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Liposome-based drug delivery systems composed of DOPE stabilized with cholesteryl hemisuccinate (CHMS) have been proposed as a drug delivery mechanism with pH-triggered release as the anionic form (CHSa) is protonated (CHS) at reduced pH; PEGylation is known to decrease this pH sensitivity. In this manuscript, we set out to use molecular dynamics (MD) simulations with a model with all-atom resolution to provide insight into why incorporation of poly(ethyleneglycol) (PEG) into DOPE–CHMS liposomes reduces their pH sensitivity; we also address two additional questions: (1) How CHSa stabilizes DOPE bilayers into a lamellar conformation at a physiological pH of 7.4? and (2) how the change from CHSa to CHS at acidic pH triggers the destabilization of DOPE bilayers? We found that (A) CHSa stabilizes the DOPE lipid membrane by increasing the hydrophilicity of the bilayer surface, (B) when CHSa changes to CHS by pH reduction, DOPE bilayers are destabilized due to a reduction in bilayer hydrophilicity and a reduction in the area per lipid, and (C) PEG stabilizes DOPE bilayers into the lamellar phase, thus reducing the pH sensitivity of the liposomes by increasing the area per lipid through penetration into the bilayer, which is our main focus.

This work is dedicated to the investigation of drug-release control by a direct effect of degradation from biodegradable metallic surfaces. Degradation behaviors characterized by surface morphology, immersion, and electrochemical techniques demonstrated that curcumin-coated zinc (c-Zn) had a higher degradation rate compared to curcumin-coated Fe (c-Fe). High anodic dissolution rate due to the higher degradation rate and widely extended groove-like degradation structure of c-Zn propelled a higher curcumin release. On the other hand, a slower curcumin release rate shown by c-Fe scaffolds is ascribed to its lower anodic dissolution and to its pitting degradation regime with relatively smaller pits. These findings illuminate the remarkable advantage of different degradation behaviors of degradable metallic surfaces in directly controlling the drug release without the need for external electrical stimulus.

Triggered release from responsive drug reservoirs activated by remote stimuli is desired in a range of fields. Critical bottlenecks are cost-efficient formulation avenues applicable for industrial scale-up, viable triggers and immediate release rather than continuous release upon activation. UV-sensitive microcapsules based on self-immolating polymers in combination with thin shells and morphological weak spots should allow for immediate triggered release. Polyphthalaldehyde-based microcapsules were prepared using several variations of the internal phase separation route. In addition, a fluorescence microscopy method was developed to study both the microcapsule morphology and the triggered release in-situ. The microcapsule formation was driven by the surface activity of the stabilizer, effectively lowering the high polymer-water interfacial tension, which is in sharp contrast to conventional encapsulation systems. Contrary to previous findings, a core-shell morphology was obtained via slow emulsion-to-suspension transformation. Rapid transformation captured intermediate inverted core-shell structures. The capsules were highly sensitive to both acid- and UV-mediated triggers, leading to an unzipping and rupturing of the shell that released the core content. Poly(methacrylic acid)-stabilized microcapsules displayed immediate UV-triggered release provided by their stimuli-sensitive blueberry morphology. Both capsules in aqueous and dry environment started to lose their core content after less than one minute of UV light exposure.

Purpose: The aim of this study was to develop and evaluate a liposome formulation that deliver oxaliplatin under magnetic field stimulus in high concentration to alleviate the off-target effects in a rat model of colorectal liver metastases (CRLM). Materials and Methods: Hybrid liposome-magnetic nanoparticles loaded with Cy5.5 dye and oxaliplatin (L-NIR- Fe3O4/OX) were synthesized by using thermal decomposition method. CRLM (CC-531) cell viability was assessed and rats orthotopically implanted with CC-531 cells were treated with L-NIR-Fe3O4/OX or by drug alone via different routes, up to 3 cycles of alternating magnetic field (AMF). Optical and MR imaging was performed to assess the targeted delivery. Biodistribution and histology was performed to determine the distribution of oxaliplatin. Results: L-NIR-Fe3O4/OX presented a significant increase of oxaliplatin release (~18%) and lower cell viability after AMF exposure (p

The design of biocompatible multiple emulsions is an important challenge in the field of controlled delivery systems for protecting and delivering compounds encapsulated and protected in the innermost phase. In this paper, we use biocompatible water – Miglyol®812 water-in-oil-in-water (W/O/W) emulsions stabilized by a stimuli-responsive diblock copolymer consisting of poly(dimethylsiloxane) (PDMS) and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) to design an easy-to-process new delivery W/O/W system. Such emulsions are formed in a single emulsification step. They present a high encapsulation yield and are shown to be stable over months. As such, the encapsulation of a hydrophilic dye (Alexa fluor) in the innermost water phase is successfully demonstrated over months. These emulsions are stimulable either by a shift in pH level or in ionic strength. The former destabilizes the multiple emulsion and leads to a simple one while the latter partly maintains the multiple character. Eventually both stimulations are effective in the dye release and molecular mechanisms are proposed for explaining the observed two-stage kinetics of release.

Peptides have attracted great interests due to their potential for versatile application in preparation of drug carriers because of their specific targeting capability to desired tissues and bioresponsiveness toward various biological molecules such as enzymes for selective cleavage or bio-responsive folding into specific conformation. Therefore, the introduction of peptides as a gatekeeper on the surface would provide MSNs with triggered release property of guest molecules in response to a variety of biological stimuli including specific enzymes at specific target sites. In this review, we discuss the recent progress of peptide gatekeepers on MSNs by classification of the stimuli for triggering the release of payloads from the mesopore. We also describe the on-off gatekeepers by employing the motif of conformational transformation of peptides in response to external stimuli. The myriad biological functions of peptides by interaction with biomolecules, cells and organs endow the peptide gatekeepers on MSNs with great potential to construct smart nanocarriers.

A new set of PVA hydrogels were formed using the boronate ester fluorescent probe, PF1 and the novel boronate fluorescent probe PT1 as the covalent crosslinkers. Treatment with aqueous H2O2 allowed triggered release of the fluorescent dye accompanied by complete dissolution of the hydrogel

Thermosensitive liposomes, as one of the stimuli-responsive drug delivery systems, receive growing attention, due to their ability to generate rapid and massive drug release in the heated area, and marginal release of contents in non-heated parts of the body. This typical triggered release behavior cannot be fitted adequately by most of the current mathematical kinetic models. The aim of this study was to establish the proper kinetic equation to describe the rapid release of drugs from trigger-sensitive drug delivery systems. We summarized all commonly used kinetic models mentioned in the literature and fitted the release data with these models, finding that only the Korsmeyer-Peppas and the Weibull models show acceptable fitting results. To better describe the release from thermosensitive liposomes with a size below 100 nm, we took Laplace pressure as a release-driving force and proposed a new equation that demonstrates improved fitting in liposomes ranging down to a size of 70 nm. Our new kinetic model shows desirable fitting, not only at the optimal temperature but also of releases within the whole release-temperature range, providing a useful kinetic model to describe release profiles of smaller nano-sized stimuli-responsive drug delivery systems.

Summary Efficient strategies for the preparation of nanostructures with tailorable functionalities have implications in enhancing the repertoire of nanomaterials in many applications. Multi-component reactions (MCRs) are very attractive because they are synthetically simple while providing unique access to incorporation of functional groups onto a system. This highly efficient process has not been brought to bear in the preparation of functional polymeric nanostructures. In this paper, we report a three-component sequential reaction that is capable of concurrently functionalizing the core and the surface of the nanoparticles and crosslinking the polymeric assemblies, along with excellent control over size (∼10 nm to ∼1 μm). Variations in core offer the opportunity to optimize the host-guest properties for non-covalent drug encapsulation, while the surface features provide the ability to tune interfacial interactions and achieve organelle targeting in cells. Encapsulation of drug molecules and their triggered release features have been utilized for intracellular drug delivery.

Growing clinical evidence around the value of delivering drugs with pulsatile, user-controlled, or patient-specific kinetics has recently resulted in extensive efforts toward the design of new functional materials that can enable on-demand externally triggered drug release using noninvasive or minimally invasive stimuli such as temperature changes, magnetic fields, light, ultrasound, and/or electric fields. While substantial technical improvements have been made toward achieving longer-term and user-defined release kinetics from such materials (based principally on innovation in materials design and the development of various triggering modalities), clinical translation of such technologies remains in its infancy; specifically, multiple residual challenges exist around the chemical complexity, biological responses, and predictability of externally triggered release vehicles when used in vivo. In this perspective, we aim to outline major recent advances in the development of externally triggered drug deliv...

Cinnamaldehyde is a natural product with antibacterial, antifungal, and anti-inflammatory properties, poorly stable in environmental conditions. Systems for the controlled release of cinnamaldehyde are of great interest to the food and pharmaceutical industries. Here, a new oxide-based construct for the release of cinnamaldehyde catalyzed by acidic pH was obtained by a facile grafting method based on amino-silane linkers and imine chemistry. The grafting procedure led to a loading of ca. 5 molecules/nm2, determined on oxide powders with CHN and TGA measurements. The covalent grafting of cinnamaldehyde, demonstrated by FTIR analyses, preserved the molecule stability, simplifying storage. Release tests were performed at different pH values (between 5.0 and 7.4). Thanks to imine chemistry, a fast cinnamaldehyde (CIN) release was observed in a pH 5.0 environment. Using 1 mg/mL suspensions, CIN concentrations within the range adopted in the food industry were obtained (12.4 ppm). The grafting procedure was also performed on a porous film based on a photocatalytic oxide, demonstrating the versatility of this method, adaptable to both powders and macroscopic materials. By taking advantage of the photoactivity of the oxide, regeneration of the fouled film was achieved upon UV irradiation for 1 h, opening the door to reusable devices for the controlled release of cinnamaldehyde.

Since more than 40 years liposomes have being extensively studied for their potential as carriers of anticancer drugs. The basic principle behind their use for cancer treatment consists on the idea that they can take advantage of the leaky vasculature and poor lymphatic drainage present at the tumor tissue, passively accumulating in this region. Aiming to further improve their efficacy, different strategies have been employed such as PEGlation, which enables longer circulation times, or the attachment of ligands to liposomal surface for active targeting of cancer cells. A great challenge for drug delivery to cancer treatment now, is the possibility to trigger release from nanosystems at the tumor site, providing efficacious levels of drug in the tumor. Different strategies have been proposed to exploit the outer and inner tumor environment for triggering drug release from liposomes and are the focus of this review.

The Diels-Alder reaction and its retro breakdown has garnered increasing research focus due to several of its advantageous properties including, atomic conservation, reversibility, and substituent retention. This is especially true in biomedical application and nanomedicine development which display a preference for rapid, efficient, and clean “click” chemistry reactions allowing for delivery of active ingredients and subsequent release upon temperature elevation. There are multiple variations on the Diels-Alder reaction based around substitution position and materials being coupled which can affect the temperature threshold for and rate of the retro reaction reversal. Hence, the Diels-Alder reaction offers a simple coupling reaction for active ingredients with tailorable release. In this review the incorporation of the Diels-Alder chemistries and linkers within the biomedical and nanomedicine field will be discussed, as well as its use in future potential technologies.

International audience; Several investigations have suggested that ultrasound triggers the release of drugs encapsulated into liposomes at acoustic pressures low enough to avoid cavitation or high hyperthermia. However, the mechanism leading to this triggered release as well as the adequate composition of the liposome membrane remain unknown. Here, we investigate the ultrasound triggered release of fluorescein disodium salt encapsulated into liposomes made of 1,2-dioleoyl-sn-glycero-3-phosphocholi (DOPC) or 1,2-distearoylphosphatidylethanolamie (DSPC) lipids with various concentrations of cholesterol (from 0 to 44 mol%). The passive release of encapsulated fluorescein was first characterized. It was observed to be higher when the membrane is in a fluid phase and increased with temperature but decreased upon addition of cholesterol. Next, the release of fluorescein was measured at 1 different acoustic frequencies (0.8, 1.1, 3.3 MHz) and peak-to-peak pressures (0, 2, 2.5, 5, 8 MPa). Measurements were performed at temperatures where DOPC and DSPC liposomes were respectively in the fluid or gel phase. We found that the release rate did not depend on the ultrasound frequency. For DOPC liposomes, the ultrasoundtriggered release of fluorescein decreased with increasing concentration of cholesterol in liposomes, while the behavior was more complex for DSPC liposomes. Overall, the triggered release from DSPC liposomes was up to ten times less than DOPC liposomes. Molecular dynamics simulations performed on a pure DOPC membrane showed that a membrane experiences, under a directional pressure of ±2.4 MPa, various changes in properties such as the area per lipid (APL). An increase in APL was notably observed when the simulation box was laterally stretched or perpendicularly compressed, which was accompanied by an increase in the number of water molecules crossing the membrane. This suggests that ultrasound most probably enhances the diffusion of encapsulated molecules at small acoustic pressures by increasing the distance between lipids.

Pyraclostrobin (Pyr) is one of the most effective fungicides. However, it can degrade via photolysis in water, it is toxic to aquatic life and if inhaled, it has a low solubility in water, that leads to difficulties when applying to plants by spraying. Additionally, the necessity of repeated (weekly) sprays of fungicides when the pathogen growth risk is the highest, such as at the temperature range of 24 to 36 &deg, C and increased humidity of about 95%, leads to loss of efficiency of the fungicide and overdose of chemicals. In the present study, pyraclostrobin was microencapsulated to solve the abovementioned issues. As a core of capsules octadecane (OD) with a melting point of 28 &deg, C was used, thus, the release of pyraclostrobin was controlled via temperature change. Pyraclostrobin-loaded submicrocapsules (PyrSMCs) were characterized using SEM, DLS, TGA/DSC, HPLC, FTIR methods, stimuli-responsivity was tested employing in vitro tests with pathogenic culture (Fungal strain of Pyrenophora teres - CPPF-453) grown in Petri dishes. Toxicity of PyrSMCs to Artemia salina was studied as well. Size of capsules was 200&ndash, 600 nm along with the presence of bigger capsules with a diameter of 1&ndash, 4 &micro, m. PyrSMCs showed excellent antifungal effects above the melting point of octadecane. PyrSMCs demonstrated 29 times less toxicity than pyraclostrobin of technical grade. Overall, results show the potential of such capsules to be applied in the agricultural industry for precise agriculture strategies.

Carbohydrate-based materials offer exciting opportunities for drug delivery. They present readily available, biocompatible components for the construction of macromolecular systems which can be loaded with cargo, and can enable targeting of a payload to particular cell types through carbohydrate recognition events established in biological systems. These systems can additionally be engineered to respond to environmental stimuli, enabling triggered release of payload, to encompass multiple modes of therapeutic action, or to simultaneously fulfil a secondary function such as enabling imaging of target tissue. Here, we will explore the use of glycomacromolecules to deliver therapeutic benefits to address key health challenges, and suggest future directions for development of next-generation systems.

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are gaseous signaling molecules (gasotransmitters) that regulate both physiological and pathological processes and offer therapeutic potential for the treatment of many diseases, such as cancer, cardiovascular disease, renal disease, bacterial and viral infections. However, the inherent labile nature of therapeutic gases results in difficulties in direct gases administration and their controlled delivery at clinically relevant ranges. Metal-organic frameworks (MOFs) with highly porous, stable, and easy-to-tailor properties have shown promising therapeutic gas delivery potential. Herein, we highlight the recent advances of MOF-based platforms for therapeutic gas delivery, either by endogenous (i.e., direct transfer of gases to targets) or exogenous (i.e., stimulating triggered release of gases) means. Reports that involve in vitro and/or in vivo studies are highlighted due to their high potential for clinical translation. Current challenges for clinical requirements and possible future innovative designs to meet variable healthcare needs are discussed.

The fabrication of novel and intelligent delivery systems that can effectively deliver therapeutics to the targeted site and release payload in enhanced/controlled manner is highly desired to overcome the multiple challenges in chemotherapy. The present article demonstrates the potential application of dual stimuli responsive nanogels as tumor microenvironment targeted drug delivery carrier. Disulfide cross-linked pH and redox responsive PEG-PDMAEMA nanogels were synthesized by atom transfer radical polymerization (ATRP). The nanogels were characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The PEG-PDMAEMA nanogels exhibited dual stimuli-responsive release of the encapsulated model anticancer drug (doxorubicin, DOX) due to the acidic pH-response of dimethyl amine group in PDMAEMA and reductive cleavage of the disulfide linkages. A relatively higher release of DOX was observed from the nanogels at pH 5.0 than at pH 7.4. DOX release was further accelerated in tumor simulated environment of pH 5.0 and 10 mM glutathione (GSH). Confocal microscopy images revealed that DOX-loaded PEG-PDMAEMA nanogels can rapidly internalize and effectively deliver the drug into the cells. The nanogels exhibited higher cytotoxicity in GSH-OEt pretreated HeLa cells than untreated cells. The dual stimuli responsive nanogels synthesized in this study exhibited many favorable traits, such as pH and redox dependent controlled release of drug, biodegradability, biocompatibility, and enhanced cytotoxicity, which endow them as a promising candidate for anticancer drug delivery.

In last few years, encapsulation of therapeutics inside of the carriers in order to protect them from decadence and programmed delivery into the target cells has become one of the most captivating and well-known research areas in both computational and biological chemistry. However, there are still many unanswered critical questions. One of the most important questions is the mechanism of drug encapsulation and release from carriers especially Boron Nitride Nanotubes (BNNTs). In this study, molecular dynamic simulation was used to study the encapsulation and release process of Gemcitabine (GEM) from BNNTs in the presence of Au cluster as a releasing agent. We realized that nanotube size extremely affects the interaction of Au clusters and nanotube which is the primary factor defining the stability of Au clusters inside of the BNNTs. Our results showed that in BNNT (17,0), Au clusters have the highest interaction with the nanotube internal wall. Interestingly, we realized that the tendency of single Au cluster differs from the collection of clusters and this phenomenon leads to the release of cargo from nanotube. Finally, we realized that van der Waals interactions are determinative energy in GEM release.

Because of their size (1-10 μm), microbubble-based drug delivery agents suffer from confinement to the vasculature, limiting tumor penetration and potentially reducing the drug efficacy. Nanobubbles (NBs) have emerged as promising candidates for ultrasound-triggered drug delivery because of their small size, allowing drug delivery complexes to take advantage of the enhanced permeability and retention effect. In this study, we describe a simple method for production of nested-nanobubbles (Nested-NBs) by encapsulation of NBs (∼100 nm) within drug-loaded liposomes. This method combines the efficient and well-established drug-loading capabilities of liposomes while utilizing NBs as an acoustic trigger for drug release. Encapsulation was characterized using transmission electron microscopy with an encapsulation efficiency of 22 ± 2%. Nested-NBs demonstrated echogenicity using diagnostic B-mode imaging, and acoustic emissions were monitored during high-intensity focused ultrasound (HIFU) in addition to monitoring of model drug release. Results showed that although the encapsulated NBs were destroyed by pulsed HIFU [peak negative pressure (PNP) 1.54-4.83 MPa], signified by loss of echogenicity and detection of inertial cavitation, no model drug release was observed. Changing modality to continuous wave (CW) HIFU produced release across a range of PNPs (2.01-3.90 MPa), likely because of a synergistic effect of mechanical and increased thermal stimuli. Because of this, we predict that our NBs contain a mixed population of both gaseous and liquid core particles, which upon CW HIFU undergo rapid phase conversion, triggering liposomal drug release. This hypothesis was investigated using previously described models to predict the existence of droplets and their phase change potential and the ability of this phase change to induce liposomal drug release.

Facile bio-inspired approach has been developed to prepare novel DOX-loaded chicken feather keratin-based core-crosslinked micelles (DOX/Ker-PEG CCMs) for pH and reduction dual-responsive tumor-specific intracellular triggered DOX delivery, by oxidation crosslinking the DOX/Ker-PEG micelles which were simply self-assembled by adjusting solution pH value to 10. The final DOX/Ker-PEG CCMs with a mean hydrodynamic diameter of 152 nm were obtained with a drug loading capacity (DLC) of 24.8%. The in vitro controlled release profiles demonstrated the pH and reduction dual-responsive triggered release of DOX from the developed bio-inspired drug delivery system (DDS), with a cumulative release of 58% within 3 days in a sustained release manner in the stimulated tumor intracellular microenvironment, while a low premature drug leakage of 14% occurred in the normal physiological medium. Furthermore, the MTT assays demonstrated that the graft copolymer Ker-PEG58 possessed excellent cytocompatibility, while the DOX/Ker-PEG CCMs exhibited an enhanced anti-tumor efficacy on the HepG2 cells than the free DOX.

Single cell manipulation is important in biosensing, biorobotics, and quantitative cell analysis. Although microbeads, droplets, and microrobots have been developed previously, it is still challenging to simultaneously excise, capture, and manipulate single cells in a biocompatible manner. Here, we describe untethered single cell grippers, that can be remotely guided and actuated on-demand to actively capture or excise individual or few cells. We describe a novel molding method to micropattern a thermally responsive wax layer for biocompatible motion actuation. The multi-fingered grippers derive their energy from the triggered release of residual differential stress in bilayer hinges composed of silicon oxides. A magnetic layer enables remote guidance through narrow conduits and fixed tissues sections ex vivo. Our results provide an important advance in high-throughput single cell scale biopsy tools important to lab-on-a-chip devices, microrobotics, and minimally invasive surgery.

An on-demand anesthetic that would only take effect when needed and where the intensity of anesthesia could be easily adjustable according to patients’ needs would be highly desirable. Here, we design and synthesize a macromolecular prodrug (P407-CM-T) in which the local anesthetic tetracaine (T) is attached to the polymer poloxamer 407 (P407) via a photo-cleavable coumarin linkage (CM). P407-CM-T solution is an injectable liquid at room temperature and gels near body temperature. The macromolecular prodrug has no anesthetic effect itself unless irradiated with a low-power blue light emitting diode (LED), resulting in local anesthesia. By adjusting the intensity and duration of irradiation, the anesthetic effect can be modulated. Local anesthesia can be repeatedly triggered., Local anesthetic sustained release systems suffer from untriggered rapid drug release upon application. Here the authors overcome this issue by covalently linking tetracaine to a polymer gel via a photo-cleavable linkage, enabling light-triggered and repeatable drug release.

Smart multifunctional drug delivery systems (DDSs) based on cytophilic fluorescent polyurethane copolymer microcapsules with high tumor cell internalization, triggered release, quick cancer cell death and real time fluorescent monitoring abilities is developed as a facile and versatile approach for precision cancer therapy.

Light triggered release of an antibiotic from a click crosslinked hydrogel was developed by conjugating ciprofloxacin through a photo-cleavable linker to the hydrogel network structure. Upon irradiation of the hydrogel material with UV light (365 nm) at low intensity, native ciprofloxacin was released into the surrounding environment and could be detected by HPLC. The antimicrobial activity of the released compound on Staphylococcus aureus was demonstrated.

Visible-light-responsive materials sparked wide interest due to visible light possessing some merits like no byproduct formation, environmental friendliness, and nearly zero energy consumption. In ...

Nanomedicines in polymeric therapeutics present a potential treatment for cancers. However, their clinical effectiveness still has room to be improved. Herein, reduction-responsive reversibly core-cross-linked micelles based on the poly(ethylene glycol)-dihydrolipoic acid (MeO-PEG

Endowing surfaces with multiple advanced functionalities, such as temperature-controlled swelling or the triggered release of functional small molecules, is attractive for a large variety of applications ranging from smart textiles to advanced biomedical applications. This Invited Feature Article summarizes recent advances in the development of upper critical solution temperature (UCST) behavior of copolymers in aqueous solutions and compares the fundamental differences between lower critical solution temperature (LCST) and UCST transitions. The effect of polymer chemistry and architecture on UCST transitions is discussed for block copolymer micelles (BCMs) and star polymers in solution and assembled at surfaces. The inclusion of such nanocontainers (i.e., BCMs and star polymers) in layer-by-layer (LbL) coatings and how to control their responsive behavior through deposition conditions and binding partners is explored. Finally, the inclusion and temperature-triggered release of functional small molecules is explored for nanocontainers in LbL coatings. Taken together, UCST nanocontainers containing LbL films are promising building blocks for the development of new generations of practical, functional surface coatings.

A facile one-pot approach has been developed to prepare novel pH-responsive ionic nanohydrogels with high drug-loading capacity and desirable size for tumor-specific intracellular triggered release of anticancer drug DOX, in which the ionic crosslinking of alginate (AL) or its derivatives (oxidized alginate (OAL) or PEGylated OAL (mPEG-OAL)) and the DOX-loading ocurred simultaneously. It was found that the modification was benificial to the formation of the DOX-loaded ionic nanohydrogels with smaller diameter and narrower size distribution, even with similar DOX loading capacity. Especially for the mPEG-OAL, the resultant mPEG-OAL/DOX ionic nanohydrogels showed a hydrodynamic diameter of 135 nm with very narrow size distribution. All the three DOX-loaded ionic nanohydrogels (AL/DOX, OAL/DOX, and mPEG-OAL/DOX) showed the pH-responsive characteristic, and the last one exhibited the best capacity for controlled release, in a sustained release mode.

The low volatility of many ionic liquids (ILs) can be used to design a specific delivery system with a triggered release mechanism for volatile fragrances. We present two different strategies for IL-supported profragrance compounds based on common fragrance alcohols. When the fragrance was attached to the cation, its release was triggered by heat, while the fragrance attached to the anion was released under basic conditions. Selection of the counterion allowed not only control of the physical properties of the resulting compound but also addition of a second functionality. Our design strategy shows that the choice of the IL components can result in safe, biocompatible ionic profragrances suitable for applications such as topical nutraceutical or cosmetic formulations.

PEGylated multi-walled carbon nanotubes (PEG-MWCNTs) were optimized as versatile vector for tumor-specific intracellular triggered release of doxorubicin (DOX), based on the effect of their length and PEGylation degree on the cytotoxicity and DOX-loading capacity. The length and surface carboxyl groups of the carboxylated multi-walled carbon nanotubes (CMWCNTs) were easily tailored by adjusting the oxidation time. The longer CMWCNTs or those with high carboxyl group content showed obvious cytotoxicity, while the PEG-MWCNTs ≤ 300 nm showed better cytocompatibility. The PEG-MWCNTs-3 of about 300 nm was selected as drug delivery vector, possessing a high drug-loading capacity of 0.55 mg/mg. They released DOX rapidly under lower pH media mimicking the tumor microenvironment with cumulative release of 57% within 24 h, while the premature leakage under the simulated physiological condition was only 10%. The WST-1 assays demonstrated the DOX-loaded PEG-MWCNTs-3 exhibited the enhanced inhibitory efficiency against HepG2 cells, in comparison with free DOX.

Hierarchical self-assembly of synthetic polypeptides has attracted increasing interests due to its protein-mimetic structure and great potential in nanotechnology and biomedical applications. However, controlling the morphology and function of polymeric nanostructures via secondary structures remains largely unexplored. Here, we report an unusual micelle-to-vesicle transformation of cholesterol-decorated poly(l-cysteine) copolymer assemblies in response to reactive oxygen species (ROS). We found that the interesting morphological transition correlates with the alteration in conformations from β-sheet to α-helix, which grants an attractive "on-off" switch for triggered release and cellular interaction. We further demonstrated the usefulness of the conformation-regulated assembly strategy both in vitro and in vivo, taking cancer treatment as a model. The work offers a new insight on the folding and hierarchical assembly of polypeptides and a novel approach for the development of smart platforms in biosensing, disease treatment, and diagnostic applications.

The aim of this study was to deliver ribonuclease A (RNase A) intracellularly using dextran nanogels for cancer treatment. To this end, positively charged RNase A was electrostatically loaded in anionic dextran nanogels with an average size of 205 nm, which were prepared by an inverse mini-emulsion technique. To chemically immobilize the loaded protein in the nanogels and prevent its unwanted release in the extracellular environment, the protein was covalently linked to the nanogel network via disulfide bonds, which are cleavable in the reductive cytosolic environment. A high loading efficiency and loading content of RNase A (75% and 20%, respectively) were obtained. Coating of the nanogels with the cationic polymer polyethyleneimine reversed the zeta potential of nanogels from −31.6 mV to +7.6 mV. The nanogels showed a fast and triggered release of RNase in the presence of glutathione. Negatively charged RNase A loaded nanogels did not show cytotoxicity, likely due to their limited cellular uptake. In contrast, PEI coated RNase A loaded nanogels showed high uptake by MDA-MB 231 breast cancer cells and exhibited a concentration-dependent cytotoxic effect by apoptosis. The results demonstrate that PEI coated nanogels are promising nano-carriers for intracellular protein delivery, encouraging further evaluation of this formulation in preclinical models.

The development of platforms for the controlled release of therapeutic molecules remains a crucial research focus, as controlled release reduces the frequency of administration, minimizes side effects and improves compliance. However, biological conditions and diseases with a progression that exhibits strong temporal dependence, or those that can result in the evolution of tolerance to the therapeutic during continuous exposure, require the development of sophisticated release systems tailored to the needs to the individual and the disease. Thus, there has been emphasis on the development of platforms with remotely controlled release mechanisms. Specifically, magnetically triggered release utilizes magnetic nanoparticles as the remote control modality. Many reviews discuss the magnetically triggered release of small molecule drugs, however, the release of biomacromolecules has not been reviewed. This review examines the limited work on the magnetically triggered release of biomacromolecules and th...

While providing the ability to magnetically enhance delivery rates, ferrogels have not been able to produce the various types of regulated delivery profiles likely needed to direct complex biological processes . For example, magnetically triggered release after prolonged periods of payload retention have not been demonstrated and little has been accomplished towards remotely controlling release rate through alterations in the magnetic signal. Also, strategies do not exist for magnetically coordinating multi-drug sequences. The purpose of this study was to develop these capabilities through improved ferrogel design and investigating how alterations in the magnetic signal impact release characteristics. Results show that delivery rate can be remotely regulated using the frequency of magnetic stimulation. When using an optimized biphasic ferrogel design, stimulation at optimized frequencies enabled magnetically triggered deliveries after a delay of 5 days that were 690- to 1950-fold higher than unstimulated baseline values. Also, a sequence of two payloads was produced by allowing one payload to initially diffuse out of the ferrogel, followed by magnetically triggered release of a different payload on day 5. Finally, it was demonstrated that two payloads could be sequentially triggered for release by first stimulating at a frequency tuned to preferentially release one payload (after 24 h), followed by stimulation at a different frequency tuned to preferentially release the other payload (After 4 days). The strategies developed here may expand the utility of ferrogels in clinical scenarios where the timing and sequence of biological events can be tuned to optimize therapeutic outcome.

The preparation and use of nanostructured lipid carriers (NLCs) as drug delivery system is constantly growing. NLCs are prepared from synthetic or natural lipids with known, but not controlled, melting point. Here we propose the preparation of NLCs combining natural lipids to have selected melting temperature. Vegetable butters were subjected to gas chromatography to determine and define each constituent and melting point. Three different NLCs suspensions were prepared from a specific blend of vegetable butters, adjusted to start melting at 29, 37 or 42°C, and characterized. Precise engineering of the delivery system will contribute to efficient temperature triggered release.

Nanocapsules with a hydrophilic core are particularly interesting for biomedical and anticorrosion applications since these nanocontainers allow encapsulating a wide range of hydrophilic payloads and controlling their release profiles. However, a major challenge associated with the preparation of these nanocapsules is the non-controlled leakage of hydrophilic payloads from the core due to osmotic pressure. Herein, we present an approach for the preparation of polymer nanocapsules that suppress the non-controlled leakage of payloads and respond to chemical reduction that triggers release of encapsulated payloads. The non-controlled leakage of hydrophilic payloads from the nanocapsules is hindered by increasing the shell thickness. These nanocapsules consisting of reduction-responsive units possess a remarkable release property only under reductive condition while cease non-controlled leakage of the payload in the aqueous release medium. The described nanocapsules can be applied for biomedical and anticorrosion applications in which triggered release of hydrophilic payloads is suitable.

The design of appropriate thermally responsive fragrance carrier systems is of significant importance for the application of fragrance in the food and tobacco industries. In this study, we investigate the potential of sorbitan monostearate and guar gum for the stabilization of menthol under ambient conditions and the thermally-induced release of menthol. Our results show that the sorbitan monostearate carrier could well stabilize the menthol for at least up to 15 days with neglectable menthol loss due to the favorable binding of menthol on the sorbitan monostearate carrier. In addition, rapid and controlled release of menthol could take place at a temperature of 80 &deg, C in the sorbitan monostearate carrier system. As a comparison, guar gum could not stabilize menthol as a result of its poor compatibility. Our results suggest that sorbitan monostearate can be an ideal carrier material for the support of fragrance. In addition, our results also provide a useful guide for the tailored design of thermally responsive fragrance carriers.

Theranostic agents based on near-infrared absorption which integrate both imaging and therapeutic functions have attracted considerable attention. However, because of the interference signal, indiscriminate treatment usually causes side effects on normal tissues during tumor treatment. To address this limitation, we propose a new synergistically triggered mechanism, release and self-assembly of Au nanospheres, for tumor theranostics based on the synergistic effect of H+ and glutathione on the tumor microenvironment. In vitro experiments reveal that Au nanospheres release from Au@ZIF-8 at a high concentration of H+ or glutathione. Importantly, Au aggregation only appears in the synergistic effect of glutathione and lower pH and exhibits strong coupling plasmonic resonance absorption in the near-infrared region and can be used as the theranostics agent. This statement was further verified by biological transmission electron microscopy and in vivo imaging. Au@ZIF-8 is stable and produces no photoacoustic signal in normal tissue; in contrast, in the presence of overexpressed glutathione and H+, Au nanospheres release from Au@ZIF-8, assemble to aggregates, and exhibit a strong signal at the tumor site for imaging and efficient photothermal therapy. This work provides a new strategy for designing theranostic agents with sequentially responsive steps to avoid interference diagnosis signals from normal tissues and reduce damage to normal tissue during treatment.

Two different drug micro-carriers consisting of doxorubicin-dextran (DOX-D)- and camptothecin-modified carboxymethyl cellulose (CPT-CMC)-loaded nucleic acid-stabilized microcapsules, MC-1 and MC-2, or two different nanocarriers consisting of nucleic-acid-locked doxorubicin (DOX)- and camptothecin (CPT)-loaded metal-organic framework nanoparticles, NMOF-1 and NMOF-2, are coupled to auxiliary constitutional dynamic networks, CDNs, for the triggered release of the drugs. CDN "S" composed of four constituents AA'', AB', BA', and BB', and two hairpin structures, H1 and H2, leads to the CDN "S"-guided unlocking of the MC-1/MC-2 carriers and the release of DOX-D and CPT-CMC or of the NMOF-1 and NMOF-2 carriers that release DOX and CPT, respectively. The unlocking processes are activated by the cleavage of H1 and H2 by BB' and BA', respectively, to yield fragmented strands that unlock the gating units of the microcapsules/NMOFs carriers. In the presence of miRNA-155 or miRNA-124, dictated orthogonal reconfiguration of CDN "S" into CDN "X" or "Y" proceeds. The miRNA-155 stimulates the reconfiguration of CDN "S" to CDN "X", where AA' and BB' are upregulated, and AB' and BA' are downregulated, leading to the enhanced release of DOX-D or DOX from the microcapsule/NMOFs carriers, and to the concomitant inhibition of the release of CPT-CMC or CPT from the respective carriers. Similarly, the miRNA-124-triggered reconfiguration of CDN "S" to CDN "Y" results in the BA'-guided cleavage of H2 and the preferred release of CPT-CMC or CPT from the respective carriers. The miRNA-triggered CDN-driven unlocking of the carriers stimulates the amplified and selective release of the drugs from the microcapsules/NMOFs carriers.

Nanotechnology has great capability in formulation, reduction of side effects, and enhancing pharmacokinetics of chemotherapeutics by designing stable or long circulating nano-carriers. However, effective drug delivery at the cellular level by means of such carriers is still unsatisfactory. One promising approach is using spatiotemporal drug release by means of nanoparticles with the capacity for content release triggered by internal or external stimuli. Among different stimuli, interests for application of external heat, hyperthermia, is growing. Advanced technology, ease of application and most importantly high level of control over applied heat, and as a result triggered release, and the adjuvant effect of hyperthermia in enhancing therapeutic response of chemotherapeutics, i.e., thermochemotherapy, make hyperthermia a great stimulus for triggered drug release. Therefore, a variety of temperature sensitive nano-carriers, lipid or/and polymeric based, have been fabricated and studied. Importantly, in order to achieve an efficient therapeutic outcome, and taking the advantages of thermochemotherapy into consideration, release characteristics from nano-carriers should fit with applicable clinical thermal setting. Here we introduce and discuss the application of the three most studied temperature sensitive nanoparticles with emphasis on release behavior and its importance regarding applicability and therapeutic potentials.

Liposomes, lipid-based vesicular systems, have attracted major interest as a means to improve drug delivery to various organs and tissues in the human body. Recent literature highlights the benefits of liposomes for use as drug delivery systems, including encapsulating of both hydrophobic and hydrophilic cargos, passive and active targeting, enhanced drug bioavailability and therapeutic effects, reduced systemic side effects, improved cargo penetration into the target tissue and triggered contents release. Pioneering work of liposomes researchers led to introduction of long-circulating, ligand-targeted and triggered release liposomes, as well as, liposomes containing nucleic acids and vesicles containing combination of cargos. Altogether, these findings have led to widespread application of liposomes in a plethora of areas from cancer to conditions such as cardiovascular, neurologic, respiratory, skin, autoimmune and eye disorders. There are numerous review articles on the application of liposomes in treatment of cancer, which seems the primary focus, whereas other diseases also benefit from liposome-mediated treatments. Therefore, this article provides an illustrated detailed overview of liposomal formulations, in vitro characterization and their applications in different disorders other than cancer. Challenges and future directions, which must be considered to obtain the most benefit from applications of liposomes in these disorders, are discussed.

Spirotetramat metabolizes to its active enol form in the plant. We described here a photocaged pesticide delivery system that can release insecticidal spirotetramat enol form upon light irradiation. Covalently linking spirotetramat-enol with photoresponsive coumarin generated the caged insecticide. The photophysical and photochemical properties, deprotection photolysis and insecticidal activities of the caged spirotetramat enol were studied. This light-triggered system can undergo cleavage to release free spirotetramat enol form at the presence of blue light (420 nm) or sunlight. Bioassays indicated that the triggered molecule has no obvious insecticidal activity against Aphis craccivora Koch at dark and could be activated by light to release the insecticidal ingredients, which provides precise control over insecticide delivery.

Graphene Derivatives (GDs) have captured the interest and imagination of pharmaceutical scientists. This review exclusively provides pharmacokinetics and pharmacodynamics information with a particular focus on biopharmaceuticals. GDs can be used as multipurpose pharmaceutical delivery systems due to their ultra-high surface area, flexibility, and fast mobility of charge carriers. Improved effects, targeted delivery to tissues, controlled release profiles, visualization of biodistribution and clearance, and overcoming drug resistance are examples of the benefits of GDs. This review focuses on the application of GDs for the delivery of biopharmaceuticals. Also, the pharmacokinetic properties and the advantage of using GDs in pharmaceutics will be reviewed to achieve a comprehensive understanding about the GDs in pharmaceutical sciences.

Introduction: The improvement of percutaneous absorption represents a clear dermatopharmaceutical aim. Recently, the hair follicle was recognized to be an important penetration pathway. Especially nanoparticles show an enhanced intrafollicular penetration and can be utilized to target specific cell populations within the hair follicle.Areas covered: The present review briefly summarizes the recent advances in follicular drug delivery of nanoparticles. Moreover, the particularities of the hair follicle as a penetration pathway are summarized which include its structure and specific barrier properties. Recently, the mechanism of the follicular penetration process has been clarified.In the meantime, different strategies have been developed to successfully improve follicular drug delivery of nanoparticles. One approach is to equip the nanocarriers with a triggered release system enabling them to release their drug load at the right time and place.Expert opinion: Follicular drug delivery with smart nanocarrier-based drug delivery systems represents a promising approach to increase the percutaneous absorption of topically applied substances. Although technical achievements and efficacy proofs concerning an increased penetration of substances are already available, the practical implementation into clinical application still represents an additional challenge and should be in the focus of interest in future research.

Post-operative infection is a catastrophic complication of spinal fusion surgery, with up to 10% occurrence, and existing preventative measures (i.e., peri-operative antibiotics) are only partially successful. To combat this clinical problem, we have designed a drug delivery system around polyetheretherketone (PEEK) clips to be used for prophylactic post-surgical release of antibiotics upon application of ultrasound. The overall hypothesis is that antimicrobial release from this system will aggressively combat post-surgical bacterial survival. This study investigated a set of acoustic parameters optimized for in vitro ultrasound-triggered coating rupture and subsequent release of encapsulated prophylactic antibiotics. We determined that a transducer frequency of 1.7 MHz produced the most consistent burst release, and that at this frequency a pulse repetition frequency of 6.4 kHz and acoustic output power of 100% (3.41 MPa) produced the greatest release, representing an important proof of principle and the basis for continued development of this novel drug delivery system.

Long-circulating PEG-modified liposome has been shown to improve pharmacokinetic properties and reduce systemic toxicity in cancer treatment. However, drug bioavailability from liposome remains a major challenge to the improvement of its therapeutic efficacy. Previously, we designed a PEGylated dual-effect liposome (named as PL-Dox-Ce6) with chlorin e6 incorporated in the lipid bilayer and Doxorubicin encapsulated in the interior. In this study, another dual-effect liposome with cisplatin encapsulated in the interior was further developed. The pharmacokinetics of these two dual-effect liposomes were studied in tumor-bearing mice. Based on the kinetic data of tumor and plasma, light irradiation was applied onto the tumors at different time points after drug administration to compare the therapeutic efficacy. We demonstrated that a single dose of the dual-effect liposomes combined with two doses of light irradiation can completely eradicate over 90% of the tumor in mice alone with significant survival rate and no toxicity. Thus, this study established a platform that utilizes the dual-effect liposome which combines photodynamic therapy and chemotherapy to improve the therapeutic outcomes of tumors.

Impaired penetration of antibiotics through bacterial biofilms is one of the reasons for failure of antimicrobial therapy. Hindered drug diffusion is caused on the one hand by interactions with the sticky biofilm matrix and on the other hand by the fact that bacterial cells are organized in densely packed clusters of cells. Binding interactions with the biofilm matrix can be avoided by encapsulating the antibiotics into nanocarriers, while interfering with the integrity of the dense cell clusters can enhance drug transport deep into the biofilm. Vapor nanobubbles (VNB), generated from laser irradiated nanoparticles, are a recently reported effective way to loosen up the biofilm structure in order to enhance drug transport and efficacy. In the present study, we explored if the disruptive force of VNB can be used simultaneously to interfere with the biofilm structure and trigger antibiotic release from light-responsive nanocarriers. The antibiotic tobramycin was incorporated in two types of light-responsive nanocarriers&mdash, liposomes functionalized with gold nanoparticles (Lip-AuNP) and graphene quantum dots (GQD)&mdash, and their efficacy was evaluated on Pseudomonas aeruginosa biofilms. Even though the anti-biofilm efficacy of tobramycin was improved by liposomal encapsulation, electrostatic functionalization with 70 nm AuNP unfortunately resulted in premature leakage of tobramycin in a matter of hours. Laser-irradiation consequently did not further improve P. aeruginosa biofilm eradication. Adsorption of tobramycin to GQD, on the other hand, did result in a stable formulation with high encapsulation efficiency, without burst release of tobramycin from the nanocarriers. However, even though laser-induced VNB formation from GQD resulted in biofilm disruption, an enhanced anti-biofilm effect was not achieved due to tobramycin not being efficiently released from GQD. Even though this study was unsuccessful in designing suitable nanocarriers for simultaneous biofilm disruption and light-triggered release of tobramycin, it provides insights into the difficulties and challenges that need to be considered for future developments in this regard.

In the last few decades, the introduction of microrobotics has drastically changed the way medicine will be approached in the future. The development of untethered steerable microdevices able to operate in vivo inside the human body allows a high localization of the therapeutical action, thus limiting invasiveness and possible medical complications. This approach results are particularly useful in drug delivery, where it is highly beneficial to administer the drug of choice exclusively to the target organ to avoid overdosage and side effects. In this context, drug releasing layers can be loaded on magnetically moveable platforms that can be guided toward the target organ to perform highly targeted release. In the present paper, we evaluate the possible application of alginate hydrogel layers on moveable platforms manufactured by coupling additive manufacturing with wet metallization. Such alginate layers are reticulated using three different physical crosslinkers: Ca, Zn or Mn. Their effect on drug release kinetics and on device functionality is evaluated. In the case of alginate reticulated using Mn, the strongly pH dependent behavior of the resulting hydrogel is evaluated as a possible way to introduce a triggered release functionality on the devices.