Stimuli-responsive Delivery Systems Research Articles

Synthesis and Characterization of Stimuli-Responsive Poly(2-dimethylamino-ethylmethacrylate)-Grafted Chitosan Microcapsule for Controlled Pyraclostrobin Release.

Controllable pesticide release in response to environmental stimuli is highly desirable for better efficacy and fewer adverse effects. Combining the merits of natural and synthetic polymers, pH and temperature dual-responsive chitosan copolymer (CS-g-PDMAEMA) was facilely prepared through free radical graft copolymerization with 2-(dimethylamino) ethyl 2-methacrylate (DMAEMA) as the vinyl monomer. An emulsion chemical cross-linking method was used to expediently fabricate pyraclostrobin microcapsules in situ entrapping the pesticide. The loading content and encapsulation efficiency were 18.79% and 64.51%, respectively. The pyraclostrobin-loaded microcapsules showed pH-and thermo responsive release. Microcapsulation can address the inherent limitation of pyraclostrobin that is photo unstable and highly toxic on aquatic organisms. Compared to free pyraclostrobin, microcapsulation could dramatically improve its photostability under ultraviolet light irradiation. Lower acute toxicity against zebra fish on the first day and gradually similar toxicity over time with that of pyraclostrobin technical concentrate were in accordance with the release profiles of pyraclostrobin microcapsules. This stimuli-responsive pesticide delivery system may find promising application potential in sustainable plant protection.

Dual stimuli-responsive saccharide core based nanocarrier for efficient Birc5-shRNA delivery.

Stimuli-responsive delivery systems show great promise in meeting the requirements of several delivery stages to achieve satisfactory gene transfection. This report describes a novel stimuli-responsive nanocarrier consisting of a dual stimuli-responsive chitosan (SCS) core and a polyethyleneimine (PEI) and polyethylene glycol (PEG) corona. The SCS core was constructed by cross-linking bio-safe chitosan saccharide via pH-sensitive hydrazone bonds and redox-sensitive disulfide bonds, which conferred the nanocarrier with a dual stimuli-responsive property. PEG and low-molecular-weight PEI were further immobilized on the core to endow the synthesized SCS-g-PEI-g-PEG with improved gene condensation, prolonged circulation and enhanced lysosome escape. In vitro and in vivo Birc5-shRNA delivery results revealed that significantly enhanced gene expression and tumor inhibition were achieved by SCS-g-PEI-g-PEG, compared with the non-stimuli-responsive counterpart CS-g-PEI-g-PEG. Moreover, the SCS-g-PEI-g-PEG nanocarrier was biocompatible as shown in both in vitro and in vivo toxicity evaluations. This study may provide a promising strategy for constructing an efficient and bio-safe delivery system for gene therapy.

Thermo-sensitive chitosan copolymer-gold hybrid nanoparticles as a nanocarrier for delivery of erlotinib

Here, using (poly(N-isopropylacrylamide)-co-oleic acid)-g-chitosan ((PNIPAAm-co-OA)-g-CS), CS copolymer-gold hybrid nanoparticles (CGH NPs) were synthesized by autoreduction of auric cations (HAuCl4) in aqueous solution in the absence of any other reducing agent. The engineered thermo-sensitive CS copolymer with free amino groups could reduce auric cations and stabilized the resultant NPs. CGH NPs were prepared using different concentrations of CS copolymer (0.1–1% w/v) and HAuCl4 (50–500μL, 0.2% w/v). They were characterized in terms of structure, surface Plasmon band, zeta potential, atomic absorption, stability, size and size distribution. The obtained CGH NPs showed a size range of 80–100nm and high stability at different pHs with no observable agglomeration/sedimentation for couple of months. The loading efficiency of erlotinib (ETB) in the CGH NPs was about 30%. The ETB was released from the CGH NPs in a thermo-responsive manner. FACS flow cytometry analysis confirmed high cellular uptake (85.81%) of CGH NPs by A549 cells. The cytotoxicity evaluations proved the cytocompatibility and high anti-tumor effect of the engineered CGH NPs. Based on these findings, having used thermo-sensitive CS copolymer, CGH NPs were obtained in one-pot procedure, which could be considered as stimuli-responsive delivery system with potential biomedical applications.

Liposomes as colloidal nanovehicles: on the road to success in intravenous drug delivery

Abstract The advancement of research in colloidal systems has led to the increased application of this technology in more effective and targeted drug delivery. Nanotechnology enables control over functionality parameters and allows innovations in biodegradable, biocompatible, and stimuli-responsive delivery systems. The first closed bilayer phospholipid system, the liposome system, has been making steady progress over five decades of extensive research and has been efficient in achieving many desirable parameters such as remote drug loading, size-controlling measures, longer circulation half-lives, and triggered release. Liposome-mediated drug delivery has been successful in overcoming obstacles to cellular and tissue uptake of drugs with improved biodistribution in vitro and in vivo. These colloidal nanovehicles have moved on from a mere concept to clinical applications in various drug delivery systems for antifungal, antibiotic, and anticancer drugs.

Recent advances in CO2 bubble-generating carrier systems for localized controlled release.

This article reviews recent progress in the development of carbon dioxide (CO2) bubble-generating drug carriers, including their designs and operating mechanisms; these carriers constitute an advanced class of stimuli-responsive delivery systems with considerable potential. The drug carriers contain stimuli-responsive agents, which are stable before they reach the target location, but enable rapid drug release that is triggered by the generation of CO2 bubbles, which are chemically inert, under certain stimuli. These CO2 bubble-generating carrier systems can be used to accumulate locally a delivered drug at the diseased tissue, while reducing side effects on the normal tissue, improving their therapeutic effectiveness. Since the generated CO2 bubbles are hyperechogenic, they may also be used as an ultrasound contrast agent in elucidating the status of the carriers and providing real-time diagnostic images. Perspectives of the future of applications of gases with therapeutic effects, such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), in such bubble-generating carrier systems, are also briefly discussed.

Tailoring stimuli-responsive delivery system driven by metal-ligand coordination bonding.

In this study, a novel coordination bonding system based on metal–tannic acid (TA) architecture on zein/carboxymethyl chitosan (CMCS) nanoparticles (NPs) was investigated for the pH-responsive drug delivery. CMCS has been reported to coat on zein NPs as delivery vehicles for drugs or nutrients in previous studies. The cleavage of either the “metal–TA” or “NH2–metal” coordination bonds resulted in significant release of guest molecules with high stimulus sensitivity, especially in mild acidic conditions. The prepared metal–TA-coated zein/CMCS NPs (zein/CMCS-TA/metal NPs) could maintain particle size in cell culture medium at 37°C, demonstrating good stability compared with zein/CMCS NPs. In vitro release behavior of doxorubicin hydrochloride (DOX)-loaded metal–TA film-coated zein/CMCS NPs (DOX-zein/CMCS-TA/metal NPs) showed fine pH responsiveness tailored by the ratio of zein to CMCS as well as the metal species and feeding concentrations. The blank zein/CMCS-TA/metal NPs (NPs-TA/metal) were of low cytotoxicity, while a high cytotoxic activity of DOX-zein/CMCS-TA/metal NPs (DOX-NPs-TA/metal) against HepG2 cells was demonstrated by in vitro cell assay. Confocal laser scanning microscopy (CLSM) and flow cytometry were combined to study the uptake efficiency of DOX-NPs or DOX-NPs-TA/metal. This system showed significant potential as a highly versatile and potent platform for drug delivery.

Poly(ethyl glyoxylate)-Poly(ethylene oxide) Nanoparticles: Stimuli-Responsive Drug Release via End-to-End Polyglyoxylate Depolymerization

The ability to disrupt polymer assemblies in response to specific stimuli provides the potential to release drugs selectively at certain sites or conditions in vivo. However, most stimuli-responsive delivery systems require many stimuli-initiated events to release drugs. "Self-immolative polymers" offer the potential to provide amplified responses to stimuli as they undergo complete end-to-end depolymerization following the cleavage of a single end-cap. Herein, linker end-caps were developed to conjugate self-immolative poly(ethyl glyoxylate) (PEtG) with poly(ethylene oxide) (PEO) to form amphiphilic block copolymers. These copolymers were self-assembled to form nanoparticles in aqueous solution. Cleavage of the linker end-caps were triggered by a thiol reducing agent, UV light, H2O2, and combinations of these stimuli, resulting in nanoparticle disintegration. Low stimuli concentrations were effective in rapidly disrupting the nanoparticles. Nile red, doxorubin, and curcumin were encapsulated into the nanoparticles and were selectively released upon application of the appropriate stimulus. The ability to tune the stimuli-responsiveness simply by changing the linker end-cap makes this new platform highly attractive for applications in drug delivery.

Development of a dual drug-loaded hydrogel delivery system for enhanced cancer therapy: in situ formation, degradation and synergistic antitumor efficiency.

Herein, a dual drug-loaded hydrogel delivery system was constructed using aldehyded pullulan (A-Pul), ε-poly-l-lysine (ε-PL), and branched polyethylenimine (BPEI) in an aqueous solution via a Schiff base reaction. CDDP and DOX were loaded into the network of hydrogels for combination drug therapy. Gelation time changed from 40 s to 240 s when reaction solutions were stored at different temperatures. Scanning electron microscopy images and swelling dynamics demonstrated that the hydrogels had a homogeneous porous structure and good swelling behavior. The in vitro degradation rate and drug release rate at pH 7.0 were faster than those at pH 7.4; this indicated that the hydrogels displayed controlled drug release and pH-dependent behavior. The hydrogels could be injected and formed in situ and degraded in vivo, and the dual-drug-loaded hydrogel displayed the most efficient tumor inhibition; this indicated the synergistic anticancer effect of the CDDP + DOX combination therapy in H22 liver tumor-bearing mice. Furthermore, the hydrogels displayed no cytotoxicity against Huh-7 cells and exhibited excellent security and biocompatibility in vivo. Therefore, the hydrogels have potential applications as multidrug carriers for enhanced synergistic therapy.

Stimuli-Responsive Polymeric Systems for Controlled Protein and Peptide Delivery: Future Implications for Ocular Delivery.

Therapeutic proteins and peptides have become notable in the drug delivery arena for their compatibility with the human body as well as their high potency. However, their biocompatibility and high potency does not negate the existence of challenges resulting from physicochemical properties of proteins and peptides, including large size, short half-life, capability to provoke immune responses and susceptibility to degradation. Various delivery routes and delivery systems have been utilized to improve bioavailability, patient acceptability and reduce biodegradation. The ocular route remains of great interest, particularly for responsive delivery of macromolecules due to the anatomy and physiology of the eye that makes it a sensitive and complex environment. Research in this field is slowly gaining attention as this could be the breakthrough in ocular drug delivery of macromolecules. This work reviews stimuli-responsive polymeric delivery systems, their use in the delivery of therapeutic proteins and peptides as well as examples of proteins and peptides used in the treatment of ocular disorders. Stimuli reviewed include pH, temperature, enzymes, light, ultrasound and magnetic field. In addition, it discusses the current progress in responsive ocular drug delivery. Furthermore, it explores future prospects in the use of stimuli-responsive polymers for ocular delivery of proteins and peptides. Stimuli-responsive polymers offer great potential in improving the delivery of ocular therapeutics, therefore there is a need to consider them in order to guarantee a local, sustained and ideal delivery of ocular proteins and peptides, evading tissue invasion and systemic side-effects.

Electrochemical techniques for investigating redox active macromolecules

This tutorial provides an overview and introduction to electrochemical analysis techniques, which are useful for studying and characterizing redox active macromolecules. The field of redox active macromolecules encompasses a diversity of molecule classes, which have in common that they are increasingly applied in vital areas such as molecular switches and biomedical devices, but also for stimuli-responsive delivery systems, and in energy-related topics such as (bio)fuel cells, organic solar cells, and electrochemical energy storage systems. Hence, the comprehensive investigation of redox macromolecules in terms of function in dependence of their redox state is a fundamental prerequisite for advancing such applications.

Redox and pH dual-responsive PEG and chitosan-conjugated hollow mesoporous silica for controlled drug release

In this paper, a hollow mesoporous silica nanoparticles (HMSN) was used as the drug vehicle to develop the redox and pH dual stimuli-responsive delivery system, in which the chitosan (CS), a biodegradable cationic polymer, was grafted on the surface of HMSN via the cleavable disulfide bonds. CS was chosen as the gatekeeper mainly due to its appropriate molecular weight as well as possessing abundant amino groups which could be protonated in the acidic condition to achieve pH-responsive drug release. In addition, the PEG was further grafted on the surface of CS to increase the stability and biocompatibility under physiological conditions. The DOX loaded DOX/HMSN-SS-CS@PEG had a relatively high drug loading efficiency up to 32.8%. In vitro release results indicated that DOX was dramatically blocked within the mesopores of HMSN-SS-CS@PEG in pH 7.4 PBS without addition of GSH. However, the release rate of DOX was markedly increased after the addition of 10mM GSH or in pH5.0 release medium. Moreover, the release of DOX was further improved in pH5.0 PBS with 10mM GSH. The HMSN-SS-CS@PEG could markedly decrease the hemolysis percent and protein adsorption, and increase the biocompatibility and stability of HMSN compared with the HMSN-SS-CS and bare HMSN. This work suggested an exploration about HMSN based stimuli-responsive drug delivery and these results demonstrated that HMSN-SS-CS@PEG exhibited dual-responsive drug release property and could be used as a promising carrier for cancer therapy.

Photomodulation of fluoride ion binding through anion-π interactions using a photoswitchable azobenzene system.

The discovery of photoswitchable azobenzene-systems that undergo trans-to-cis photoisomerisation was a milestone in supramolecular chemistry. Such photoswitches have possible applications in data storage, stimuli responsive delivery systems, and molecular machines due to fast and selective switching. However, the light induced cis isomer of azobenzene is rather unstable and reverts thermally and photochemically to the thermodynamically stable trans configuration. We report, for the first time, controlled photoswitching of an azo-naphthalenediimide (azo-NDI) which can be achieved upon binding of fluoride ions through anion-π interaction. This NDI-F–NDI “sandwich” stabilises the cis configuration through the generation of an NDI•− radical anion, and a dianionic, NDI2− species that becomes unusually stable in the cis form. The sandwiched cis form reverts to the trans form only upon decomplexation of F−. A model pollutant was successfully degraded using the photogenerated NDI-F–NDI sandwich. This opens a wide range of applications in molecular and supramolecular nanotechnology.

Sistemas de liberación de insulina sensibles a la glucosa

The design of carriers for insulin delivery has recently attracted major research attentions in the biomedical field. In general, the release of drug from polymers is driven via a variety of polymers. Several mechanisms such as matrix release, leaching of drug, swelling, and diffusion are usually adopted for the release of drug through polymers. Insulin is one of the most predominant therapeutic drugs for the treatment of both diabetes mellitus; type-I (insulin-dependent) and type II (insulin-independent). Currently, insulin is administered subcutaneously, which makes the patient feel discomfort, pain, hyperinsulinemia, allergic responses, lipodystrophy surrounding the injection area, and occurrence of miscarried glycemic control. Therefore, significant research interest has been focused on designing and developing new insulin delivery technologies to control blood glucose levels and time, which can enhance the patient compliance simultaneously through alternative routes as non-invasive insulin delivery. The aim of this review is to emphasize various non-invasive insulin delivery mechanisms including oral, transdermal, rectal, vaginal, ocular, and nasal. In addition, this review highlights different smart stimuli-responsive insulin delivery systems including glucose, pH, enzymes, near-infrared, ultrasound, magnetic and electric fields, and the application of various polymers as insulin carriers. Finally, the advantages, limitations, and the effect of each non-invasive route on insulin delivery are discussed in detail.

Single-Layered MoS2-PEI-PEG Nanocomposite-Mediated Gene Delivery Controlled by Photo and Redox Stimuli.

Stimuli-responsive gene delivery systems maximize therapeutic efficacy by controlling the cytosolic conveyance and rate of effective gene release. We present herein a hybrid nanocomposite composed of a 2D nanomaterial, MoS2, modified by attaching two polymers (polyethylenimine (PEI) and polyethylenglycol (PEG)) via disulfide bonds. This MoS2-PEI-PEG nanocomposite interacts with DNA by electrostatic interaction, and accordingly forms a nanosized complex with high stability. Photothermal conversion of MoS2 nanosheet is employed in order to induce photothermally triggered endosomal escape upon the near infrared light irradiation. After endosomal escape, polymers are detached from the MoS2 nanosheet by the intracellular reducing agent, glutathione (GSH), resulting in effective gene release from the nanocomposite. This sequential process initiated by external and internal stimuli remarkably enhances gene delivery efficiency by effective endosomal escape and gene release without severe cytotoxicity. Our rationally designed MoS2 nanocomposite provides a spatiotemporally controllable platform to deliver genetic material into cells.

Redox and pH dual-responsive mesoporous silica nanoparticles for site-specific drug delivery

In this paper, a mesoporous silica nanoparticles (MSN)-based redox and pH dual-responsive delivery system (MSN-SS-PAA) was developed for site-specific drug delivery, in which poly(acrylic acid) (PAA), a polyanion polymer, was grafted on the outlets of MSN via the cleavable disulfide bonds. PAA was chosen as a gatekeeper to block drugs within the mesopores of MSN mainly because PAA possesses many favorable features, such as appropriate molecular weight to block the entrances of MSNs, good biocompatibility, and ability to prolong the blood circulation time and improve the dispersing stability of MSN in physiological conditions. RhB, a fluorescent dye, was used as a model drug. In vitro release profiles indicated that RhB was markedly blocked within the mesopores in the absence of GSH or in pH 7.4 PBS; however, the release of RhB was dramatically increased after the addition of GSH or in pH 5.0 PBS. Moreover, the release of RhB was further improved in the simultaneous presence of GSH and pH 5.0 PBS. This paper provided an exploration of stimuli-responsive delivery system and the results demonstrated that MSN-SS-PAA exhibiting dual-responsive drug release property can be further considered as a promising candidate for cancer therapy.

ChemInform Abstract: Hyperbranched Polyphosphates: Synthesis, Functionalization and Biomedical Applications

AbstractReview: 50 refs.

Dual stimuli-responsive multi-drug delivery system for the individually controlled release of anti-cancer drugs.

A dual stimuli-responsive multi-drug delivery system was developed for "cancer cocktail therapy". Upon UV irradiation, microcapsules could rapidly release the small-molecule drugs, and thereafter the macromolecular drugs would be released in the presence of MMP in the tumor cells. This system will find great potential as a novel chemotherapeutic combination for cancer treatment.

Eccentric magnetic microcapsules for orientation-specific and dual stimuli-responsive drug release.

In this paper, we fabricated uniform polydimethylsiloxane (PDMS) magnetic microcapsules with eccentric internal structures and employed them as a novel delivery system for orientation-specific and dual stimuli-responsive controlled drug release. These eccentric microcapsules contained Fe3O4 nanoparticles in their inner cores. Because of the paramagnetic Fe3O4 nanoparticles, the eccentric microcapsules could be accurately moved by a magnetic field, leading to the precise control of the microcapsule locations. Also, due to the eccentric structures of the magnetic microcapsules, the capsules exhibited a non-uniform magnetic property; the capsules could be aligned by magnetic fields with their thin walls facing the magnet, resulting in a precise orientation-specific control of the microcapsules. More interestingly, the eccentric magnetic microcapsules demonstrated a dual stimuli-responsive controlled release of inclusions involving a sustained release under ultrasound and an intense release under laser stimulation. Furthermore, we studied the efficacy of doxorubicin (DOX) release from the microcapsules regulated by laser stimulation by performing in vitro cell tests with and without an applied magnetic field. The cell tests showed that the orientation-specific control of the microcapsules under a magnetic field (when the thin walls of the eccentric microcapsules were oriented towards the cell) improved the efficacy of the drug released from the microcapsules. The results suggested that our eccentric magnetic microcapsules hold all the properties needed for a site-specific, orientation-specific and dual stimuli-responsive delivery system, demonstrating a great potential application for multifunctional controlled drug release.

Integration of simultaneous and cascade release of two drugs into smart single nanovehicles based on DNA-gated mesoporous silica nanoparticles

Stimuli-responsive multidrug delivery systems need to be invented for clinical combination therapy by the controlled release behavior of each drug individually. A facile, effective, and universal platform was built for simultaneous and cascade release of two drugs from DNA-gated gold nanorod-embedded mesoporous silica nanoparticles (MSNs) functionalized with titanium(IV)-chelating phosphonates. Coordination chemistry is the first strategy for DNA capping through multivalent chelating interactions in drug delivery systems not only as a gatekeeper but also as a drug carrier. One drug was entrapped in the MSN pores, and the other drug intercalated within the capping duplex DNA. The two drugs were simultaneously released upon triggering of endonuclease degradation or photothermal dehybridization and were successively released upon first triggering of basic pH and subsequent triggering of photothermal heating. The designed native DNA-gated MSN delivery systems integrated a simultaneous and cascade release of two drugs into smart single nanovehicles for promising practical applications in targeted combination drug therapy.

Interplay of stimuli-responsiveness, drug loading and release for a surface-engineered dendrimer delivery system

The objectives of this study were to generate novel thermo and pH dual responsive poly(amidoamine) (PAMAM) via precise surface engineering, and investigate the interplay of dendrimer stimuli-responsiveness and the loading and release properties of a model agent, vitamin E acetate (VEAc). A higher dendrimer generation and maximized VEAc loading at elevated pH all contributed to a lower cloud point (CP) of the dendrimer-VEAc complex. The drug loading in G3.5 surface-engineered PAMAM was 22 mol/mol (pH 7.0) and 10 mol/mol (pH 5.0), which corresponded to a complex CP value at ca. 13 °C (pH 7.0) and 46 °C (pH 5.0), respectively. At physiological conditions, only less than 40% of VEAc was liberated when reaching the plateau, whilst more than 90% of VEAc was released from such system within 6 h at pH 5.0. This was due to the transition of dendrimer surface from dehydrated state to hydrated state upon pH dropping, enabling rapid drug release for therapeutic action. This smart stimuli-responsive dendritic delivery system holds promise for the efficient drug delivery to tissues with pH abnormality such as tumor.