Temperature-sensitive Drug Delivery System Research Articles

Molecular understanding of the self-assembly of an N-isopropylacrylamide delivery system for the loading and temperature-dependent release of curcumin

Global changes and drug abuse are forcing humanity to face various disease problems, and alternative therapies with safe natural substances have important research value. This paper combines various techniques in quantum chemical calculations and molecular simulations to provide molecular-level insight into the dynamics of the self-assembly of N-isopropylacrylamide (NIPAM) for loading curcumin (CUR). The results indicate that increasing the chain length of NIPAM molecules reduces their efficiency in encapsulating and locking CUR, and electrostatic interactions and van der Waals interactions are the main driving forces behind the evolution of system configurations in these processes. The isopropyl groups of NIPAM and the two phenolic ring planes of CUR are the main contact areas for the interaction between the two types of molecules. The thermosensitive effect of NIPAM can alter the distribution of isopropyl groups in NIPAM molecules around CUR. As a result, when the temperature rises from ambient temperature (300 K) to human characteristic temperature (310 K), the NIPAM-CUR interactions and radial distribution functions suggest that body temperature is more suitable for drug release. Our findings offer a vital theoretical foundation and practical guidance for researchers to develop temperature-sensitive drug delivery systems tailored for CUR, addressing its clinical application bottleneck.

Preparation and performance of a stimuli-responsive drug delivery system: novel light-triggered temperature-sensitive drug-loaded microcapsules.

Stimuli-responsive/smart drug delivery systems (DDSs), particularly those that use temperature as a stimuli-response factor to activate drug release, are the subject of recent research. A phase change material (PCM) is a popular thermally responsive material that can be used as a drug carrier and only when the system temperature is above the phase change point is the drug released following the phase change material changing from solid to liquid. In this study, a novel NIR light-triggered temperature-sensitive drug delivery system is developed for controllable release of acyclovir (ACV). For this purpose, a mixture of a phase change material (T38) and an ACV compound is first emulsified with copper oxide nanoparticles (CuO NPs) as a Pickering stabilizer and a photothermal conversion material, and then encapsulated with SiO2 to form a photothermal stimuli-responsive delivery system. This system shows a uniform spherical shape with a well-distinct core-shell structure, and is further experimentally proven to be able to controllably release drugs with solid-liquid transition of the phase change carrier upon temperature change. These results indicate that cumulative release of ACV can reach 51.2% at 40 °C within 20 hours, which is much higher than 27.3% release achieved below the melting point of T38. In addition, CuO NPs with excellent photothermal conversion ability endow the system with precisely controllable drug delivery via NIR light stimulation, where the cumulative drug release can reach 83.6% after 7 cycles of light stimulation, allowing controlled release at a specific time or location.

Assessment of temperature-sensitive properties of ionically crosslinked sodium alginate/hydroxypropyl cellulose blend microspheres: preparation, characterization, and in vitro release of paracetamol

Today, polymer systems can be formed to respond to single stimuli or multiple stimuli by changing their properties. The use of these systems, which are designed to be sensitive to stimuli, is expanding in a wide range of applications. Herein, microspheres of sodium alginate (NaAlg) and hydroxypropyl cellulose (HPC) sensitive to dual stimuli for the controlled release of model drug paracetamol were produced by the ionotropic gelation method in the presence of Zn2+ ions. FTIR, DSC, TGA, SEM, and particle size measurements were used to describe the blend microspheres. Low critical solution temperatures (LCST) of polymer blends at different ratios were determined and the biggest change according to the LCST value of HPC was found to be approximately 1–2 °C lower than 41 °C in microspheres with a NaAlg/HPC ratio of 50/50. In vitro release experiments of paracetamol from microspheres were carried out in a gastrointestinal tract simulation environment at two different temperatures (37 °C and 47 °C). From the release profiles, paracetamol release varied depending on the NaAlg/HPC ratio, the paracetamol content in the microspheres, the exposure time to Zn2+ ions, and the pH of the medium. Among the microsphere formulations, the highest entrapment efficiency was 57.86%, obtained for B7 formulation microspheres with a NaAlg/HPC ratio of 70/30, a paracetamol loading percentage of 20%, and a crosslinking time of 5 min. RESEARCH HIGHLIGHTS Microspheres of sodium alginate (NaAlg) and hydroxypropyl cellulose (HPC) sensitive to dual stimuli for the controlled release of model drug paracetamol were produced by the ionotropic gelation method in the presence of Zn2+ ions. LCST values of the microspheres with a NaAlg/HPC ratio of 50/50 were significantly lower by 1–2 °C than the LCST value of HPC, and the release results supported the temperature sensitivity of the microspheres. Among the microsphere formulations, the highest entrapment efficiency was 57.86% obtained for B7 formulation microspheres. These microspheres can be used as a temperature-sensitive drug delivery system in the biomedical field and also as an encapsulation system of cancer drugs for cancer treatment modalities such as hyperthermia.

Thermoresponsive GenisteinNLC-dexamethasone-moxifloxacin multi drug delivery system in lens capsule bag to prevent complications after cataract surgery

Cataract surgery is the most common intraocular procedure. To decrease postsurgical inflammation, prevent infection and reduce the incidence of secondary cataract, we built a temperature-sensitive drug delivery system carrying dexamethasone, moxifloxacin and genistein nanostructured lipid carrier (GenNLC) modified by mPEG-PLA based on F127/F68 as hydrogel. Characterizations and release profiles of the drug delivery system were studied. In vitro functions were detected by CCK-8 test, immunofluorescence, wound-healing assay, real time-PCR and western blotting. The size of GenNLCs was 39.47 ± 0.69 nm in average with surface charges of − 4.32 ± 0.84 mV. The hydrogel gelation temperature and time were 32 °C, 20 s with a viscosity, hardness, adhesiveness and stringiness of 6.135 Pa.s, 54.0 g, 22.0 g, and 3.24 mm, respectively. Transmittance of the gel-release medium was above 90% (93.44 ± 0.33% to 100%) at range of 430 nm to 800 nm. Moxifloxacin released completely within 10 days. Fifty percent of dexamethasone released at a constant rate in the first week, and then released sustainably with a tapering down rate until day 30. Genistein released slowly but persistently with a cumulative release of 63% at day 40. The thermoresponsive hydrogel inhibited the proliferation, migration and epithelial-mesenchymal transition of SRA 01/04 cells, which were confirmed by testing CCK-8, wound-healing assay, western blot, real time-PCR (RT-PCR) and immunofluorescence. These results support this intracameral thermoresponsive in situ multi-drug delivery system with programmed release amounts and release profiles to cut down the need of eye drops for preventing inflammation or infection and to reduce posterior capsular opacification following cataract surgery.

Pickering nano-emulsions stabilized by solid lipid nanoparticles as a temperature sensitive drug delivery system

The development of biomaterials with low environmental impact has seen increased interest in recent years. In this field, lipid nanoparticles have found a privileged place in research and industry. The purpose of this study was to develop Pickering O/W nano-emulsions only stabilized by solid lipid nanoparticles (SLNs), as a new generation of safe, non-toxic, biocompatible, and temperature-sensitive lipid nano-carriers. The first part is dedicated to understanding the interfacial behavior of SLNs and their related stabilization mechanisms onto nano-emulsions formulated by ultrasonication. Investigations were focused on the surface coverage as a function of the SLN size and volume fraction of dispersed oil, in order to prove that the droplet stabilization is effectively performed by the nanoparticles, and to disclose the limitations of this formulation. Characterization is performed by dynamic light scattering and transmission electron microscopy. The second part of the study investigated SLN adsorption on a model oil/water interface (surface tension and rheology) through an axisymmetrical drop shape analysis (drop tensiometer), following the interfacial tension and the rheological behavior. The objective of this part is to characterize the phenomenon governing the droplet/interface interactions, and disclose the rheological behavior of the interfacial SLN monolayer. The effect of temperature was also investigated, proving a real destabilization of the nano-suspension when the sample is heated above a temperature threshold, impacting on the integrity of the SLNs, which partially melt, and strongly enhancing the release of a model drug (ketoprofen) encapsulated in the nano-emulsion oil core. To conclude, Pickering nano-emulsions only stabilized by SLNs appear to be a very efficient innovative drug nano-carrier, opening new doors as a potential temperature-sensitive drug delivery system.

Improvement of Anticancer Drug Release by Cobalt Ferrite Magnetic Nanoparticles through Combined pH and Temperature Responsive Technique.

This work reports the application possibilities of cobalt ferrite (CoFe2 O4 ) magnetic nanoparticles (CFMNPs) for stimuli responsive drug delivery by magnetic field induced hyperthermia technique. The CFMNPs were characterized by X-ray diffraction (XRD) with Rietveld analysis, field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), selected area electron diffraction (SAED), fourier transform infrared spectroscopy (FTIR), thermogravimetry and differential thermal analysis (TG-DTA), vibrating sample magnetometer (VSM) and superconducting quantum interference device (SQUID) magnetometry. Particles were functionalized with folic acid (FA) by EDC-NHS coupling method and loaded with anticancer drug (DOX) by activated folate ions. The drug release was studied as a function of time at two different temperatures (37 and 44 °C) under pH∼5.5 and 7. It was observed that the drug release rate is higher at elevated temperature (44 °C) and acidic pH∼5.5 as compared to our normal body temperature and pH∼7 using the CFMNPs. This way, we have developed a pH and temperature sensitive drug delivery system, which can release the anticancer drug selectively by applying ac magnetic field as under ac field particles are heated up. We have calculated the amount of heat generation by the particles around 1.67 °C per second at ∼600 Hz frequency. By MTT assay on cancer cell and normal cell, it was confirmed that CFMNPs are nontoxic and biocompatible in nature, which assures that our synthesized particles can be successfully used in localized cancer treatment by stimuli responsive drug delivery technique.

Core-Sheath Nanofibers as Drug Delivery System for Thermoresponsive Controlled Release

In this work, a smart drug delivery system of core-sheath nanofiber is reported. The core-sheath nanofibers were prepared with thermoresponsive poly-(N-isopropylacrylamide) (as core) and hydrophobic ethyl cellulose (as sheath) by coaxial electrospinning. Analogous medicated fibers were prepared by loading with a model drug ketoprofen (KET). The fibers were cylindrical without phase separation and have visible core-sheath structure as shown by scanning and transmission electron microscopy. X-ray diffraction patterns demonstrated the drug with the amorphous physical form was present in the fiber matrix. Fourier transform infrared spectroscopy analysis was conducted, finding that there were significant intermolecular interactions between KET and the polymers. Water contact angle measurements proved that the core-sheath fibers from hydrophilic transformed into hydrophobic when the temperature reached the lower critical solution temperature. In vitro drug-release study of nanofibers with KET displayed that the coaxial nanofibers were able to synergistically combine the characteristics of the 2 polymers producing a temperature-sensitive drug delivery system with sustained-release properties. In addition, they were established to be nontoxic and suitable for cell growth. These findings show that the core-sheath nanofiber is a potential candidate for controlling drug delivery system.

Improvement of drug delivery by hyperthermia treatment using magnetic cubic cobalt ferrite nanoparticles

In this study, we report a novel synthesis method, characterization and application of a new class of ferromagnetic cubic cobalt ferrite magnetic nanoparticles (MNPs) for hyperthermia therapy and temperature triggered drug release. The MNPs are characterized by XRD, TEM, FESEM, AC magnetic hysteresis and VSM. These MNPs were coated with folic acid and loaded with an anticancer drug. The drug release studies were done at two different temperatures (37°C and 44°C) with progress of time. It was found that higher release of drug took place at elevated temperature (44°C). We have developed a temperature sensitive drug delivery system which releases the heat sensitive drug selectively as the particles are heated up under AC magnetic field and controlled release is possible by changing the external AC magnetic field.

Thermoresponsive, and reversibly emissive, core–shell nanogel composed of PNIPAM and carbon nanodots

We prepared a core–shell structured nanogel composed of carbon nanodots (C-dots), fluorescein, and poly(N-isopropylacrylamide) (PNIPAM) via emulsion copolymerization. The hybrid nanogel material was responsive to temperature as an emissive hybrid material and showed reversible and ratiometric changes in fluorescence emission according to temperature cycles at 25 and 45 °C, resulting from the shrinking of the PNIPAM copolymer chains with temperature variation. Dynamic light scattering, transmission electron microscopy were used to characterize the morphology and size of the particles. The hybrid nanogel was sensitive enough to temperature to be promising in biological application, such as temperature-sensitive drug delivery system and bioimaging.

A novel two-level microstructured poly(N-isopropylacrylamide) hydrogel for controlled release

The aim of this work was to demonstrate that conventional poly(N-isopropylacrylamide) (PNIPAAm) hydrogels can improve their shrinkage and release properties solely due to the introduction of a heterogeneous density fluctuation-based microstructure. To this end, a novel structurally engineered PNIPAAm hydrogel was designed and compared with a chemically similar, but homogeneous, PNIPAAm hydrogel reference. For the two-step preparation PNIPAAm microgels were firstly synthesized with surface amine groups and further functionalized with polymerizable acrylate groups. In the second step the microgels, themselves acting as crosslinkers, were crosslinked to form a bulk network by inter-connecting the microgels with linear PNIPAAm chains. Although the chemical composition of the newly prepared hydrogel was generally the same as conventional PNIPAAm hydrogels (a relative control), significantly improved shrinkage properties and a more efficient "on-off" switching induced by temperature modulations were observed for the novel gel as compared with the homogeneous reference. These improved shrinkage properties were ascribed to the novel structure, which is believed to enable rapid shrinking of the small microgel crosslinkers and, thereupon, the generation of a sufficient number of diffusion channels for quick water release. Rhodamine B and ibuprofen (IBU) as model compounds were completely released from this novel gel at 20 degrees C, whereas at temperatures above the lower critical solution temperature release stopped after initial 40% and 70% "bursts" for rhodamine B and IBU, respectively, due to shrinkage of the gel network. This approach may provide an avenue to design temperature-sensitive drug delivery systems with state of the art switching properties and fast release kinetics by combining the here presented innovative strategy with complementary enhancements, such as the introduction of porosity.

The rheological and thermal characteristics of freeze-thawed hydrogels containing hydrogen peroxide for potential wound healing applications

The current study involves the development of a hydrogel carrier for a H 2O 2 delivery system. In this work poly (vinyl alcohol) (PVA) and poly (acrylic acid) (PAA) based hydrogels were prepared, and their mechanical and physical properties examined. The novel aspect of this research is the differing functionality created by varying the concentration of H 2O 2. The mechanical and thermal properties were determined by parallel plate rheometry and modulated differential scanning calorimetry (MDSC) respectively. The results indicated that the hydrogels containing H 2O 2 are significantly weaker than those synthesised using water alone at test temperatures of 30 and 45 ∘C. MDSC analysis suggested that thermal transitions occur at temperatures that may make these hydrogels useful as temperature sensitive drug delivery systems. The chemical structure of the hydrogels was confirmed by means of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), while swelling experiments in distilled water indicate that the swelling of the gels is temperature dependent.

Thermo-responsive systems for controlled drug delivery

Controlled drug delivery systems represent advanced systems that can be tightly modulated by stimuli in order to treat diseases in which sustained drug release is undesirable. Among the many different stimuli-sensitive delivery systems, temperature-sensitive drug delivery systems offer great potential over their counterparts due to their versatility in design, tunability of phase transition temperatures, passive targeting ability and in situ phase transitions. Thus, thermosensitive drug delivery systems can overcome many of the hurdles of conventional drug delivery systems in order to increase drug efficacies, drug targeting and decrease drug toxicities. In an effort to further control existing temperature-responsive systems, current innovative applications have combined temperature with other stimuli such as pH and light. The result has been the development of highly sophisticated systems, which demonstrate exquisite control over drug release and represent huge advances in biomedical research.

온도감응성 키토산 중성용액을 이용한 약물송달시스템

In the present study, chitosan-glycerophosphate sodium salt solution as a thermosensitive system (TSS) was used to formulate a temperature-sensitive drug delivery system (TSDDS) containing acetaminophen (AAP). The optimized TSS was prepared by measuring gelation temperature, gelation time and rheological properties of TSS. The optimized gelation temperature and time of TSS were and 100 seconds, respectively. The viscosity of TSS was also suitable for maintaining gel structure at . The release profiles of TSDDS in PBS/pH 7.4 with various apparatuses and mass loss of TSDDS were investigated. The time required to release 50% of AAP from TSDDS () was 120 min with the formation of pore on the surfaces, which was 2 times longer than that from AAP-chitosan gel. In addition, TSDDS was degraded approximately 80% within 4 hr and then degraded slowly for 20 hrs. In conclusion, AAP-TSS (TSDDS) formulated in this study might be suitable for some specific uses such as subcutaneous injection and rectal formulation.

Investigation of the influence of freeze-thaw processing on the properties of polyvinyl alcohol/polyacrylic acid complexes

Physically crosslinked poly (vinyl alcohol)/poly (acrylic acid) hydrogels were prepared by freeze thaw processing. The hydrogels were formed in, either, water or a water/DMSO mixture and the chemical, mechanical, and thermal properties were determined by FTIR analysis, rotational rheometry and modulated DSC respectively. The results indicate that the hydrogels containing DMSO are significantly stronger than those containing water alone at temperatures between 20 and 40°C. Materials with different characteristics can be created by varying the solvent and the polymer feed ratios. DSC analysis indicated that thermal transitions are present at temperatures that may make these hydrogels useful in temperature sensitive drug delivery systems.

Doxorubicin-encapsulated thermosensitive liposomes modified with poly( N-isopropylacrylamide- co-acrylamide): Drug release behavior and stability in the presence of serum

In the field of the temperature sensitive drug delivery systems, we studied on the surface modification of liposomes by using poly( N-isopropylacrylamide- co-acrylamide) (PNIPAM-AAM) and polyethyleneglycol (PEG) to increase the release of doxorubicin (DOX) from liposomes and prolong the stability of liposomes in the presence of serum. The release of DOX from the PNIPAM-AAM/PEG modified liposomes is enhanced around the transition temperature of the polymer. In addition, the stability of the PNIPAM-AAM/PEG modified liposomes in serum shows a high level comparing with polymer unmodified liposomes. These results suggest that the modification on the surface of liposomes with both PNIPAM-AAM and PEG enhances the drug release from liposomes and reduces the protein adsorption in serum.

Hydrogen-bonded polymer gel and its application as a temperature-sensitive drug delivery system

The mixture of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer (F-68) and poly vinyl alcohol (PVA) forms a polymer complex gel by intra/intermolecular interaction via hydrogen bonding in water, which is verified by differential scanning calorimetry. With 30 wt% F-68 aqueous solution and 15 wt% PVA aqueous solution, F-68/PVA complex gel was prepared and its swelling transition was observed at approximately 37°C. Based on the temperature-sensitivity of hydrogen bondings in F-68/PVA complex gel, temperature sensitive drug delivery system has been designed and characterized. For the stability in the aqueous media, F-68/PVA complex gel was prepared with a form of polymeric bead, followed by the encapsulation with poly(lactide-co-glycolide) membrane. With changing the ratio of F-68/PVA, the swelling transition of polymer complex gel was manipulated and pulsatile release of acetoaminophen, used as a model drug, was demonstrated in response to pulsatile change of temperature between 35°C and 40°C.

Improvement of temperature-sensitivity of poly( N-isopropylacrylamide)-modified liposomes

As a novel temperature-sensitive drug delivery system, we have designed liposomes coated with poly( N-isopropylacrylamide), which exhibits a coil–globule transition at 32–35°C. In a previous study [ K. Kono, H. Hayashi, T. Takagishi, J. Control. Release 30 (1994) 69–75], it was shown that the release of contents from the polymer-coated liposomes is enhanced above the transition temperature of the polymer but the release is not controlled completely by the conformational change of the polymer. In this study, to improve temperature-sensitivity of the poly( N-isopropylacrylamide)-modified liposomes, the influence of lipid composition on the temperature-sensitivity of the liposomes was investigated. A copolymer of N-isopropylacrylamide and N,N-didodecylacrylamide was synthesized by free radical copolymerization. While the copolymer was insoluble in water, it exhibited a coil–globule transition around 28°C when incorporated into an egg yolk phosphatidylcholine membrane. The copolymer-modified egg yolk phosphatidylcholine/dioleoylphosphatidylethanolamine liposomes were prepared by sonication or reverse phase evaporation. Release of calcein from the copolymer-modified liposomes was very slow below the transition temperature of the copolymer, whereas the release was enhanced above the transition temperature. Incorporation of dioleoylphosphatidylethanolamine into liposome membranes enhanced release greatly above the transition temperature of the copolymer. Fluorometric measurements using 8-anilino-1-naphthalenesulfonate and 1,6-diphenyl-1,3,5-hexatriene suggested that the copolymer decreases membrane fluidity of the liposomes near and above the transition temperature of the copolymer and that interaction between the copolymer and the liposome membranes is enhanced by inclusion of dioleoylphosphatidylethanolamine.