Endogenous and Exogenous Stimuli-Responsive Drug Delivery Systems for Programmed Site-Specific Release

In this study, we reviewed state-of-the-art endogenous-based and exogenous-based stimuli-responsive drug delivery systems (DDS) for programmed site-specific release to overcome the drawbacks of conventional therapeutic modalities. This particular work focuses on the smart chemistry and mechanism of action aspects of several types of stimuli-responsive polymeric carriers that play a crucial role in extracellular and intracellular sections of diseased tissues or cells. With ever increasing scientific knowledge and awareness, research is underway around the globe to design new types of stimuli (external/internal) responsive polymeric carriers for biotechnological applications at large and biomedical and/or pharmaceutical applications, in particular. Both external/internal and even dual/multi-responsive behavior of polymeric carriers is considered an essential element of engineering so-called ‘smart’ DDS, which controls the effective and efficient dose loading, sustained release, individual variability, and targeted permeability in a sophisticated manner. So far, an array of DDS has been proposed, developed, and implemented. For instance, redox, pH, temperature, photo/light, magnetic, ultrasound, and electrical responsive DDS and/or all in all dual/dual/multi-responsive DDS (combination or two or more from any of the above). Despite the massive advancement in DDS arena, there are still many challenging concerns that remain to be addressed to cover the research gap. In this context, herein, an effort has been made to highlight those concerning issues to cover up the literature gap. Thus, the emphasis was given to the drug release mechanism and applications of endogenous and exogenous based stimuli-responsive DDS in the clinical settings.

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title: The Smart Drug Delivery System and Its Clinical Potential
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title: Protease-sensitive, polymer-caged liposomes: a method for making highly targeted liposomes using triggered release.
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title: Dual enzyme responsive and targeted nanocapsules for intracellular delivery of anticancer agents
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title: Nonviral vectors for gene delivery.
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title: Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: concepts and applications.
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title: Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery.
abstract: The past couple of years have witnessed a tremendous progress in the development of glutathione-responsive nano-vehicles for targeted intracellular drug and gene delivery, as driven by the facts that (i) many therapeutics (e.g. anti-cancer drugs, photosensitizers, and anti-oxidants) and biotherapeutics (e.g. peptide and protein drugs, and siRNA) exert therapeutical effects only inside cells like the cytosol and cell nucleus, and (ii) several intracellular compartments such as cytosol, mitochondria, and cell nucleus contain a high concentration of glutathione (GSH) tripeptides (about 2-10 mM), which is 100 to 1000 times higher than that in the extracellular fluids and circulation (about 2-20 μM). Glutathione has been recognized as an ideal and ubiquitous internal stimulus for rapid destabilization of nano-carriers inside cells to accomplish efficient intracellular drug release. In this paper, we will review recent results on GSH-responsive nano-vehicles in particular micelles, nanoparticles, capsules, polymersomes, nanogels, dendritic and macromolecular drug conjugates, and nano-sized nucleic acid complexes for controlled delivery of anti-cancer drugs (e.g. doxorubicin and paclitaxel), photosensitizers, anti-oxidants, peptides, protein drugs, and nucleic acids (e.g. DNA, siRNA, and antisense oligodeoxynucleotide). The unique disulfide chemistry has enabled novel and versatile designs of multifunctional delivery systems addressing both intracellular and extracellular barriers. We are convinced that GSH-responsive nano-carrier systems have enormous potential in targeted cancer therapy.

title: Oxidation-responsive polymeric vesicles
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title: Side-chain selenium-containing amphiphilic block copolymers: redox-controlled self-assembly and disassembly†
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title: Glucose-oxidase based self-destructing polymeric vesicles.
abstract: We have designed oxidation-responsive vesicles from synthetic amphiphilic block copolymers ("polymersomes") of ethylene glycol and propylene sulfide. Thioethers in the hydrophobic poly(propylene sulfide) block are converted into the more hydrophilic sulfoxides and sulfones upon exposure to an oxidative environment, changing the hydrophilic-lipophilic balance of the macroamphiphile and thus inducing its solubilization. Here we sought to explore generation of the oxidative environment and induction of polymersome destabilization through production of hydrogen peroxide by the glucose-oxidase (GOx)/glucose/oxygen system. We studied the encapsulation of GOx within polymersomes, its stability and activity, and glucose-triggered polymersome destabilization. Stimulus-responsive polymersomes may find applications as nanocontainers in sensing devices and as drug delivery systems.

title: Uptake and intracellular fate of disulfide-bonded polymer hydrogel capsules for Doxorubicin delivery to colorectal cancer cells.
abstract: Understanding the interactions between drug carriers and cells is of importance to enhance the delivery of therapeutics. The release of therapeutics into different intracellular environments, such as the lysosomes or the cell cytoplasm, will impact their pharmacological activity. Herein, we investigate the intracellular fate of layer-by-layer (LbL)-assembled, submicrometer-sized polymer hydrogel capsules in a human colon cancer derived cell line, LIM1899. The cellular uptake of the disulfide-stabilized poly(methacrylic acid) (PMA(SH)) capsules by colon cancer cells is a time-dependent process. Confocal laser scanning microscopy and transmission electron microscopy reveal that the internalized capsules are deformed in membrane-enclosed compartments, which further mature to late endosomes or lysosomes. We further demonstrate the utility of these redox-responsive PMA(SH) capsules for the delivery of doxorubicin (DOX) to colon cancer cells. The DOX-loaded PMA(SH) capsules demonstrate a 5000-fold enhanced cytotoxicity in cell viability studies compared to free DOX.

title: Controlled release of DNA from poly(vinylpyrrolidone) capsules using cleavable linkers.
abstract: The design of polymer carriers with tunable degradation and cargo release is fundamental for applications in drug and gene delivery. In this study, we report low-fouling poly(N-vinyl pyrrolidone) (PVPON) capsules assembled via hydrogen bonding and stabilized using covalent cross-linking. We first investigated the effects of pH and ionic strength to optimize the assembly conditions. A model therapeutic cargo (plasmid DNA) was then loaded in the capsules and used for encapsulation and release studies. Two bisazide cross-linkers that contain a disulfide bond, termed PEG₈ (poly(ethylene glycol)) and PEG(16), were employed to stabilize the multilayer films, and used to tune the degradation and cargo release behavior of the capsules in simulated cytoplasmic conditions. The results suggest that PEG₈-stabilized capsules were more efficiently cross-linked, and hence displayed higher plasmid encapsulation. Consequently, the capsules cross-linked with PEG₈ also showed a two-fold reduction in degradation rate. This ability to achieve controlled carrier degradation and cargo release makes these capsules of potential interest for drug and gene delivery.

title: New coupling agents for the synthesis of immunotoxins containing a hindered disulfide bond with improved stability in vivo.
abstract: Two new coupling agents were synthesized for making immunotoxins containing disulfide bonds with improved stability in vivo: sodium S-4-succinimidyloxycarbonyl-alpha-methyl benzyl thiosulfate (SMBT) and 4-succinimidyloxycarbonyl-alpha-methyl-alpha(2-pyridyldithio)tolue ne (SMPT). Both reagents generate the same hindered disulfide linkage in which a methyl group and a benzene ring are attached to the carbon atom adjacent to the disulfide bond and protect it from attack by thiolate anions. An immunotoxin consisting of monoclonal anti-Thy-1.1 antibody (OX7) linked by means of the SMPT reagent to chemically deglycosylated ricin A-chain had better stability in vivo than an immunotoxin prepared with 2-iminothiolane hydrochloride (2IT) which generates an unhindered disulfide linkage. About 48 h after i.v. injection into mice, one-half of the SMPT-linked immunotoxin present in the blood was in intact form and one-half as released free antibody, whereas equivalent breakdown of the 2IT-linked immunotoxin was seen at about 8 h after injection. Consequently, the blood levels of the SMPT-linked immunotoxin remained higher than those of the 2IT-linked immunotoxin despite loss of immunotoxin from the blood by other mechanisms. Forty-eight h after injection, 10% of the injected dose of the SMPT-linked immunotoxin remained in the bloodstream as compared with only 1.5% of the 2IT-linked immunotoxin. The ability of immunotoxins prepared with the new reagents to inhibit protein synthesis by Thy-1.1-expressing AKR-A/2 lymphoma cells in vitro was identical to that of immunotoxins prepared with 2IT or N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP). Clonogenic assays showed that fewer than 0.01% of AKR-A/2 cells survived exposure to high concentrations of OX7-abrin A-chain immunotoxins prepared with SMBT, 2IT, or SPDP. Twelve clones of cells which had survived treatment with the SMBT-linked immunotoxin were isolated. None of the clones was selectively resistant to the SMBT-linked immunotoxin when retested in cytotoxicity assays. In conclusion, immunotoxins prepared with the new coupling agents should have improved antitumor activity in vivo because they are longer lived and do not break down so readily to release free antibody which could compete for the target antigens.

title: Block catiomer polyplexes with regulated densities of charge and disulfide cross-linking directed to enhance gene expression.
abstract: A block catiomer polyplex, showing a high stability in the extracellular medium and an efficient release of plasmid DNA (pDNA) in the intracellular compartment, was developed by controlling both the cationic charge and disulfide cross-linking densities of the backbone polycations. Poly(ethylene glycol)-poly(L-lysine) block copolymer (PEG-PLL) was thiolated using either of two thiolation reagents, N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) or 2-iminothiolane (Traut's reagent), to investigate the effects of both the charge and disulfide cross-linking densities on the properties of the polyplexes. The introduction of thiol groups by SPDP proceeded through the formation of amide linkages to concomitantly decrease the cationic charge density of PLL segment, whereas Traut's reagent promoted the thiolation with the introduction of cationic imino groups to keep the charge density constant. These thiolated PEG-PLLs were complexed with pDNA to form the disulfide cross-linked block catiomer polyplexes, which had the size of approximately 100 nm. Both thiolation methods were similarly effective in introducing disulfide cross-links to prevent the polyplex from the dissociation through a counter polyanion exchange in the extracellular oxidative condition. On the other hand, the efficient release of pDNA responding to the reductive condition mimicking the intracellular environment was only achieved for the polyplex thiolated with SPDP, a system compensating for the decrease in the charge density with the disulfide cross-linking. This distinctive sensitivity toward oxidative and reductive environments was nicely correlated with the remarkable difference in the transfection efficiency between these two types of thiolated polyplexes (SPDP and Traut's reagent types): the former revealed approximately 50 times higher transfection efficiency toward 293T cells than the latter. Obviously, the balance between the densities of the cationic charge and disulfide cross-linking in the thiolated polyplex played a crucial role in the delivery and controlled release of entrapped pDNA into the microenvironment of intracellular compartment to achieve the high transfection efficiency.

title: Antiangiogenic gene therapy of solid tumor by systemic injection of polyplex micelles loading plasmid DNA encoding soluble flt-1.
abstract: In this study, a polyplex micelle was developed as a potential formulation for antiangiogenic gene therapy of subcutaneous pancreatic tumor model. Poly(ethylene glycol)-poly(l-lysine) block copolymers (PEG-PLys) with thiol groups in the side chain of the PLys segment were synthesized and applied for preparation of disulfide cross-linked polyplex micelles through ion complexation with plasmid DNA (pDNA) encoding the soluble form of vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), which is a potent antiangiogenic molecule. Antitumor activity and gene expression of polyplex micelles with various cross-linking rates were evaluated in mice bearing subcutaneously xenografted BxPC3 cell line, derived from human pancreatic adenocarcinoma, and polyplex micelles with optimal cross-linking rate achieved effective suppression of tumor growth. Significant gene expression of this micelle was detected selectively in tumor tissue, and its antiangiogenic effect was confirmed by decreased vascular density inside the tumor. Therefore, the disulfide cross-linked polyplex micelle loading sFlt-1 pDNA has a great potential for antiangiogenic therapy against subcutaneous pancreatic tumor model by systemic application.

title: Biologically responsive polymeric nanoparticles for drug delivery.
abstract: Responsive nanoparticles that release their drug cargo in accordance with a change in pH or oxidative stress are of significant clinical interest as this approach offers the opportunity to link drug delivery to a specific location or disease state. This research news article reviews the current state of this field by examining a series of published articles that highlight the novelty and benefits of using responsive polymeric particles to achieve functionally-targeted drug delivery.

title: Effect of block sequence and block length on the stimuli-responsive behavior of polyampholyte brushes: hydrogen bonding and electrostatic interaction as the driving force for surface rearrangement
abstract: Diblock polyampholyte brushes with different block sequences (Si/SiO2/poly(acrylic acid)-b-poly(2-vinylpyridine) (PAA-b-P2VP) brushes and Si/SiO2/P2VP-b-PAA brushes) and different block lengths were synthesized by sequent surface-initiated atom transfer radical polymerization (ATRP). The PAA block was obtained through hydrolysis from the corresponding poly(tert-butyl acrylate). The polyampholyte brushes demonstrated unique pH-responsive behavior. In the intermediate pH region, the brushes exhibited a less hydrophilic wetting behavior and a rougher surface morphology due to the formation of polyelectrolyte complex through electrostatic interaction between oppositely charged blocks. In the low pH and high pH regions, the rearrangement of polyampholyte brushes showed great dependence on the block sequence and block length. The polyampholyte brushes with P2VP-b-PAA sequence underwent rearrangement during alternative treatment by acidic aqueous solution (low pH value) and basic aqueous solution (high pH value). The brushes with PAA-b-P2VP sequence did not show obvious rearrangement. Nevertheless, with increasing the length of inner PAA block for PAA-b-P2VP brushes, the hydrogen-bonding interaction between blocks became strong enough to implement surface rearrangement and eventually localized the inner PAA block at the polymer–air interface in the low pH region. In the high pH region, polymer brushes had least chance of surface rearrangement. P2VP block was more localized at the interface despite of the length of inner block.

title: pH-Sensitive degradable polymersomes for triggered release of anticancer drugs: a comparative study with micelles.
abstract: pH-Sensitive degradable polymersomes and micelles were prepared based on diblock copolymer of poly(ethylene glycol) (PEG) and an acid-labile polycarbonate, poly(2,4,6-trimethoxybenzylidenepentaerythritol carbonate) (PTMBPEC). Polymersomes of PEG(1.9k)-PTMBPEC(6k) revealed average sizes of 100-200 nm. The acetals of polymersomes, similar to those of PEG(5k)-PTMBPEC(5.8k) micelles, though stable at pH 7.4 were prone to fast hydrolysis at mildly acidic pH of 4.0 and 5.0, with half lives of 0.5 and 3d, respectively. The acetal hydrolysis resulted in significant size increase of polymersomes, to over 1000 nm in 24h at pH 4.0. Drug encapsulation studies revealed that polymersomes were able to simultaneously load paclitaxel (PTX, hydrophobic) and doxorubicin hydrochloride (DOX.HCl, hydrophilic), whereas micelles loaded PTX only. Notably, polymersomes showed lower drug loading efficiencies for PTX than micelles (30.0-37.7% versus 61.4-65.2%). The in vitro release studies demonstrated that release of PTX and DOX.HCl from polymersomes was highly pH-dependent, i.e. significantly faster drug release at mildly acidic pH of 4.0 and 5.0 compared to physiological pH. Furthermore, much higher release rates were observed for PTX release from the polymersomes compared to that from the micelles under otherwise the same conditions. These pH-sensitive nano-sized degradable polymersomes hold great promise for combination therapy for cancers.

title: More effective nanomedicines through particle design.
abstract: Nanomedicine is an emerging field that applies concepts in nanotechnology to develop novel diagnostics and therapies. Physical and chemical properties of particles, including size, shape, modulus, surface charge and surface chemistry, play an important role in determining particle-cell interactions, cellular trafficking mechanisms, biodistribution, and pharmacokinetics. This discussion focuses on both nanoparticles and microparticles since microparticles can also provide many insights for the development of drug carriers and possess advantages over nanoparticles in certain applications. This review covers recent major advancement in the nanomedicine field and also highlights studies using the PRINT technology.

title: Hyperbranched double hydrophilic block copolymer micelles of poly(ethylene oxide) and polyglycerol for pH-responsive drug delivery.
abstract: We report the synthesis of a well-defined hyperbranched double hydrophilic block copolymer of poly(ethylene oxide)-hyperbranched-polyglycerol (PEO-hb-PG) to develop an efficient drug delivery system. In specific, we demonstrate the hyperbranched PEO-hb-PG can form a self-assembled micellar structure on conjugation with the hydrophobic anticancer agent doxorubicin, which is linked to the polymer by pH-sensitive hydrazone bonds, resulting in a pH-responsive controlled release of doxorubicin. Dynamic light scattering, atomic force microscopy, and transmission electron microscopy demonstrated successful formation of the spherical core-shell type micelles with an average size of about 200 nm. Moreover, the pH-responsive release of doxorubicin and in vitro cytotoxicity studies revealed the controlled stimuli-responsive drug delivery system desirable for enhanced efficiency. Benefiting from many desirable features of hyperbranched double hydrophilic block copolymers such as enhanced biocompatibility, increased water solubility, and drug loading efficiency as well as improved clearance of the polymer after drug release, we believe that double hydrophilic block copolymer will provide a versatile platform to develop excellent drug delivery systems for effective treatment of cancer.

title: Catechol Polymers for pH-Responsive, Targeted Drug Delivery to Cancer Cells
abstract: A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug–polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug–polymer conjugates. The pH-sensitive catechol–boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.

title: pH Sensitive Hydrogels in Drug Delivery: Brief History, Properties, Swelling, and Release Mechanism, Material Selection and Applications
abstract: Improving the safety efficacy ratio of existing drugs is a current challenge to be addressed rather than the development of novel drugs which involve much expense and time. The efficacy of drugs is affected by a number of factors such as their low aqueous solubility, unequal absorption along the gastrointestinal (GI) tract, risk of degradation in the acidic milieu of the stomach, low permeation of the drugs in the upper GI tract, systematic side effects, etc. This review aims to enlighten readers on the role of pH sensitive hydrogels in drug delivery, their mechanism of action, swelling, and drug release as a function of pH change along the GI tract. The basis for the selection of materials, their structural features, physical and chemical properties, the presence of ionic pendant groups, and the influence of their pKa and pKb values on the ionization, consequent swelling, and targeted drug release are also highlighted.

title: Diblock copolymers with tunable pH transitions for gene delivery.
abstract: A series of diblock copolymers containing an endosomal-releasing segment composed of diethylaminoethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The materials were designed to condense plasmid DNA (pDNA) through electrostatic interactions with a cationic poly(N,N-dimethylaminoethyl methacrylate) (DMAEMA) first block. The pDMAEMA was employed as a macro chain transfer agent (macroCTA) for the synthesis of a series in which the relative feed ratios of DEAEMA and BMA were systematically varied from 20% to 70% BMA. The resultant diblock copolymers exhibited low polydispersity (PDI ≤ 1.06) with similar molecular weights (M(n) = 19.3-23.1 kDa). Dynamic light scattering (DLS) measurements in combination with (1)H NMR D(2)O studies demonstrated that the free copolymers assemble into core-shell micelles at physiological pH. Reduction of the solution pH to values representative of endosomal/lysosomal compartments induced an increase in the net cationic charge of the core through protonation of the DEAEMA residues. This protonation promotes micelle destabilization and exposure of the hydrophobic BMA residues that destabilize biological membranes. The pH value at which this micelle-to-unimer transition occurred was dependent on the hydrophobic content of the copolymer, with higher BMA-containing copolymer compositions exhibiting pH-induced transitions to the membrane-destabilizing state at successively lower pH values. The ability of the diblock copolymers to deliver pDNA was subsequently investigated using a GFP expression vector in two monocyte cell lines. High levels of DNA transfection were observed for the copolymer compositions exhibiting the sharpest pH transitions and membrane destabilizing activities, demonstrating the importance of tuning the endosomal-releasing segment composition.

title: pH-switchable polymer nanostructures for controlled release
abstract: A diblock copolymer consisting of poly(methyl acrylate) (PMA) and poly(pentafluorophenyl acrylate) (PPFPA) was synthesized by RAFT polymerization methods. The PPFPA block was then substituted with N,N-diisopropylethylenediamine and the end group modified with one of two hydrophilic groups to form pH-responsive copolymers. The self-assembly properties of these polymers were investigated and shown by TEM and DLS to form micelles at acidic pH and vesicles at basic pH. The encapsulation and controlled release of a hydrophilic dye molecule, Rhodamine B, was demonstrated using fluorescence spectroscopy.

title: Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization.
abstract: The objective of the present study was to synthesize novel pH-sensitive block copolymers forming supramolecular assemblies and to explore their potential as poorly water-soluble drug carriers for oral delivery. Diblock copolymers of polyethylene glycol and t-butyl methacrylate (tBMA), ethyl acrylate (EA) or n-butyl acrylate (nBA) were synthesized by atom transfer radical polymerization (ATRP). The pH-sensitive polymers obtained by hydrolysis of t-butyl groups were characterized for aggregation behaviour. Poorly water-soluble model drugs, i.e., indomethacin (IND), fenofibrate (FNB) and progesterone (PRG), were incorporated in supramolecular assemblies by dialysis or oil-in-water (O/W) emulsion methods. Process parameters for emulsion method were studied to maximize drug loading. Progesterone release was evaluated in vitro as a function of pH. Polymers with controlled molecular weights and low polydispersities were obtained by ATRP. All polymers exhibited pH-dependent aggregation behaviour and their critical aggregation concentration (CAC) decreased with increase in the hydrophobic block length. Drug loadings of <6% and 6-14% w/w were achieved by the dialysis and emulsion methods, respectively. Polymer composition, drug concentration and solubilization of polymer in water or dichloromethane (DCM) affected the loading. Progesterone release from supramolecular assemblies increased when the pH of the release medium was raised from 1.2 to 7.2. The results suggest that these supramolecular assemblies with high drug loadings and pH-dependent release kinetics can potentially enhance the oral bioavailability of poorly water-soluble drugs.

title: Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers.
abstract: This review describes our recent efforts on the design and preparation of intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) (PEG-PAA) block copolymers. The polymeric micelles feature a spherical sub-100 nm core-shell structure in which anticancer drugs are loaded avoiding undesirable interactions in vivo. Chemical modification of the core-forming block of PEG-PAA with a hydrazone linkage allows the polymeric micelles to release drugs selectively at acidic pH (4-6). Installation of folic acids on the micelle surface improves cancer cell-specific drug delivery efficiency along with pH-controlled drug release. These intelligent micelles appear to be superior over classical micelles that physically incorporate drugs. Studies showed both controlled drug release and targeted delivery features of the micelles reduced toxicity and improved efficacy significantly. Further developments potentiate combination delivery of multiple drugs using mixed micelles. Therefore clinically relevant performance of the polymeric micelles provides a promising approach for more efficient and patient-friendly cancer therapy.

title: Polymer--cisplatin conjugate nanoparticles for acid-responsive drug delivery.
abstract: We report the synthesis of novel acid-responsive therapeutic nanoparticles (NPs) with sub-100 nm size consisting of polymer--cisplatin conjugates. The uniqueness of these drug delivery polymeric NPs lies in the covalent conjugation of each cisplatin drug to the hydrophobic segment of two biocompatible diblock copolymer chains through a hydrazone bond, resulting in highly differential drug release profile at different environmental acidity. We demonstrate that the synthesized polymer--cisplatin conjugates can readily precipitate to form sub-100 nm NPs in aqueous solution due to their very low critical micelle concentration (CMC). The resulting NPs show well-controlled cisplatin loading yield, excellent acid-responsive drug release kinetics, and enhanced in vitro cytotoxicity against ovarian cancer cells as compared to free cisplatin. As an environmentally sensitive drug delivery vehicle, these NPs can potentially minimize the drug loss during NP circulation in the blood, where the pH value is neutral, and trigger rapid intracellular drug release after the NPs are endocytosed by the target cells. This characteristic drug release profile holds the promise to suppress cancer cell chemoresistance by rapidly releasing a high dose of chemotherapy drugs inside the tumor cells, thereby improving the therapeutic efficacy of the drug payload.

title: A novel pH- and ionic-strength-sensitive carboxy methyl dextran hydrogel.
abstract: A fast and simple method for the preparation of pH-sensitive hydrogel membranes for drug delivery and tissue engineering applications has been developed using carbodiimide chemistry. The hydrogels were formed by the intermolecular cross-linking of carboxymethyl dextran (CM-dextran) using 1-ethyl-(3-3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). Infrared spectra of the hydrogels suggest the formation of ester bonds between the hydroxyl and carboxyl groups in the CM-dextran. The porosity of the hydrogels produced, as shown by protein diffusion, increases in response to changes in the pH and the ionic strength of the external medium. The results show pH-dependent swelling behaviour arising from the acidic pedant groups in the polymer network. The diffusion of the protein lysozyme through the hydrogel membranes increased with increases in both pH (5.0-9.0) and ionic strength. The effect of changes of pH and ionic strength on the hydrogel's permeability was shown to be reversible. Scanning electron microscopy of these hydrogels showed that pH-dependent changes in permeability are mirrored by morphological changes in gel structure.

title: Effects of end group polarity and molecular weight on the lower critical solution temperature of poly(N‐isopropylacrylamide)
abstract: The lower critical solution temperatures (LCSTs) for mass fractionated samples of poly(N-isopropylacrylamide) (PNIPAM) were studied to determine the effect of polymer molecular weight on the LCST using a high throughput temperature gradient apparatus. PNIPAM fractions prepared by a conventional radical polymerization using azoisobutyronitrile (AIBN) as the initiator had LCSTs that were largely invariant with molecular weight or dispersity. Only slight deviations were noted with lower molecular weight samples. An 18-kDa sample had a 0.6 °C higher LCST. A 56-kDa sample had a 0.2 °C higher LCST. PNIPAM derivatives prepared with a triphenylmethyl (trityl) functionalized azo initiator were also prepared and mass fractionated. These samples' LCSTs were identical to those of PNIPAM samples prepared using AIBN initiation when higher molecular weight samples were compared. The trityl-containing PNIPAM fractions' LCSTs varied when the molecular weight decreased below 100 kDa. Acidolysis of the trityl end groups provided a third set of PNIPAM derivatives whose LCST differed only with samples with Mw values < 60 kDa. These results show there is no effect of molecular weight on LCST until the degree of polymerization is such that end group structure becomes significant.

title: "Smart" alginate-hydroxypropylcellulose microbeads for controlled release of heparin.
abstract: "Smart" (thermosensitive) alginate-hydroxypropylcellulose (Alg/HPC) microbeads for controlled release of heparin were synthesized and the release profiles at various temperatures and for various alginate/HPC compositions were measured. Microbeads of regular spherical shape (ca. 3 microm in diameter) containing efficiently encapsulated heparin were obtained using an emulsification method. The internal structure of the bead was estimated by fluorescence microscopy using dansyl alginate as a labelled component. The microbeads surface structure and morphology were imaged in a dry state using scanning electron microscopy (SEM) and in water using atomic force microscopy (AFM). The microbead surface was shown to be covered by the regular network of pores with a mesh of ca. 30-60 nm. Lower critical solution temperature (LCST) of the Alg/HPC systems was measured spectrophotometrically (cloud point measurements). Heparin release profiles were obtained based on spectrophotometric detection of heparin complex with Azure A. Three-stage sustained release for at least 16 days was observed at 37 degrees C. This was correlated with the size of the pores present at the surface of microbeads. The release profile can be controlled by the temperature and composition of the Alg/HPC microbeads.

title: Fast pH- and Ionic Strength-Responsive Hydrogels in Microchannels
abstract: A simple method for the preparation of pH- and ionic strength-sensitive hydrogels that exhibit fast response times is described. Patterned hydrogel objects were prepared inside microchannels by photopolymerization of monomer mixtures containing water and surfactant. The swelling process, initiated by an abrupt change in pH, exhibited second-order kinetics. Compared to conventional hydrogels synthesized from a neat monomer mixture alone, the new hydrogels swell and shrink faster by approximately one order of magnitude. Fully swollen hydrogels prepared from mixtures containing water and surfactant were observed to be sensitive to ionic strength changes. The effects of cross-linking density and acrylic acid composition on the response rate were investigated and were found to have little effect on response times. The fast response was thus attributed to the porous structure generated from the surfactant phase template during the polymerization.

title: “Smart” materials-based near-infrared light-responsive drug delivery systems for cancer treatment: A review
abstract: To overcome drawbacks of conventional chemotherapy for cancer treatment, stimuli-responsive drug delivery systems (DDSs) including internal and external stimuli-based cues are the potential candidates. Both internal and external stimuli-responsive behavior can be utilized for engineering of the so-called ‘smart’ DDSs. Drug release triggered by external stimuli is more controllable and avoid individual variability. Among them, light-responsive DDSs are more promising because of spatiotemporal control. With considerable penetration features, near-infrared (NIR) light is potential stimulus with clinical implication. There are three types of NIR-responsive DDSs (NIRDDSs) based on the mechanism, i.e., (1) photothermal effect, (2) two-photon absorption, and (3) up-converting nanoparticles (UCNPs). Photothermal effect-based DDS has been extensively studied because of their tunable optical properties and flexible surface chemistry. Carbon nanomaterials, gold nanomaterials, indocyanine green, and metallic sulfides/oxides are the commonly employed photothermal agents. Two-photon absorption-based DDSs provide higher excitation and overcome the drawback of UV/Visible light-sensitive DDSs of poor penetration. UCNPs are inorganic crystalline nanoscale particles (1–100 nm) that exhibit photon up-conversion, i.e., conversion of NIR excitation light into UV/Visible emission light and empower deeper penetration into biological samples due to reduced light scattering. In this review, we discussed different NIRDDSs. The emphasis was also given to their drug release mechanisms and applications in the treatment of cancer.

title: Internal stimuli-responsive nanocarriers for drug delivery: Design strategies and applications.
abstract: The design of internal stimuli-responsive nanocarriers has been extensively used for delivery of various active compounds including drugs, peptides and genes. These nanosystems are not only designed for improved solubility, enhanced bioavailability, and prolonged blood circulation time, furthermore, they can be tailored chemically to achieve selective drug release at the desired sites of action, which can enable them to bypass physiological or pathological obstacles and achieve enhanced therapeutic efficacy. This review presents current functional moieties responsive to a variety of internal stimuli, including pH, redox, enzyme, temperature. Their design strategies and biomedical applications are also highlighted in detail. It is expected that this review can provide inspiration and impetus for exploiting more promising internal stimuli-responsive nano-systems for drug delivery.

title: Dual-drug loaded Janus graphene oxide-based thermoresponsive nanoparticles for targeted therapy
abstract: Graphene oxide (GO) is extensively recognized as an effective material in a variety of fields and specifically for various biomedical applications. However, the modification of each side of a GO sheet, needed for preparation of heterogeneous nanoparticles, is yet hypothetical and unclear. Here, we have developed a new strategy for the synthesis of two-faced GOs by simultaneous anchoring of different polymers with different hydro-affinity via Pickering emulsion (two-phase media). Alkynyl-modified GO was prepared for unsymmetrically attaching azidated-poly(ɛ-caprolactone) (PCL) and (N-isopropylacrylamide-co-acrylamide-co-allylamine) terpolymer to the surface of GO through click reaction. During this reaction, a thermoresponsive nanoparticles with specific morphology, known as “Janus” nanostructure, will be produced. PCL/terpolymer homostructure was also fabricated via solution (one-phase) reaction, where two types of polymers were grafted on the both surfaces of GO disorderly, named “mixed” nanoparticles. In the following, drug loaded nanocarriers were synthesized by simultaneously using quercetin and 5-FU as hydrophobic and hydrophilic drugs. The bioapplicability of these nanoparticles were evaluated by comparison of their in vitro release profiles and cell cytotoxicity at two temperatures of 37 and 40 °C.

title: NIR-controlled morphology transformation and pulsatile drug delivery based on multifunctional phototheranostic nanoparticles for photoacoustic imaging-guided photothermal-chemotherapy.
abstract: Stimuli-responsive nanoparticles are focused to promote the pathological specificity and controlled therapeutic activation in biomedicine, but the multifunctional modulation remains challenging. Herein, size and morphology switchable phototheranostic nanoparticles are developed for photoacoustic (PA) imaging-guided photothermal-chemotherapy. Multifunctional polypyrrole (PPy) nanoparticles with the template of upper critical solution temperature (UCST) polymers are designed to achieve light-controlled pulsatile drug release and concurrent activation of photothermal therapy (PTT). Wherein the UCST-featured inner core is loaded with camptothecin (CPT), the outer corona is tethered with thermo-cleavable doxorubicin (DOX) prodrug and further in-situ coated with PPy, affording the resultant CPT@DOX-UCST/PPy nanoparticles. Upon 808 nm continuous laser illumination, significant heating generated from light-absorbable PPy results in DOX prodrug cleavage and considerable size swelling (∼125-fold), which in turn promotes simultaneous dual drug release, and thus triggering the combined therapeutic activation of PTT and chemotherapy. When laser is switched off, the discontinued photothermal generation makes the nanoparticle shrink back, thereby avoiding the leakage of CPT and DOX. In vivo experiments demonstrate the favorable tumor accumulation and prolonged tumor retention (>24 h) for long-term PA imaging-guided combination therapy. Current multifunctional nanoparticles integrated with light-controlled swelling/shrinking and synergistic therapeutic activation/silence represent a promising platform for precision cancer theranostics.

title: Smart External Stimulus-Responsive Nanocarriers for Drug and Gene Delivery
abstract: The concept of smart drug delivery vehicles involves designing and preparing a nanostructure (or microstructure) that can be loaded with a cargo. This can be a therapeutic drug, a contrast agent for imaging, or a nucleic acid for gene therapy. The nanocarrier serves to protect the cargo from degradation by enzymes in the body, to enhance the solubility of insoluble drugs, to extend the circulation half-life, and to enhance its penetration and accumulation at the target site. Importantly, smart nanocarriers can be designed to be responsive to a specific stimulus, so that the cargo is only released or activated when desired. In this volume we cover smart nanocarriers that respond to internal stimuli that are intrinsic to the target site. These stimuli are specific to the cell type, tissue or organ type, or to the disease state (cancer, infection, inflammation etc). pH-responsive nanostructures can be used for cargo release in acidic endosomal compartments, in the lower pH of tumors, and for specific oral delivery either to the stomach or intestine. Nanocarriers can be designed to be substrates of a wide-range of enzymes that are over-expressed at disease sites. Oxidation and reduction reactions can be taken advantage of in smart nanocarriers by judicious molecular design. Likewise, nanocarriers can be designed to respond to a range of specific biomolecules that may occur at the target site. In this volume we also cover dual and multi-responsive systems that combine stimuli that could be either internal or external.

title: Understanding the phase transition of linear poly(N-isopropylacrylamide) gel under the heating and cooling processes
abstract: Temperature-dependent ATR-FTIR spectra of linear poly( N -isopropylacrylamide) (PNiPAAm) gel during the heating and cooling processes were analyzed by using principal component analysis (PCA) and two-dimensional (2D) correlation spectroscopy. Temperature-dependent variation of bands due to C–H stretching mode and those arising from the C O stretching coupling with N–H bending modes were investigated to better understand coil to globule transition of linear PNiPAAm gel. Results of PCA and 2D correlation spectroscopy demonstrated that the coil to globule transition mechanism of PNiPAAm gel varies for increasing and decreasing temperatures. Furthermore, the change of the side chain is showed variation of main chain in linear PNiPAAm gel during heating process, on the other hands, bands of the vibration of C–H stretching mode are changed before the C O stretching coupling with N–H bending modes during cooling process.

title: PNIPAAM modified mesoporous hydroxyapatite for sustained osteogenic drug release and promoting cell attachment.
abstract: This work presented a sustained release system of simvastatin (SIM) based on the mesoporous hydroxyapatite (MHA) capped with poly(N-isopropylacrylamide) (PNIPAAM). The MHA was prepared by using cetyltrimethylammonium bromide (CTAB) as a template and the modified PNIPAAM layer on the surface of MHA was fabricated through surface-initiated atom transfer radical polymerization (SI-ATRP). The SIM loaded MHA-PNIPAAM showed a sustained release of SIM at 37 °C over 16 days. The bone marrow mesenchymal stem cell (BMSC) proliferation was assessed by cell counting kit-8 (CCK-8) assay, and the osteogenic differentiation was evaluated by alkaline phosphatase (ALP) activity and Alizarin Red staining. The release profile showed that the release of SIM from MHA-SIM-PNIPAAM lasted 16 days and the cumulative amount of released SIM was almost seven-fold than MHA-SIM. Besides, SIM loaded MHA-PNIPAAM exhibited better performance on cell proliferation, ALP activity, and calcium deposition than pure MHA due to the sustained release of SIM. The quantity of ALP in MHA-SIM-PNIPAAM group was more than two fold than pure MHA group at 7 days. Compared to pure MHA, better BMSC attachment on PNIPAAM modified MHA was observed using fluorescent microscopy, indicating the better biocompatibility of MHA-PNIPAAM.

title: Synthesis and characterization of poly (N-isopropylacrylamide)-g-carboxymethyl chitosan copolymer-based doxorubicin-loaded polymeric nanoparticles for thermoresponsive drug release
abstract: Thermoresponsive graft copolymer (PNIPAm-g-OCMC) with PNIPAm and chitosan was prepared by conjugation of amine-terminated PNIPAm with O-carboxymethylchitosan through graft-onto method. The results of FTIR and proton NMR confirmed the synthesis of a copolymer. Furthermore, XRD analysis revealed conjugation reaction of polymeric materials. Doxorubicin-loaded polymeric nanoparticles (D-PNPs) were fabricated using copolymer by gelation method. Morphology illustration through TEM showed the spherical shape of D-PNPs. Particles size measurement study indicates thermoresponsive properties of D-PNPs at various temperatures. Lower critical solution temperature (LCST) of D-PNPs was obtained at 38 °C predicted by turbidimetry analysis. Release studies at three different temperatures notified that thermoresponsive doxorubicin release of D-PNPs. The release of doxorubicin was slower at 25 °C, moderately released at 37 °C, and faster released at 42 °C due to adjustment of the framework of the D-PNPs. Based on the results such as transmittance measurement, particle size observation, and release studies, we declare that the D-PNPs exhibit temperature-responsive behavior, which could make them appropriate for a thermoresponsive drug delivery.

title: Light-triggerable formulations for the intracellular controlled release of biomolecules.
abstract: New therapies based on the use of biomolecules [e.g., proteins, peptides, and non-coding (nc)RNAs] have emerged during the past few years. Given their instability, adverse effects, and limited ability to cross cell membranes, delivery systems are required to fully reveal their biological potential. Sophisticated nanoformulations responsive to light offer an excellent opportunity for the controlled release of these biomolecules, enabling the control of timing, duration, location, and dosage. In this review, we discuss the design principles for the delivery of biomolecules, in particular proteins and RNA-based therapeutics, by light-triggerable formulations. We further discuss the opportunities offered by these formulations in terms of endosomal escape, as well as their limitations.

title: Visible Light Controlled Release of Anticancer Drug through Double Activation of Prodrug.
abstract: We designed and synthesized a novel double activatable prodrug system (drug-linker-deactivated photosensitizer), containing a photocleavable aminoacrylate-linker and a deactivated photosensitizer, to achieve the spatiotemporally controlled release of parent drugs using visible light. Three prodrugs of CA-4, SN-38, and coumarin were prepared to demonstrate the activation of deactivated photosensitizer by cellular esterase and the release of parent drugs by visible light (540 nm) via photounclick chemistry. Among these prodrugs, nontoxic coumarin prodrug was used to quantify the release of parent drug in live cells. About 99% coumarin was released from the coumarin prodrug after 24 h of incubation with MCF-7 cells followed by irradiation with low intensity visible light (8 mW/cm(2)) for 30 min. Less toxic prodrugs of CA-4 and SN-38 killed cancer cells as effectively as free drugs after the double activation.

title: A NIR-controlled cage mimicking system for hydrophobic drug mediated cancer therapy.
abstract: Most chemotherapeutic drugs commonly suffer from several shortcomings, including the lack of aqueous solubility, limited stability and adverse side effects. Although caging strategy has recently been employed as an effective approach to conceal and stabilize these drugs to achieve light-activated cancer therapy, it is plagued by the sophisticated drug modification process and deleterious solvent usage. In addition, using UV or Visible light to remove photocaged group is restricted to its limited tissue penetration ability in and phototoxicity. In this paper, by anchoring photochromic spiropyran on the mesoporous silica coated upconversion nanoparticles (UCNP-SP), we design a NIR-controlled cage mimicking system. Our results indicate that hydrophobic drug can be concealed inside the channels of the nanocarrier with high stability and "uncaged" via NIR irradiation-triggered hydrophobicity-hydrophilicity switch of the spiropyran molecules, finally inducing drug release and recovering their bioactivity. Moreover, under NIR illumination, the UV/Visible emissions from UCNP can also efficaciously initiate the generation of reactive oxygen species (ROS) by Curcumin, further improving the therapeutic efficiency. Both in vitro and in vivo experimental results validate that NIR irradiated nanosystem can produce remarkably enhanced antitumor efficiency.

title: Near-infrared light-triggered drug release from UV-responsive diblock copolymer-coated upconversion nanoparticles with high monodispersity.
abstract: The preparation of a new near-infrared (NIR) light-responsive nanocarrier for controlled drug release is demonstrated. Upconversion nanoparticles (UCNPs) were coated with an amphiphilic diblock copolymer through surface-initiated atom transfer radical polymerization, in which the inner block is hydrophobic, ultraviolet (UV)-sensitive poly(4,5-dimethoxy-2-nitrobenzyl methacrylate) (PNB), and the outer block is hydrophilic poly(methoxy polyethylene glycol monomethacrylate) (POEG). The resulting polymer/UCNP nanocarrier is thermally stable in water over a wide temperature range (5-70 °C) and is uniform in size (120 nm hydrodynamic diameter, polydispersity index <0.1). The diblock copolymer self-assembly on the surface of each UCNP occurs in aqueous solution, which allows encapsulation of antitumor drugs like doxorubicin (DOX) by the hydrophobic "micelle-like" core of PNB surrounding the NIR-sensitive UCNP. Under 980 nm laser exposure, the UV light emitted by the single UCNP is absorbed by the PNB inner layer, which results in cleavage of o-nitrobenzyl groups and formation of carboxylic acid groups. The increasing hydrophilicity of the diblock copolymer resulting from the NIR light-triggered photochemical reaction can thus disrupt the nanocarrier and leads to the release of DOX molecules. This diblock copolymer self-assembly-based approach to constructing NIR light-responsive nanocarriers of well-defined structures is general and offers possibilities for photocontrolled drug delivery.

title: Near‐infrared light‐triggered drug release from a multiple lipid carrier complex using an all‐in‐one strategy
abstract: The present study reports a drug delivery system comprising nanostructured lipid carrier (NLCs) within liposomes (Lip‐NLCs). This multiple lipid carrier complex features laser‐triggered responsive drug release. Both hydrophobic and hydrophilic drugs can be loaded into the same formulation by applying an all‐in‐one strategy. We hypothesized that if we loaded the hydrophobic near‐infrared (NIR) dye IR780 into the liposome phospholipid bilayer, the bilayer would be disrupted by laser irradiation so that drug release would be triggered remotely at the tumor site. We used in vitro and in vivo methods to verify that laser irradiation facilitated controlled release of both hydrophobic and hydrophilic drugs. The degree of drug release triggered by NIR laser light could be adjusted by varying the laser intensity and irradiation time. Following laser treatment, hydrophilic AMD3100 was released from the aqueous liposome chamber and then bound with CXCR4 receptors on the tumor cell surface to inhibit metastasis. NLCs carrying lipophilic IR780 were also released from the aqueous chamber of liposomes and taken up into tumor cells to enhance the photothermal therapeutic effect of IR780. More importantly, Lip‐NLCs loaded with IR780 and AMD3100 (IR780‐AMD‐Lip‐NLCs) exhibited enhanced anti‐tumor and anti‐metastasis effects. These results suggest that Lip‐NLCs are a safe and simply prepared all‐in‐one platform for delivery of drugs with different solubilities. This system facilitates easily controlled release of cargoes to achieve multi‐functional combined therapy.

title: Near-infrared-light responsive nanoscale drug delivery systems for cancer treatment
abstract: Owning to its excellent tissue penetration capacity, near-infrared (NIR)-light has attracted intensive research interests in nanomedicine for either direct photothermal killing of cancers or precisely controlled drug release in recent years. Unlike conventional nanoscale drug delivery systems (NDDSs), NIR-responsive NDDSs can specifically destroy cancer cells under exposure to NIR light, which in the meanwhile shows better tissue penetration compared to visible or UV light with shorter wavelengths. To date, a great number of NIR-light responsive drug delivery systems, by utilizing NIR-light induced photothermal effect, two-photon excitation (TPE), or upconversion nanoparticles (UCNPs), have been successfully fabricated and shown promising treatment outcomes in preclinical experiments. Moreover, by combining with other therapeutic modalities (e.g. chemotherapy, photodynamic therapy, gene therapy), such NIR-light responsive NDDSs may offer promising synergistic effects in cancer treatment. In this review, we will introduce different types of NIR-light responsive systems and the latest progresses in their applications for cancer therapy.

title: Photo-redox activated drug delivery systems operating under two photon excitation in the near-IR.
abstract: We report the design and synthesis of a nano-container consisting of mesoporous silica nanoparticles with the pore openings covered by "snap-top" caps that are opened by near-IR light. A photo transducer molecule that is a reducing agent in an excited electronic state is covalently attached to the system. Near IR two-photon excitation causes inter-molecular electron transfer that reduces a disulfide bond holding the cap in place, thus allowing the cargo molecules to escape. We describe the operation of the "snap-top" release mechanism by both one- and two-photon activation. This system presents a proof of concept of a near-IR photoredox-induced nanoparticle delivery system that may lead to a new type of photodynamic drug release therapy.

title: Improved near infrared-mediated hydrogel formation using diacrylated Pluronic F127-coated upconversion nanoparticles.
abstract: In situ hydrogel synthesis based on photopolymerization has been recognized as a promising strategy that can be used for tissue augmentation. In this study, we developed an efficient in situ gelation method to prepare bulk hydrogels via near infrared (NIR)-mediated photopolymerization using acrylated polyethylene glycol and diacrylated Pluronic F127-coated upconversion nanoparticles (UCNPs). In our system, upon 980-nm laser irradiation, UCNPs transmit visible light, which triggers the activation of eosin Y to initiate polymerization. We found that the UCNPs coated with diacrylated Pluronic F127 can enhance the photopolymerization efficiency and thus enable the production of bulk hydrogel with requirement of a lower NIR light power compared to that required with the bare UCNPs. This photopolymerization approach will be beneficial to achieve in situ polymerization in vivo for various biomedical applications such as cell/drug delivery and construction of tissue augments.

title: A photosensitive liposome with NIR light triggered doxorubicin release as a combined photodynamic‐chemo therapy system
abstract: &NA; The targeted drug delivery with the help of nanocarriers and the controlled drug release at the lesion sites are the most effective ways to enhance therapeutic efficacy and reduce side effects. Here, we built a light sensitive liposome (Her2‐I&D‐LSL) which was formed by a special phospholipid (PLsPC) and a hydrophobically modified photosensitizer (ICG‐ODA). DOX was employed as the therapeutic drug, encapsulating in the internal phase of the liposome whose surface was modified by Her2 antibodies for recognizing tumor cells with high Her2 receptor expression. Mediated by NIR light, Her2‐I&D‐LSL was proved to generate sufficient ROS to realize PDT, which then triggered the release of DOX for combined chemotherapy. The ROS generation and DOX release were verified to be strictly controlled by NIR light and the proportion of ICG‐ODA. Thanks to the mediation of Her2 receptor, the specific DOX release and the combination of PDT‐chemotherapy triggered by NIR light, Her2‐I&D‐LSL showed a significant accumulation in MCF7 and SKOV3 tumors, thus leading to the strongest tumor growth inhibition effect compared to PDT alone (I‐LSL) or chemotherapy alone (D‐LSL). Her2‐I&D‐LSL also possessed a great biocompatibility due to the targeted treatment, holding promise for future cancer therapy in clinic.

title: External triggering and triggered targeting strategies for drug delivery
abstract: Drug delivery systems that are externally triggered to release drugs and/or target tissues hold considerable promise for improving the treatment of many diseases by minimizing nonspecific toxicity and enhancing the efficacy of therapy. These drug delivery systems are constructed from materials that are sensitive to a wide range of external stimuli, including light, ultrasound, electrical and magnetic fields, and specific molecules. The responsiveness conferred by these materials allows the release of therapeutics to be triggered on demand and remotely by a physician or patient. In this Review, we describe the rationales for such systems and the types of stimuli that can be deployed, and provide an outlook for the field. Externally triggered drug delivery systems use both new and established materials that are sensitive to various stimuli. These systems provide opportunities to improve the treatment of many diseases.

title: Magnetic field-inducible drug-eluting nanoparticles for image-guided thermo-chemotherapy.
abstract: Multifunctional nanoparticles integrating cancer cell imaging and treatment modalities into a single platform are recognized as a promising approach; however, their development currently remains a challenge. In this study, we synthesized magnetic field-inducible drug-eluting nanoparticles (MIDENs) by embedding superparamagnetic iron oxide nanoparticles (Fe3O4; SPIONs) and cancer therapeutic drugs (doxorubicin; DOX) in a temperature-responsive poly (lactic-co-glycolic acid) (PLGA) nanomatrix. Application of an external alternating magnetic field (AMF) generated heat above 42 °C and subsequent transition of the PLGA polymer matrix (Tg = 42-45 °C) from the glassy to the rubbery state, facilitating the controlled release of the loaded DOX, ultimately allowing for simultaneous hyperthermia and local heat-triggered chemotherapy for efficient dual cancer treatment. The average size of the synthesized MIDENs was 172.1 ± 3.20 nm in diameter. In vitro studies showed that the MIDENs were cytocompatible and especially effective in destroying CT26 colon cancer cells with AMF application. In vivo studies revealed that the MIDENs enabled enhanced T2 contrast magnetic resonance imaging and a significant suppression of malignant tumor growth under an AMF. Our multifunctional MIDENs, composed of biocompatible substances and therapeutic/imaging modalities, will be greatly beneficial for cancer image-guided thermo-chemotherapy applications.

title: Iron oxide-loaded nanotheranostics: major obstacles to in vivo studies and clinical translation.
abstract: A major issue in current cancer therapies is the lack of selectivity, which leads to damage in healthy tissues. Therefore, researchers have focused on numerous innovative targeting strategies to address this problem with the goal of increasing selectivity to avoid or minimize accumulation in healthy tissues. These strategies include (i) passive targeting, (ii) active targeting and (iii) stimuli-mediated targeting. Moreover, due to the high intra- and inter-variability found in tumors, nanotheranostics, which is the combination of a therapeutic and an imaging agent in a single vector, have emerged as indispensable tools for personalized therapy. Superparamagnetic iron oxide (SPIO) are MRI contrast agents that produce predominant T2 relaxation effects with excellent sensitivity compared with other MRI agents. Therefore, they have received increased interest in the field of theranostics during the past decade. However, few studies have been successfully conducted in vivo. This review aims to provide an overview of the targeted SPIO-based nanotheranostics recently used in pre-clinical studies and the major obstacles to in vivo studies and clinical translation. In the first section, we discuss personalized therapy as a biomedical application of theranostics. Then, we summarize the different imaging agents that have been used for theranostic purposes, with a focus on SPIO. In the third section, we detail recent advances in targeted SPIO-based nanotheranostics that have been used in pre-clinical studies. In the final sections, we discuss the limitations for in vivo studies, clinical translation and the clinical perspectives of SPIO-based nanotheranostics.

title: A pH and magnetic dual-response hydrogel for synergistic chemo-magnetic hyperthermia tumor therapy
abstract: To overcome the toxicity of chemotherapy, increasing attention has been paid to local drug delivery systems (DDSs). pH-Sensitive hydrogels have emerged as promising DDS materials in the biomedical field due to their remarkable characteristics. However, the pH environment in tumor varies from person to person, which makes the applicability of systems based on pH challenging. In this study, we developed a contractible hydroxypropyl methyl cellulose (HPMC)/Fe3O4 hydrogel with dual-response pH and magnetic properties aiming to overcome the limitations of pH-sensitive hydrogel drug delivery systems and further increase their efficiency in tumor therapy. The HPMC/Fe3O4 hydrogel could act as a drug delivery system that combines pH-sensitive triggering and magnetic dual-response drug release for synergistic chemo-magnetic hyperthermia therapy. The drug delivery profile of the HPMC/Fe3O4/doxorubicin hydrochloride (DOX) hydrogel was determined in vitro and revealed a remarkable pH-sensitive performance. After synergistic chemo-magnetic hyperthermia treatment, mice with 4T1 breast cancer xenografts recovered without any recurrence or metastasis, demonstrating the synergistic effect of chemotherapy and magnetic hyperthermia therapy. Meanwhile, reduced toxicity and superior anticancer effects were achieved due to the combined effect of the pH and magnetic hyperthermia response properties. This study demonstrated the high efficacy and low toxicity of the improved design of HPMC/Fe3O4 for drug delivery, which may provide a promising approach for the application of chemo-magnetic hyperthermia cancer therapy.

title: Tough Magnetic Chitosan Hydrogel Nanocomposites for Remotely Stimulated Drug Release.
abstract: As one of important biomaterials for localized drug delivery system, chitosan hydrogel still suffer several challenges, including poor mechanical properties, passive drug release behavior and lack of remote stimuli response. To address these challenges, a facile in situ hybridization method was reported for fabricate tough magnetic chitosan hydrogel (MCH), which remotely switched drug release from passive release to pulsatile release under a low frequency alternating magnetic field (LAMF). The in situ hybridization method avoided the aggregation of magnetic nanoparticles (MNPs) in hydrogel, which simultaneously brings 416% and 265% increase in strength and elastic modulus, respectively. The mechanical property enhancement was contributed by the physical crosslinking of in situ synthesized MNPs. When a LAMF with 15 min ON-15 min OFF cycles was applied to MCH, the fraction release showed zigzag shape and pulsatile release behavior with quick response. The cumulative release and fraction release of drug from MCH were improved by 67.2% and 31.9%, respectively. MTT results and cell morphology indicated that the MCH have excellent biocompatibility and no acute adverse effect on MG-63 cells. The developed tough MCH system holds great potential for applications in smart drug release system with noninvasive characteristics and magnetic field stimulated drug release behavior.

title: Polymer-Grafted Mesoporous Silica Nanoparticles as Ultrasound-Responsive Drug Carriers.
abstract: A new ultrasound-responsive system based on mesoporous silica nanoparticles was developed for biomedical applications, grafting a copolymer on their surface that acts as gatekeeper of the pores. The nanoparticles can be loaded with a cargo at low temperature (4 °C), taking advantage of the open conformation that the polymer presents under these conditions. Then, at 37 °C the copolymer collapses closing the pore entrances and allowing the nanoparticles to carry the drugs at physiological temperature without premature release, which is of great importance when dealing with cytotoxic drugs in cancer treatments. Upon ultrasound irradiation, the sensitive polymer changes its hydrophobicity and, therefore, its conformation toward coil-like opening the gates and releasing the cargo. These hybrid nanoparticles have been shown to be noncytotoxic and can be internalized into LNCaP cells retaining their ultrasound-responsive capability in the cytoplasm of the cells. Moreover, doxorubicin-loaded hybrid MSNs were incubated with LNCaP cells to show their capacity to induce cell death only when the nanoparticles had been exposed to ultrasound. This work demonstrates that our hybrid-MSNs can be triggered by remote stimuli, which is of capital importance for future applications in drug delivery and cancer therapy.

title: On-Demand Drug Release from Dual-Targeting Small Nanoparticles Triggered by High-Intensity Focused Ultrasound Enhanced Glioblastoma-Targeting Therapy.
abstract: Glioblastoma is one of the most challenging and intractable tumors with the difficult treatment and poor prognosis. Unsatisfactory traditional systemic chemotherapies for glioblastoma are mainly attributed to the insufficient and nonspecific drug delivery into the brain tumors as well as the incomplete drug release at the tumor sites. Inspired by the facts that angiopep-2 peptide is an acknowledged dual-targeting moiety for brain tumor-targeting delivery and high-intensity focused ultrasound (HIFU) is an ideal trigger for drug release with an ultrahigh energy and millimeter-sized focus ability, in the present study, a novel HIFU-responsive angiopep-2-modified small poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticle (NP) drug delivery system holding doxorubicin/perfluorooctyl bromide (ANP-D/P) was designed to increase the intratumoral drug accumulation, further trigger on-demand drug release at the glioblastoma sites, and enhance glioblastoma therapy. It was shown that the ANP-D/P was stable and had a small size of 41 nm. The angiopep-2 modification endowed the ANP-D/P with improved blood-brain barrier transportation and specific accumulation in glioblastoma tissues by 17 folds and 13.4 folds compared with unmodified NPs, respectively. Under HIFU irradiation, the ANP-D/P could release 47% of the drug within 2 min and induce the apoptosis of most tumor cells. HIFU-triggered instantaneous drug release at the glioblastoma sites eventually enabled the ANP-D/P to achieve the strongest antiglioblastoma efficacy with the longest median survival time (56 days) of glioblastoma-bearing mice and the minimum vestiges of tumor cells in the pathological slices among all groups. In conclusion, the HIFU-responsive ANP-D/P in this study provided a new way for glioblastoma therapy with a great potential for clinical applications.

title: Mesoporous silica nanoparticles engineered for ultrasound-induced uptake by cancer cells.
abstract: A novel smart hierarchical ultrasound-responsive mesoporous silica nanocarrier for cancer therapy is presented here. This dynamic nanosystem has been designed to display different surface characteristics during its journey towards tumor cells. Initially, the anticancer-loaded nanocarriers are shielded with a polyethylene glycol layer. Upon exposure to high frequency ultrasound, the polymer shell detaches from the nanoparticles, exposing a positively charged surface. This favors the internalization in human osteosarcoma cells, where the release of topotecan takes place, drastically enhancing the cytotoxic effect.

title: PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: In vitro and in vivo investigations.
abstract: A novel ultrasound-responsive liposomal system for tumor targeting was prepared in order to increase the antitumor efficacy and decrease serious side effects. In this paper, PLGA nanoparticles were used ultrasound-responsive agents instead of conventional microbubbles. The PLGA-nanoparticles were prepared by an emulsion solvent evaporation method. The liposomes were prepared by a lipid film hydration method. Particle size, zeta potential, encapsulation efficiency and drug loading capacity of the liposomes were studied by light scattering analysis and dialysis. Transmission electron microscopy (TEM) and atomic force microscope (AFM) were used to investigate the morphology of liposomes. The release in vitro was carried out in the pH 7.4 phosphate buffer solutions, as a result, liposome L3 encapsulating PLGA-nanoparticles displayed good stability under simulative physiological conditions and quickly responsive release under the ultrasound. The release in vivo was carried out on the rats, as a result, liposome L3 showed higher bioavailability than traditional intravenous injectable administration, and liposome L3 showed higher elimination ratio after stimulation by ultrasound than L3 without stimulation. Thus, the novel ultrasound-responsive liposome encapsulating PLGA-nanoparticles has a potential to be developed as a new drug delivery system for anti-tumor drug.

title: Electrically actuatable smart nanoporous membrane for pulsatile drug release.
abstract: We report on the fabrication of electrically responsive nanoporous membrane based on polypyrrole doped with dodecylbenzenesulfonate anion (PPy/DBS) that was electropolymerized on the upper part of anodized aluminum oxide membrane. The membrane has regular pore size and very high pore density. Utilizing a large volume change of PPy/DBS depending on electrochemical state, the pore size was acutated electrically. The actuation of the pores was experimentally confirmed by in situ atomic force microscopy and in situ flux measurement. We also demonstrated successfully pulsatile (or on-demand) drug release by using fluorescently labeled protein as a model drug. Because of a fast switching time (less than 10 s) and high flux of the drugs, this membrane could be used for emergency therapy of angina pectoris and migraine, which requires acute and on-demand drug delivery, and hormone-related disease and metabolic syndrome.

title: Design, engineering and structural integrity of electro-responsive carbon nanotube- based hydrogels for pulsatile drug release.
abstract: Triggerable drug delivery from polymeric implants offers the possibility to generate remote-controlled drug release profiles that may overcome the deficiencies of conventional administration routes (intravenous injections and oral administration) including the toxicity due to overdose and systemic administration. An electro-responsive delivery system was engineered to deliver drug molecules in a pulsatile manner, controlled by the on/off application of electric voltage. Pristine multi-walled carbon nanotubes (pMWNTs) were incorporated into a polymethacrylic acid (PMAA)-based hydrogel matrix by in situ radical polymerisation. The effect of pMWNTs and cross-linker concentration on the electrical and mechanical properties of the hydrogel hybrids was thoroughly investigated. The incorporation of pMWNTs into the polymeric network improved the electrical properties of the hydrogel hybrids and drug release from the gels was significantly enhanced at high pMWNT concentrations, reaching 70% of the loaded dose after two short electrical stimulations. The presence of pMWNTs within the hydrogel matrix affected however the mechanical properties of the hydrogel by decreasing the pore size and therefore the swelling/de-swelling of the gels. The damage to the hybrid gel surfaces after electrical stimulation and the loss of the pulsatile release profile at high cross-linker concentrations suggested that the mechanism of drug release involved a compressing effect and intensified the stress on the polymeric network as a result of the electrical properties of pMWNTs.

title: Drug release from electric-field-responsive nanoparticles.
abstract: We describe a new temperature and electric field dual-stimulus responsive nanoparticle system for programmed drug delivery. Nanoparticles of a conducting polymer (polypyrrole) are loaded with therapeutic pharmaceuticals and are subcutaneously localized in vivo with the assistance of a temperature-sensitive hydrogel (PLGA-PEG-PLGA). We have shown that drug release from the conductive nanoparticles is controlled by the application of a weak, external DC electric field. This approach represents a novel interactive drug delivery system that can show an externally tailored release profile with an excellent spatial, temporal, and dosage control.

title: Electrically controlled release of insulin using polypyrrole nanoparticles.
abstract: Conducting polymers present an opportunity for developing programmable, adjustable, spatially, and temporally controllable drug delivery systems. While several small molecule drugs have been released from thin conductive polymeric films successfully, delivering large molecule therapeutics, such as polypeptides and nucleic acids, has remained a significant challenge. Poor drug loading (∼ng cm-2) of thin films coupled with film instability has, in many cases, made conducting polymer films refractory to clinical development. To address these limitations, we have utilized conductive polymer nanoparticulate backbones to controllably release insulin, a high molecular weight, clinically relevant polypeptide. We find that the interaction between insulin and the polymer scaffold can be described by a simple Langmuir-type adsorption model. By modifying the ratio of the amount of nanoparticles to the amount of insulin, we have obtained drug loading percentages estimated to be as high as 51 wt% percent. In vivo experiments in mice confirmed retained bioactivity of the released insulin after electrical stimulation.

title: Electroresponsive and cell-affinitive polydopamine/polypyrrole composite microcapsules with a dual-function of on-demand drug delivery and cell stimulation for electrical therapy
abstract: Electrical therapy has attracted significant attention because it can modulate cell behaviors and accelerate tissue repair. However, the effectiveness of electrical therapy is limited. This work develops electroresponsive and conductive polydopamine-polypyrrole microcapsules (PDA-PPy-MCs) on titanium surfaces using electrochemical deposition. During the electrochemical process, PDA and dexamethasone (DEX) as the anion are doped into a PPy backbone to neutralize its positive charge. PDA-PPy-MCs possess the cell affinity of PDA, the microstructure of MCs and the electroresponsive capability of PPy. The incorporation of PDA promotes the conductivity and adhesive strength of PPy. PDA-PPy-MCs can respond to electrical signals to release DEX on demand because of the redox behavior of PPy. The microstructure and PDA improve the drug-loading capability of PDA-PPy-MCs. A high-throughput bone marrow stromal cell (BMSC) culture system is designed to study the synergistic effects of composition, microstructure and electrical stimulation on cell behavior. The results indicate that PDA and the microporous structure not only enhance the biocompatibility of PDA-PPy-MC but also strengthen the effect of electrical stimulation. In vivo implantation shows that PDA-PPy-MCs have good biocompatibility. The high cell affinity, microstructure, conductivity and ability to control drug delivery using electrical signals make PDA-PPy-MCs a promising candidate for an on-demand drug delivery and electrical therapy system. Turning conductive polymers into porous microcapsules makes it easier to deliver drugs and modify cell behavior using electrical stimulation. Electrical therapy can treat diseases such as Parkinson's by altering how cells grow and communicate with each other. Xiong Lu and co-workers from Southwest Jiaotong University in China now report a way to improve the precision of electrical treatments using porous electroresponsive microcapsules on three-dimensional printed porous titanium. The microcapsules consist of conductive polypyrrole molecules and cell-friendly mussel-inspired polydopamine units, and were prepared using polystyrene spheres template by electrochemical deposition. The microporous material capable of on-demand loading and release of drugs. High-throughput studies of bone marrow stromal cell cultures demonstrated that the new polymer can manipulate cell behavior by the synergistic effects of porous structure, cell-friendly units and electrical potentials during incubation. Electrical therapy has been recognized as an alternative medical treatment for tissue repair in recent years. The principle of electrical therapy is the modulation of cell behavior by applying electrical signals. However, to date, the effectiveness of electrical therapy is limited. Herein, we developed electroresponsive and conductive polydopamine-polypyrrole microcapsules on the surfaces of electrical therapy devices, which can locally and precisely release drugs and apply electrical stimulation to modulate cell behaviors.

title: On demand delivery of ionic drugs from electro-responsive CNT hybrid films
abstract: Electro-responsive hybrid hydrogel films were prepared by UV-induced polymerization of Acrylamide and N,N′-ethylene bisacrylamide to be applied for the on/off delivery of therapeutics. Multi-walled carbon nanotubes were covalently incorporated into films and acted as a functional element for both enhancing the electro-responsivity and modulating the release of anionic and cationic drugs as diclofenac sodium salt and ciprofloxacin. Hybrid hydrogel films were characterized by Raman spectroscopy, optical microscopy, conductivity measurements, and biocompatibility on human mesenchymal stem cells. Swelling behaviour and drug release profiles were evaluated in the presence of an external applied electric voltage and mathematically modelled. The application of an external electric voltage resulted in a faster release of anionic drugs, while a slower release was recorded for cationic drugs.

title: Rational Design of Multi-Stimuli-Responsive Nanoparticles for Precise Cancer Therapy.
abstract: Stimuli-responsive nanoparticles with target capacity are of great interest in drug delivery for cancer therapy. However, the challenge is to achieve highly smart release with precise spatiotemporal control for cancer therapy. Herein, we report the preparation and properties of multi-stimuli-responsive nanoparticles through the co-assembly of a 3-arm star quaterpolymer with a near-infrared (NIR) photothermal agent and chemotherapeutic compound. The nanoparticles can exhibit NIR light/pH/reduction-responsive drug release and intracellular drug translocation in cancer cells, which further integrate photoinduced hyperthermia for synergistic anticancer efficiency, thereby leading to tumor ablation without tumor regrowth. Thus, this rational design of nanoparticles with multiple responsiveness represents a versatile strategy to provide smart drug delivery paradigms for cancer therapy.

title: Dual pH/reduction-responsive hybrid polymeric micelles for targeted chemo-photothermal combination therapy.
abstract: The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed new pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs exhibited nano-sized structure (∼100 nm) with good monodispersity, high encapsulation efficiency of both ICG and DOX, triggered DOX release in response to acid pH and reduction environment, and excellent temperature conversion with laser irradiation. In vitro cellular uptake study indicated FA Co-PMs achieved significant targeting to BEL-7404 cells via folate receptor-mediated endocytosis, and laser-induced hyperthermia further enhanced drug accumulation into cancer cells. In vivo biodistribution study indicated that FA Co-PMs prolonged drug circulation and enhanced drug accumulation into the tumor via EPR effect and FA targeting. Furthermore, the ICG-based photo-triggered hyperthermia combined with DOX-based chemotherapy synergistically induced the BEL-7404 cell death and apoptosis, and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs were promising theranostic nanocarriers for versatile antitumor drug delivery and imaging-guided cancer chemo-photothermal combination therapy.



The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed novel pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs triggered DOX release in response to acid pH and reduction environment and exhibited excellent temperature conversion with laser irradiation. The results indicated FA Co-PMs achieved significant targeting to BEL-7404 cells in vitro and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs displayed great potential in imaging-guided cancer chemo-photothermal combination therapy as theranostic nanocarriers.

title: Synthesis and biological evaluation of redox/NIR dual stimulus-responsive polymeric nanoparticles for targeted delivery of cisplatin.
abstract: Functional drug delivery systems enabling various favorable characteristics including specific targets, efficient cellular uptake and controllable release. At present work, a folate and cRGD dual modified nanoparticles based on NIR light and glutathione dual stimuli-responsive release system was successfully prepared and which simultaneously deliver cisplatin and ICG to tumor sites to enhance controllability. The prepared nanoparticles showed a stable uniform spherical morphology of 77.59 nm particle size range in PBS (pH = 7.4, 25 °C) and the encapsulated cisplatin were rapidly released in acidic environment especially added glutathione (GSH) and NIR irradiation. Moreover, the prepared nanoparticles can be efficiently internalized by tumor cells through the enhanced dual targeted ligands (folate and cRGD) for ICG imaging. The cytotoxicity assays showed that the cells viability decreased to 1.95% (SGC-7901) when been exposed to NIR light, and which further decreased to 1.25% in MCF-7 cells. Thus, the prepared nanoparticles showed excellent performance for photothermal conversion therapy of tumor cells and especially on human breast tumor cells. Our research highlights the great potential of stimuli-responsive smart nanoparticles in biomaterial and nano-biomedicine.

title: Construction of polymer coated core–shell magnetic mesoporous silica nanoparticles with triple responsive drug delivery
abstract: Multi-responsive drug delivery systems are playing a very important role in nanomedicine, as they can feature as smart carriers releasing their payload on demand. In this study, magnetic, reductive and thermo triple-responsive nanocarriers based on core–shell magnetic mesoporous silica nanoparticles (MMSNPs) modified with a thermo responsive polymer poly(N-isopropylacrylamide) (PNIPAAm) have been developed. Photoinduced electron/energy transfer-reversible addition fragmentation chain transfer (PET-RAFT) polymerization, mediated by a ruthenium-based photoredox Ru(bpy)3Cl2 catalyst was used to graft PNIPAAm onto MMSNPs. A series of characterization and testing techniques were applied to confirm the structures of the synthesized nanocarriers to assess their efficiency as drug delivery systems. Doxorubicin (DOX) was easily encapsulated into the nanocarriers with a high loading capacity, and quickly released in response to the triple-responsive systems. The MMSNPs remained intact in all synthetic steps, during the loading of the drug and the in vitro release tests. Thus, these multi responsive polymer grafted Fe3O4-capped-MSN models are not only magnetically guided, but also represent a promising candidate in the formulation of targeted delivery of therapeutic agents to temperature and more reductive environment tissues, such as tumors and inflammatory sites.