Thermo-responsive Drug Carriers Research Articles

Shear stress induced lipid order and permeability changes of giant unilamellar vesicles

BackgroundThe permeability of a lipid bilayer is a function of its phase state and depends non-linearly on thermodynamic variables such as temperature, pressure or pH. We investigated how shear forces influence the phase state of giant unilamellar vesicles and their membrane permeability. MethodsWe determined the permeability of giant unilamellar vesicles composed of different phospholipid species under shear flow in a tube at various temperatures around and far off the melting point by analyzing the release of fluorescently labelled dextran. Furthermore, we quantified phase state changes of these vesicles under shear forces using spectral decomposition of the membrane embedded fluorescent dye Laurdan. ResultsWe observed that the membrane permeability follows a step function with increasing permeability at the transition from the gel to the fluid phase and vice versa. Second, there was an all-or-nothing permeabilization near the main phase transition temperature and a gradual dye release far off the melting transition. Third, the Laurdan phase state analysis suggests that shear forces induce a reversible melting temperature shift in giant unilamellar vesicle membranes. Major conclusionsThe observed effects can be explained best in a scenario in which shear forces directly induce membrane pores that possess relatively long pore lifetimes in proximity to the phase transition. General significanceOur study elucidates the release mechanism of thermo-responsive drug carriers as we found that liposome permeabilization is not continuous but quantized. Furthermore, the shear force induced melting temperature shift must be taken into consideration when thermo-responsive liposomes are designed.

Preparation of a thermo-responsive drug carrier consisting of a biocompatible triblock copolymer and fullerene.

A triblock copolymer (PEG-b-PUEM-b-PMPC; EUM) comprising poly(ethylene glycol) (PEG), thermo-responsive poly(2-ureidoethyl methacrylate) (PUEM), and poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC) blocks was synthesized via controlled radical polymerization. PEG and PMPC blocks exhibit hydrophilicity and biocompatibility. The PUEM block exhibits an upper critical solution temperature (UCST). PMPC can dissolve hydrophobic fullerenes in water to form a complex by grinding PMPC and fullerene powders. Fullerene-C70 (C70) and EUM were ground in a mortar and phosphate-buffered saline (PBS) was added to synthesize a water-soluble complex (C70/EUM). C70/EUM has a core-shell-corona structure, whose core is a complex of C70 and PMPC, the shell is PUEM, and corona is PEG. The maximum C70 concentration dissolved in PBS was 0.313 g L-1 at an EUM concentration of 2 g L-1. The C70/EUM hydrodynamic radius (Rh) was 34 nm in PBS at 10 °C, which increased due to the PUEM block's UCST phase transition with increasing temperature, and Rh attained a constant value of 38 nm above 36 °C. An anticancer drug, doxorubicin, was encapsulated in the PUEM shell by hydrophobic interactions in C70/EUM at room temperature, which can be released by heating. The generation of singlet oxygen (1O2) from C70/EUM upon visible-light irradiation was confirmed using the singlet oxygen sensor green indicator. Water-soluble C70/EUM may be used as a carrier that releases encapsulated drugs when heated and as a photosensitizer for photodynamic therapy.

In situ thermoresponsive curcumin-loaded dual polymeric nanoassemblies for wound healing and care of femoral fracture after surgery

Approximately 6.3 million fractures occur annually in the United States. Fractures (for example, hip fractures) occur in 2.4% population per year. A new clinical solution to this issue is the use of biomaterials with a dual purpose of bone healing and prevention of infection. In this study, advanced biomedical curcumin nanoparticles combined with a copolymeric matrix that had a dual function were developed and shown to promote antiinflammatory, functional recovery, and successful neuroprotective effects. The application of curcumin nanoparticles packaged in a thermoresponsive drug carrier device improves sustainability, bioavailability of blood, longevity, and biocompatibility. This nanocomposite showed enhancement of neuroprotection, axonal growth performance, and theoretically, functional recovery at the location of femoral fracture injury, by curcumin-primed polycaprolactone (PCL) (Cur-CS@PCL). Various microscopic methods (SEM, TEM, and LS) verified the morphology and shape of the manufactured Cur-CS@PCL nanoassemblies. In addition to these membranes being used at different temperatures, they improved the drug charge films and exhibited better-regulated release profiles for Cur. Thus, our data provide a simple hybrid clinical approach for the prevention and rehabilitation of femoral fractures in humans.

How can smart dressings change the future of wound care?

How can smart dressings change the future of wound care?

Effect of Dexamethasone on Thermoresponsive Behavior of Poly(2-Oxazoline) Diblock Copolymers.

Thermoresponsive polymers play an important role in designing drug delivery systems for biomedical applications. In this contribution, the effect of encapsulated hydrophobic drug dexamethasone on thermoresponsive behavior of diblock copolymers was studied. A small series of diblock copoly(2-oxazoline)s was prepared by combining thermoresponsive 2-n-propyl-2-oxazoline (nPrOx) and hydrophilic 2-methyl-2-oxazoline (MeOx) in two ratios and two polymer chain lengths. The addition of dexamethasone affected the thermoresponsive behavior of one of the copolymers, nPrOx20-MeOx180, in the aqueous medium by shifting the cloud point temperature to lower values. In addition, the formation of microparticles containing dexamethasone was observed during the heating of the samples. The morphology and number of microparticles were affected by the structure and concentration of copolymer, the drug concentration, and the temperature. The crystalline nature of formed microparticles was confirmed by polarized light microscopy, confocal Raman microscopy, and wide-angle X-ray scattering. The results demonstrate the importance of studying drug/polymer interactions for the future development of thermoresponsive drug carriers.

Gold nanorods-encapsulated thermosensitive drug carriers for NIR light-responsive anticancer therapy

Thermoresponsive polymers incorporated with photo-absorbing agents have been widely utilized for controlled drug delivery using light as an external stimulus. However, previously developed thermoresponsive drug carriers have disadvantages such as low biocompatibility and implantation failure. In the present study, gold nanorods (GNRs)-encapsulated poly(N-vinyl caprolactam) (PVCL) (GNR-PVCL) microparticles were synthesized by the stop-flow lithography (SFL) method. The SFL method enabled the fabrication of near-infrared (NIR) light-responsive GNR-PVCL microparticles of uniform size, which can allow localized injection. Doxorubicin (DOX) was encapsulated into GNR-PVCL microparticles to achieve NIR light-responsive anticancer therapy. DOX-loaded GNR-PVCL (DOX-GNR-PVCL) microparticles exhibited NIR light-triggered drug release due to the photothermal effect of GNRs, which increases the local temperature above the volume phase transition temperature of GNR-PVCL microparticles. In addition, DOX-GNR-PVCL exhibited controlled DOX release in response to the periodic irradiation of NIR light. Moreover, we demonstrated the efficient intracellular release of DOX upon NIR light exposure, and thus, NIR light-responsive anticancer activity. This study demonstrates that DOX-GNR-PVCL microparticles have significant potential as implantable drug carriers enabling NIR light-triggered drug release.

Multi-stimuli-responsive, liposome-crosslinked poly(ethylene glycol) hydrogels for drug delivery

The development of hybrid hydrogels has been of great interest over recent decades, especially in the field of biomaterials. Such hydrogels provide various opportunities in tissue engineering, drug delivery, and regenerative medicine due to their ability to mimic cellular environments, sequester and release therapeutic agents, and respond to stimuli. Herein we report the synthesis and characterization of an injectable poly(ethylene glycol) hydrogel crosslinked via thiol-maleimide reactions and containing both chemically crosslinked temperature-sensitive liposomes (TSLs) and matrix metalloproteinase-sensitive peptide crosslinks. Rheological studies demonstrate that the hydrogel is mechanically stable and can be synthesized to achieve a range of physically applicable moduli. Experiments characterizing the in situ drug delivery and degradation of these materials indicate that the TSL gel responds to both thermal and enzymatic stimuli in a local environment. Doxorubicin, a widely used anticancer drug, was loaded in the TSLs with a high encapsulation efficiency and the subsequent release was temperature dependent. Finally, TSLs did not compromise viability and proliferation of human and murine fibroblasts, supporting the use of these hydrogel-linked liposomes as a thermo-responsive drug carrier for controlled release.

Thermo-sensitive micelles based on amphiphilic poly(butylene 2-methylsuccinate)-poly(ethylene glycol) multi-block copolyesters as the pesticide carriers

A novel bio-based and biodegradable aliphatic multi-block copolyester, poly(butylene 2-methylsuccinate)-poly(ethylene glycol) (PBMS-PEG), was synthesized from 1,4-butanediol (BDO), 2-methylsuccinate acid (MSA) and poly(ethylene glycol) (PEG) via direct esterification and polycondensation process with tetrabutyl titanate as catalyst. Thermo-sensitive PBMS-PEG micelles were obtained by self-assembly of amphiphilic block copolyesters in aqueous medium by dialysis method. These micelles with different PEG contents have sizes varying from 74.3 nm to 138.3 nm and are stable in water over 200 days without any precipitation. A hydrophobic pesticide, Avermectin, was encapsulated in micelles by the same dialysis method. Such PBMS-PEG micelles can be used as thermo-responsive drug carrier owing to their controlled lower critical solution temperature (LCST) which can be accurately adjusted by varying the PEG proportion. The LCST increases from 27.0 °C to 40.0 °C while increasing the PEG proportion from 30% to 60%. By using the HPLC measurements, the results show when the drug loading is up to 20%, the loading efficiency is still nearly 100%. The properties of these amphiphilic micelles show that the delivery system has a promising potential to be further explored for developing a highly effective and biodegradable hydrophobic-pesticide-release formulation.

Microfluidic fabrication of biocompatible poly(N-vinylcaprolactam)-based microcarriers for modulated thermo-responsive drug release.

Various thermo-responsive polymers have been developed for controlled drug delivery upon the local application of external heat. The development of thermo-responsive polymers with high biocompatibility and tunable thermo-sensitivity is crucial for safe and efficient therapeutic application. In this study, thermo-responsive drug carriers featuring tunable thermo-sensitivities were synthesized using biocompatible poly(N-vinyl caprolactam) (PVCL) and stop-flow lithography. The PVCL-based particles showed selective drug release depending on temperature, illustrating their feasibility for on-demand controlled drug delivery. The volume phase transition temperature (VPTT) of the PVCL-based particles can be adjusted to vary from room temperature to body temperature by controlling their monomer compositions. In addition, modulated drug release was achieved by constructing multicompartments of different thermo-sensitivities within the PVCL particles. To accomplish thermo-responsive anticancer therapy, doxorubicin (DOX) was encapsulated into the PVCL particles as an anticancer drug. The DOX-loaded PVCL particles exhibited both thermo-responsive drug release and anticancer activity. This study demonstrates that thermo-responsive PVCL particles are highly promising carriers for safe and targeted anticancer therapy.

Smart Bandage for Monitoring and Treatment of Chronic Wounds.

Chronic wounds are a major health concern and they affect the lives of more than 25 million people in the United States. They are susceptible to infection and are the leading cause of nontraumatic limb amputations worldwide. The wound environment is dynamic, but their healing rate can be enhanced by administration of therapies at the right time. This approach requires real-time monitoring of the wound environment with on-demand drug delivery in a closed-loop manner. In this paper, a smart and automated flexible wound dressing with temperature and pH sensors integrated onto flexible bandages that monitor wound status in real-time to address this unmet medical need is presented. Moreover, a stimuli-responsive drug releasing system comprising of a hydrogel loaded with thermo-responsive drug carriers and an electronically controlled flexible heater is also integrated into the wound dressing to release the drugs on-demand. The dressing is equipped with a microcontroller to process the data measured by the sensors and to program the drug release protocol for individualized treatment. This flexible smart wound dressing has the potential to significantly impact the treatment of chronic wounds.

A Textile Dressing for Temporal and Dosage Controlled Drug Delivery

AbstractChronic wounds do not heal in an orderly fashion in part due to the lack of timely release of biological factors essential for healing. Topical administration of various therapeutic factors at different stages is shown to enhance the healing rate of chronic wounds. Developing a wound dressing that can deliver biomolecules with a predetermined spatial and temporal pattern would be beneficial for effective treatment of chronic wounds. Here, an actively controlled wound dressing is fabricated using composite fibers with a core electrical heater covered by a layer of hydrogel containing thermoresponsive drug carriers. The fibers are loaded with different drugs and biological factors and are then assembled using textile processes to create a flexible and wearable wound dressing. These fibers can be individually addressed to enable on‐demand release of different drugs with a controlled temporal profile. Here, the effectiveness of the engineered dressing for on‐demand release of antibiotics and vascular endothelial growth factor (VEGF) is demonstrated for eliminating bacterial infection and inducing angiogenesis in vitro. The effectiveness of the VEGF release on improving healing rate is also demonstrated in a murine model of diabetic wounds.

Biocompatible Poly(N-isopropylacrylamide)-halloysite Nanotubes for Thermoresponsive Curcumin Release

The grafting of poly(N-isopropylacrylamide) (PNIPAAM) onto the halloysite external surface is proposed in order to obtain a novel thermoresponsive drug carrier for curcumin delivery. The new nanomaterial is characterized by means of FT-IR spectroscopy, thermogravimetric analysis, and SEM investigations. A high density of polymer chain was achieved at the nanoparticle surface. The PNIPAAM dehydration phenomenon was observed in water above 32 °C that is nearly coincident with the lower critical solution temperature for the polymer. The colloidal stability as well as the wettability of the obtained nanomaterial may be triggered by temperature stimuli. In vitro tests simulating the gastro-intestinal transit demonstrated that the proposed delivery system allows a targeted release of curcumin, preventing its degradation in an acidic medium. We synthesized a new hybrid nanoparticle that is very promising for several applications due to the copresence of a biocompatible region, to the temperature response, and to...

Thermoresponsive copolymer/SiO2 nanoparticles with dual functions of thermally controlled drug release and simultaneous carrier decomposition.

The preparation of thermoresponsive drug carriers with a self-destruction property is presented. These drug carriers were fabricated by incorporation of drug molecules and thermoresponsive copolymer, poly(N-isopropylacrylamide-co-acrylamide), into silica nanoparticles in a one-pot preparation process. The enhanced drug release was primarily attributed to faster molecule diffusion resulting from the particle decomposition triggered by phase transformation of the copolymer upon the temperature change. The decomposition of the drug carriers into small fragments should benefit their fast excretion from the body. In addition, the resulting drug-loaded nanoparticles showed faster drug release in an acidic environment (pH 5) than in a neutral one. The controlled drug release of methylene blue and doxorubicin hydrochloride and the self-decomposition of the drug carriers were successfully characterized by using TEM, UV/Vis spectroscopy, and confocal microscopy. Together with the nontoxicity and excellent biocompatibility of the copolymer/SiO2 composite, the features of controlled drug release and simultaneous carrier self-destruction provided a promising opportunity for designing various novel drug-delivery systems.

Lipidic composite vesicles based on poly(NIPAM), chitosan or hyaluronan: behaviour under stresses

Giant Unilamellar Vesicles (GUVs) consisting in self-closed lipid bilayers of 0.5-100 µm diameter are considered as oversimplified models of cells because of their biological membrane and micrometric size while Large Unilamellar Vesicles (LUVs) of 100-500 nm diameter have applications in drug delivery. To improve structural and mechanical properties of these vesicles, we have developed two categories of composite polymer-vesicles. The first category is prepared by encapsulating solutions or networks of poly (N-isopropyl-acrylamide) (polyNIPAM) chains. PolyNIPAM exhibiting a Low Critical Solution Temperature (LCST) at 32°C, composite NIPAM-vesicles are thermoresponsive. The second category of vesicles is obtained by adsorption of polyelectrolytes (chitosan or hyaluronan or both layer-by-layer) on their outer surface. Chitosan and hyaluronan are respectively positively and negatively charged polymers; both are biocompatible and allow to tune the net charge of the vesicles. All these composite vesicles hold promise as passive mechanical models of cells and as drug carriers because of their improved structural and mechanical properties and enhanced resistance to various mechanical or chemical stresses if compared to unmodified vesicles. Poly (NIPAM) vesicles present the additional advantage to be potential thermo-responsive drug carriers, collapsing reversibly at 32°C with a release of 98% of their internal solution.

In situ growth of a thermoresponsive polymer from a genetically engineered elastin-like polypeptide

We report the in situgrowth of a thermoresponsive dumbbell-like polymer conjugate of a genetically engineered triblock elastin-like polypeptide (tELP). Atom transfer radical polymerization (ATRP) was used to directly grow a PEG-like polymer selectively from the first and third blocks of the tELP to form a poly(oligo(ethylene glycol) methyl ether methacrylate) (poly(OEGMA)) brush conjugate with quantitative yield. We found that in situgrowth of poly(OEGMA) from tELP significantly changed the inverse phase transition and rheological behaviors of tELP. Dynamic light scattering (DLS) and turbidity measurements as a function of temperature showed that the inverse phase transition behavior of the conjugate was not determined by the tELP but by poly(OEGMA). Oscillatory rheological measurements indicated that the conjugate started to form a physical hydrogel at a temperature of 55 °C. In vitro enzymatic degradation studies showed that the conjugate could be degraded by collagenase. These results suggest that this class of conjugates may be potentially useful as an injectable, thermoresponsive drug carrier for local drug delivery and as a scaffold for tissue engineering.

Effects of surface wettability and roughness of microchannel on flow behaviors of thermo-responsive microspheres therein during the phase transition

The flow characteristics of monodisperse thermo-responsive poly( N-isopropylacrylamide) (PNIPAM) microspheres during the phase transition in microchannels with different surface wettabilities and roughnesses are investigated systematically. Glass microchannels are modified by hydroxylation treatment to achieve hydrophilic surface, by self-assembly of chlorotrimethylsilane to realize hydrophobic surface, and by coating with silica nanoparticles to generate rough surface. The phase transition of PNIPAM microspheres in microchannels is induced by local heating. The results show that the surface wettability and roughness of microchannel significantly affect the flow behaviors of PNIPAM microspheres during the phase transition. It is much easier for the PNIPAM microspheres in microchannel with hydrophobic surface to stop right after the phase transition than those in microchannel with hydrophilic surface, and it is also much easier for the PNIPAM microspheres in microchannel with rough surface to stop right after the phase transition than those in microchannel with smooth surface. These results indicate that hydrophobic and rough surface properties of the microchannel can enhance the site-specific targeting of PNIPAM microspheres caused by the phase transition. The results in this study provide valuable information for the application of thermo-responsive drug carriers in site-specific targeting therapy.

Effect of molecular architecture of hydrophobically modified poly( N-isopropylacrylamide) on the formation of thermoresponsive core-shell micellar drug carriers

Terminal-incorporation of hydrophilic or hydrophobic groups dramatically influences the phase transition of poly( N-isopropylacrylamide) (PIPAAm) because of a critical role of the polymer chain ends in initiation of the phase transition. Incorporation of an amino or hydroxyl group to one end of PIPAAm remarkably raised the LCST (lower critical solution temperature) and slowed down the rate of the phase transition, and these effects were more pronounced as the mole fraction of hydrophilic groups increased compared to the random copolymers of PIPAAm and hydrophilic co-monomers, such as acrylic acid (AAc) or dimethylacrylamide (DMAAm). Hydrophilic effects were more remarkable for hydroxyl groups, due to stronger hydrogen bonding with water. Terminal-modification (hydrophobization) was also more effective in producing hydrophobic effects on the PIPAAm phase transition in comparison with PIPAAm copolymers that were randomly modified along the main chain with hydrophobic co-monomers. Moreover, terminal-located hydrophobic groups were able to form hydrophobic microdomains that were clearly isolated from PIPAAm chains in aqueous media by the aggregation of hydrophobic segments. As a result, the obtained micellar aqueous solution showed the same LCST as pure PIPAAm, while the PIPAAm random copolymer with hydrophobic co-monomers formed incompletely separated microdomains.The LCST for this random copolymer was reduced with increasing hydrophobic co-monomer mole fraction. Hydrophobically terminal-modified PIPAAm produced thermo-responsive core-shell structures that exhibited the same LCST and the same thermal response rate as those of free linear PIPAAm chains. Such polymeric micellar structures show reversible thermoresponsive aggregation/dispersion and deformation/reformation in heating/cooling cycles through the LCST for pure PIPAAm. These properties indicate the possibility of using such a system as a thermoresponsive drug carrier with double targeting mechanisms, in both passive and active manners.