amino groups of PEI‐FA and the phosphate groups on the HMSNP surfaces, blocking the mesopores and preventing the loaded drugs from leakage. Folic acid acts as the targeting ligand that enables the co‐delivery system to selectively bind with and enter into the target cancer cells. PEI‐FA‐coated HMSNPs show enhanced siRNA binding capability on account of electrostatic interactions between the amino groups of PEI‐FA and siRNA, as compared with that of MSNPs. The electrostatic interactions provide the feasibility of pH‐controlled release. In vitro pH‐responsive drug/siRNA co‐delivery experiments were conducted on HeLa cell lines with high folic acid receptor expression and MCF‐7 cell lines with low folic acid receptor expression for comparison, showing effective target delivery to the HeLa cells through folic acid receptor meditated cellular endocytosis. The pH‐responsive intracellular drug/siRNA release greatly minimizes the prerelease and possible side effects of the delivery system. By simultaneously delivering both doxorubicin (Dox) and siRNA against the Bcl‐2 protein into the HeLa cells, the expression of the anti‐apoptotic protein Bcl‐2 was successfully suppressed, leading to an enhanced therapeutic efficacy. Thus, the present multifunctional nanoparticles show promising potentials for controlled and targeted drug and gene co‐delivery in cancer treatment.     

Chitosan‐Capped Mesoporous Silica Nanoparticles as pH‐Responsive Nanocarriers for Controlled Drug Release

Herein, we present a straightforward synthesis of pH‐responsive chitosan‐capped mesoporous silica nanoparticles (MSNs). These MCM‐41‐type MSNs could be used as nanocapsules to accommodate guest molecules. Subsequently, (3‐glycidyloxypropyl)trimethoxysilane was grafted onto the surface of the MSNs, which served as a bridge to link between MSNs and chitosan, which is ubiquitous in nature and commercially available. Owing to the pH‐responsive and biocompatible features of chitosan, the loading and release of an anti‐cancer drug, doxorubicin hydrochloride, were carried out in vitro, in which the composite chitosan‐capped MSNs (CS‐MSNs) showed excellent environmental response. As the pH value of the media decreased, the degree of drug release correspondingly increased. Moreover, thanks to the perfect biocompatibility of chitosan, the CS‐MSNs exhibited lower cytotoxicity than that of the naked MSNs in an MTT assay. In addition, the in vitro kill potency against MCF‐7 breast‐cancer cells was enhanced over time, as well as with increasing concentration of the drug‐loaded CS‐MSNs. These results indicate that CS‐MSNs are promising candidates for pH‐responsive drug delivery in cancer therapy.     

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     

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.     

Fructose 1,6‐Bisphosphate Trisodium Salt as A New Phosphorus Source for the Rapid Microwave Synthesis of Porous Calcium–Phosphate Microspheres and their Application in Drug Delivery

Calcium phosphates (CPs), as the major inorganic component of biological hard tissues, have been investigated for applications as biomaterials owing to their excellent biocompatibility. However, the traditional synthetic CPs are usually prepared from inorganic phosphorus and calcium sources. Herein, we report a new strategy for the synthesis of a variety of calcium–phosphate nanostructures, including porous amorphous calcium phosphate (ACP) microspheres, hydroxyapatite (HAP) nanorods, and ACP/HAP composite microspheres, by using fructose 1,6‐bisphosphate trisodium salt (FBP) as an organic phosphorus source in aqueous solution in a rapid microwave‐assisted hydrothermal reaction. The important role of FBP and the effect of the experimental conditions on the formation and evolution of the CPs nanostructures were investigated. The crystal phase and composition of the as‐prepared products were characterized by powder X‐ray diffraction (XRD), FTIR spectroscopy, and thermogravimetric (TGA) analysis and the morphologies of the products were characterized by SEM and TEM. This method is facile, rapid, surfactant‐free, and environmentally friendly. The as‐prepared porous ACP microspheres have a relatively high drug‐loading capacity and good sustained drug‐release behavior; thus, they are promising for applications in drug delivery.     

pH‐responsive starch microparticles for a tumor‐targeting implant

Much progress has been made toward stimuli‐responsive polysaccharide‐based selective tumor therapy not only because polysaccharides have nontoxic biodegradability and biocompatibility but also because their stimuli‐sensitive characteristics enable the proper transport of payloads into tumors. Here, we attempted to deliver an antitumor drug, doxorubicin (DOX), using starch‐based microparticles coupled with pH‐responsive 3‐(diethylamino)propylamine. The microparticles of starch conjugated with 3‐(diethylamino)propylamine (SDEAP) allowed for the change in hydrophobicity of SDEAPs in a pH‐dependent manner. The results revealed that SDEAPs effectively carried and released DOX and selectively killed tumor cells under acidic condition. Overall, this study suggests that DOX‐loaded SDEAPs can be further explored as a strategy for applications to acidic tumor‐targeting implants owing to the drug‐deliver efficiency and tumor selectivity.     

Self‐Assembled Aptamer‐Based Drug Carriers for Bispecific Cytotoxicity to Cancer Cells

Monovalent aptamers can deliver drugs to target cells by specific recognition. However, different cancer subtypes are distinguished by heterogeneous biomarkers and one single aptamer is unable to recognize all clinical samples from different patients with even the same type of cancers. To address heterogeneity among cancer subtypes for targeted drug delivery, as a model, we developed a drug carrier with a broader recognition range of cancer subtypes. This carrier, sgc8c‐sgd5a (SD), was self‐assembled from two modified monovalent aptamers. It showed bispecific recognition abilities to target cells in cell mixtures; thus broadening the recognition capabilities of its parent aptamers. The self‐assembly of SD simultaneously formed multiple drug loading sites for the anticancer drug doxorubicin (Dox). The Dox‐loaded SD (SD–Dox) also showed bispecific abilities for target cell binding and drug delivery. Most importantly, SD–Dox induced bispecific cytotoxicity in target cells in cell mixtures. Therefore, by broadening the otherwise limited recognition capabilities of monovalent aptamers, bispecific aptamer‐based drug carriers would facilitate aptamer applications for clinically heterogeneous cancer subtypes that respond to the same cancer therapy.     

Yolk‐Shell Porous Microspheres of Calcium Phosphate Prepared by Using Calcium L‐Lactate and Adenosine 5′‐Triphosphate Disodium Salt: Application in Protein/Drug Delivery

A facile and environmentally friendly approach has been developed to prepare yolk‐shell porous microspheres of calcium phosphate by using calcium L ‐lactate pentahydrate (CL) as the calcium source and adenosine 5′‐triphosphate disodium salt (ATP) as the phosphate source through the microwave‐assisted hydrothermal method. The effects of the concentration of CL, the microwave hydrothermal temperature, and the time on the morphology and crystal phase of the product are investigated. The possible formation mechanism of yolk‐shell porous microspheres of calcium phosphate is proposed. Hemoglobin from bovine red cells (Hb) and ibuprofen (IBU) are used to explore the application potential of yolk‐shell porous microspheres of calcium phosphate in protein/drug loading and delivery. The experimental results indicate that the as‐prepared yolk‐shell porous microspheres of calcium phosphate have relatively high protein/drug loading capacity, sustained protein/drug release, favorable pH‐responsive release behavior, and a high biocompatibility in the cytotoxicity test. Therefore, the yolk‐shell porous microspheres of calcium phosphate have promising applications in various biomedical fields such as protein/drug delivery.     

Drug release by pH‐responsive molecular tweezers: Atomistic details from molecular modeling

pH‐responsive molecular tweezers have been proposed as an approach for targeting drug‐delivery to tumors, which tend to have a lower pH than normal cells. We performed a computational study of a pH‐responsive molecular tweezer using ab initio quantum chemistry in the gas‐phase and molecular dynamics (MD) simulations in solution. The binding free energy in solution was calculated using steered MD. We observe, in atomistic detail, the pH‐induced conformational switch of the tweezer and the resulting release of the drug molecule. Even when the tweezer opens, the drug molecule remains near a hydrophobic arm of the molecular tweezer. Drug release cannot occur, it seems, unless the tweezer is in a hydrophobic environment with low pH. © 2014 Wiley Periodicals, Inc.     

Reduction and pH dual‐responsive block copolymers containing pendent p‐nitrobenzyl carbamate functionalities: Synthesis and self‐assembly behavior

We report on the preparation of reduction‐responsive amphiphilic block copolymers containing pendent p‐nitrobenzyl carbamate (pNBC)‐caged primary amine moieties by reversible addition–fragmentation chain transfer (RAFT) radical polymerization using a poly(ethylene glycol)‐based macro‐RAFT agent. The block copolymers self‐assembled to form micelles or vesicles in water, depending on the length of hydrophobic block. Triggered by a chemical reductant, sodium dithionite, the pNBC moieties decomposed through a cascade 1,6‐elimination and decarboxylation reactions to liberate primary amine groups of the linkages, resulting in the disruption of the assemblies. The reduction sensitivity of assemblies was affected by the length of hydrophobic block and the structure of amino acid‐derived linkers. Using hydrophobic dye Nile red (NR) as a model drug, the polymeric assemblies were used as nanocarriers to evaluate the potential for drug delivery. The NR‐loaded nanoparticles demonstrated a reduction‐triggered release profile. Moreover, the liberation of amine groups converted the reduction‐responsive polymer into a pH‐sensitive polymer with which an accelerated release of NR was observed by simultaneous application of reduction and pH triggers. It is expected that these reduction‐responsive block copolymers can offer a new platform for intracellular drug delivery. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1333–1343     

Gemini Surfactants Templated Mesoporous Silica Microparticles: from Solid to Hollow Mesoporous Spheres

We synthesized a series of mesoporous silica microparticles (MSs) using cationic gemini surfactants C_14–2‐n (n = 2, 6, 10, 14) as templates. The porous structures and pore size of these MSs can be tuned by varying the length of alkyl chain in gemini surfactant templates. These MSs showed effective doxorubicin (DOX) loading and a pH‐responsive drug release characteristics. These results indicate that the MSs, especially the hollow mesoporous silica nanoparticles, have great potential for biomedical applications.     

Structure‐Directing Agents for the Synthesis of TiO2‐Based Drug‐Delivery Systems

A series of titanium oxides was prepared by using a surfactant‐template method (STM) and used as a carrier for the sustained release of ibuprofen, which was chosen as a model drug. This STM provides an efficient route to TiO₂ matrices with both high surface area (when compared with those that were obtained by using traditional synthetic approaches) and well‐defined mesoporous textures. Some parameters of the synthetic procedure were varied: pH value, surfactant, and thermal treatment. The physicochemical nature of the surface carriers were investigated by means of N₂‐physisorption measurements and FTIR spectroscopy. The effect of the amount of drug on the release kinetics was also investigated. The drug delivery was evaluated in vitro in four different physiological solutions (that simulated the gastrointestinal tract) to analyze the behavior of the TiO₂‐based systems if they were to be formulated as oral DDSs. Our optimized approach is a good alternative to the classical methods that are used to prepare efficient TiO₂‐based drug‐delivery systems.