Thermoresponsive Drug Delivery Systems Research Articles

Optimization of Glibenclamide Loaded Thermoresponsive SNEDDS Using Design of Experiment Approach: Paving the Way to Enhance Pharmaceutical Applicability.

Thermoresponsive self-nanoemulsifying drug delivery systems (T-SNEDDS) offer a promising solution to the limitations of conventional SNEDDS formulations. Liquid SNEDDS are expected to enhance drug solubility; however, they are susceptible to leakage during storage. Even though solid SNEDDS offers a solution to this storage instability, they introduce new challenges, namely increased total dosage and potential for drug trapping within the formulation. The invented T-SNEDDS was used to overcome these limitations and improve the dissolution of glibenclamide (GBC). Solubility and transmittance studies were performed to select a suitable oil and surfactant. Design of Experiments (DoE) software was used to study the impact of propylene glycol and Poloxamer 188 concentrations on measured responses (liquefying temperature, liquefying time, and GBC solubility). The optimized formulation was subjected to an in vitro dissolution study. The optimized T-SNEDDS consisted of Kolliphor EL and Imwitor 308 as surfactants and oil. The optimized propylene glycol and Poloxamer 188 concentrations were 13.7 and 7.9% w/w, respectively. It exhibited a liquefying temperature of 35.0 °C, a liquefying time of 119 s, and a GBC solubility of 5.51 mg/g. In vitro dissolution study showed that optimized T-SNEDDS exhibited 98.8% dissolution efficiency compared with 2.5% for raw drugs. This study presents a promising approach to enhance pharmaceutical applicability by resolving the limitations of traditional SNEDDS.

Berberine loaded thermosensitive lipid nanoparticles: in vitro characterization, in silico study, and in vivo anti-arthritic effect

Thermoresponsive drug delivery systems have been used to treat diseases that cause hyperthermia or elevated body tissue temperatures, viz., rheumatoid arthritis and different cancers. The aim of the study was to enhance berberine (BER) release using thermosensitive nanostructured lipid carriers (TNLCs) through intra-articular administration for the management of arthritis. TNLCs were prepared using binary mixtures of stearic acid and decanoic acid as solid and liquid lipids, respectively. Lipid mixtures with an optimum melting point were assessed using differential scanning calorimetry studies. In vitro characterization of the BER TNLCs included particle size, zeta potential, entrapment efficiency, and drug release at 37 °C and 41 °C. Joint diameter measurement, real-time polymerase chain reaction (RT-PC) analysis, enzyme-linked immunosorbent assay (ELISA) for inflammatory markers, and histological evaluation of the dissected joints were all performed in vivo on rats with adjuvant-induced arthritis. In vitro characterization revealed negatively charged BER-loaded TNLCs with a spherical shape, particle size less than 500 nm, BER entrapment efficiency up to 79%, and a high drug release rate at an elevated temperature of 41 °C. In silico studies revealed the affinity of BER to different formula components and to the measured biomarkers. In vivo assessment of the optimum TNLCs showed that BER TNLCs were superior to the BER solution suspension regarding their effect on inflammatory biomarkers, joint diameter, and histological studies.

A review of thermoresponsive drug delivery systems based on LCST/UCST polymer nanofibers

Drug delivery systems and thermoresponsive polymers are garnering more interest due to technological advancement. The synthesis, characteristics, and uses of stimuli-responsive polymers in drug delivery systems are discussed in this paper. LCST and UCST polymers, two subtypes of thermoresponsive polymers, are also discussed, along with their processes and biomedical applications. The paper also discusses the use of conventional nanofibers and stimuli-responsive nanofibers for drug delivery systems and the most recent developments in electrospinning technology. The article also analyses the difficulties facing drug delivery systems today. This paper makes the case that novel electrospinning technologies must be developed in addition to further research into drug delivery systems based on UCST polymers with strong biocompatibility and biodegradability.

Role of Bovine Serum Albumin Addition in Micellization and Gel Formation of Poloxamer 407.

The combination of the thermoresponsive polymer and protein has demonstrated great promise in its applications in drug delivery and tissue engineering fields. This study described the impact of bovine serum albumin (BSA) on the micellization and sol-gel transition behaviors of poloxamer 407 (PX). The micellization of aqueous PX solutions with and without BSA was examined using isothermal titration calorimetry. In the calorimetric titration curves, the pre-micellar region, the transition concentration region, and the post-micellar region were observed. The presence of BSA had no noticeable impact on critical micellization concentration, but the inclusion of BSA caused the pre-micellar region to expand. In addition to studying the self-organization of PX at a particular temperature, the temperature-induced micellization and gelation of PX were also explored using differential scanning calorimetry and rheology. The incorporation of BSA had no discernible effect on critical micellization temperature (CMT), but it did affect gelation temperature (Tgel) and gel integrity of PX-based systems. The response surface approach illustrated the linear relation between the compositions and the CMT. The major factor affecting the CMT of the mixtures was the concentration of PX. The alteration of the Tgel and the gel integrity were discovered to be a consequence of the intricate interaction between PX and BSA. BSA mitigated the inter-micellar entanglements. Hence, the addition of BSA demonstrated a modulating influence on Tgel and a softening effect on gel integrity. Understanding the influence of serum albumin on the self-assembly and gelation of PX will enable the creation of thermoresponsive drug delivery and tissue engineering systems with controlled gelation temperatures and gel strength.

Thermo-responsive release of diclofenac sodium from poly (ε-caprolactone)/glyceryl trilaurate co-continuous composite prepared by heat treatment

Nowadays, it is still a tough challenge to prepare thermo-responsive drug delivery system without the use of poly(N-isopropylacrylamide) (PNIAPAM) and its derivatives. Herein, we attempted to fabricate a novel co-continuous composite with thermo-responsive drug release behavior induced by the phase transition of dispersed phase. Poly (ϵ-caprolactone) (PCL) scaffold with connected porous structure was prepared first, followed by the introduce and impregnating of diclofenac sodium/glyceryl trilaurate (DS/C12) hot melt mixture. After solidification at 25 °C, PCL/C12 composites with co-continuous structure were obtained. The connected porous structure of PCL scaffold and morphology of PCL/C12 composites were confirmed by scanning electron microscope. The thermo-responsive drug release mechanism of PCL/C12 composites was investigated by differential scanning calorimeter and two-dimensional infrared correlation spectroscopy. The results indicated that the temperature of onset melting and melting point of C12 was about 41.5 °C and 47.5 °C, respectively. When the temperature was switched from 37 °C to 45 °C, C12 underwent a melt transition, and the regular aggregation of C12 molecular chain was disrupted, accelerating the release of DS. The in vitro release results presented that PCL/C12 composites could achieve on-off controlled release of DS under alternative temperature of 45 °C and 37 °C. According to the comprehensive test results, this PCL/C12 composites should have promising application in bone tissue engineering. Schematic diagram illustrating of the preparation of poly (ϵ-caprolactone)/glyceryl trilaurate (PCL/C12) co-continuous composite (a) and its on-off controlled release behavior of diclofenac sodium (DS) under alternative temperature of 45 °C and 37 °C (b and c). • Poly (ϵ-caprolactone)/glyceryl trilaurate (PCL/C12) co-continuous composite was fabricated. • PCL/C12 composite achieved on-off controlled release of diclofenac sodium under alternative temperature of 45 °C and 37 °C. • The controlled drug release behavior of PCL/C12 composite was induced by the phase transition of C12. • This thermo-responsive composite was prepared without the use of poly(N-isopropylacrylamide) and its derivatives. • This work provided a promising strategy and method for the preparation of thermo-responsive drug delivery systems.

Thermosensitive Polymers and Thermo-Responsive Liposomal Drug Delivery Systems.

Temperature excursions within a biological milieu can be effectively used to induce drug release from thermosensitive drug-encapsulating nanoparticles. Oncological hyperthermia is of particular interest, as it is proven to synergistically act to arrest tumor growth when combined with optimally-designed smart drug delivery systems (DDSs). Thermoresponsive DDSs aid in making the drugs more bioavailable, enhance the therapeutic index and pharmacokinetic trends, and provide the spatial placement and temporal delivery of the drug into localized anatomical sites. This paper reviews the fundamentals of thermosensitive polymers, with a particular focus on thermoresponsive liposomal-based drug delivery systems.

Comparison of thermoresponsive Diels-Alder linkers for the release of payloads from magnetic nanoparticles via hysteretic heating

Investigation into the use of thermally reversible Diels-Alder chemistry coupled with magnetic iron oxide nanoparticles has grown over the last decade. This technology has been used for a variety of applications such as thermoresponsive materials, catalytic chemistry, and drug delivery systems. In this study, we evaluate two distinct thermally labile Diels-Alder linkers for the release of payloads from the surface of magnetic iron oxide nanoparticles. Density functional theory (DFT) computational predictions of the Gibbs free energy and enthalpy reaction barriers were performed and revealed a dramatic difference in reverse energy barriers between the two linkers. These thiophene-based cycloadducts were then synthesized, conjugated to the surface of iron oxide nanoparticles, and characterized by NMR and ESI-MS. The results of the modeling were confirmed when the functionalized nanoparticles were subjected to immersion heating and the payload release rates observed were in agreement with the DFT calculations. Similarly, AMF-RF hysteretic heating of the functionalized nanoparticles revealed payload release rates that correlated with the DFT calculations and the data from the heat immersion studies. Together, these results indicate that these distinct thermally labile Diels-Alder linkers can be used to fine-tune the kinetics of payload release from nanoparticles.

Preparation of poly (N-isopropylacrylamide)/polycaprolactone electrospun nanofibres as thermoresponsive drug delivery systems in wound dressing

A thermo-sensitive film composed of polycaprolactone and poly(N-isopropylacrylamide) was fabricated via electrospinning, with ketoconazole as the model drug. The morphology, elemental composition, and surface hydrophilicity of the nanofibres were characterized, and the results showed that nanofibres switched from a hydrophilic to a hydrophobic state as the temperature increased from 25 °C to 37 °C. The drug release profiles of the films suggested that sustained drug release behavior was achieved, and a lower temperature induced a faster delivery. Therefore, the prepared nanofibres could be highly applicable as wound dressings for on-demand and sustained drug release systems based on their temperature-responsive properties.

Thermoresponsive behavior of poly(DEGMA)-based copolymers. NMR and dynamic light scattering study of aqueous solutions

We studied temperature behavior of diblock copolymers of poly[2-(2-methoxyethoxy)ethyl methacrylate] (PDEGMA) with poly(N-(2-hydroxypropyl)methacrylamide and a statistical copolymer PDEGMA-co-N-propargylmethacrylamide in aqueous solutions. NMR spectra and dynamic light scattering showed that the copolymers exhibit a reversible phase transition which depends on the composition of the block copolymer and slightly on polymer concentration. In contrast to statistical copolymer, different behavior of proton groups in polymer backbone (and in the nearest side chain OCH2 group) on the one hand and in other side chain groups of the PDEGMA on the other hand was observed for diblock copolymers. Additionally, two types of water molecules were detected in solutions of the diblock copolymers above the phase transition –“free” with long and “bound” with short spin-spin relaxation times T2. NOESY spectra indicate that a core- to- shell morphology is unlikely in these block copolymers. This report emphasizes the importance of understanding of the self-association of copolymers in solution on the molecular level and provides important information for the design of “smart” thermoresponsive polymer-based drug delivery systems.

Amino Acid Functionalized Single−Wall Carbon Nanotubes in Thermoresponsive Drug Delivery Systems: A Computational Study

AbstractIn this research, a computational study was conducted to evaluate the usability of amino acid functionalized single−walled carbon nanotubes (AA−SWCNTs) in the thermoresponsive drug delivery systems. The Taxol (TXL) was used as a model lipophilic drug and temperatures of 300, 310, and 315 K were selected. At first, docking studies were carried out to find the binding mode of the TXL to the surface of AA−SWCNTs. Then, molecular dynamic studies were performed. The molecular mechanics/generalized Born surface area (MM/GBSA) approach was used to evaluate the binding energies of AA−SWCNT/TXL systems. Based on the calculated binding energies in the three mentioned temperatures, Gln−, Gly−, Pro−, and Ser−SWCNT have the ability to release the TXL by increase of temperature; the weaker van der Waals interactions at higher temperature can be regarded as the origin of such observation. From another point of view, Gln− and Ser−SWCNT showed improved solubility in the aqueous media by considering the calculated logP values. These two systems are good candidates to be used in the thermoresponsive drug delivery systems.

Solid lipid nanoparticles for thermoresponsive targeting: evidence from spectrophotometry, electrochemical, and cytotoxicity studies.

Thermoresponsive drug delivery systems are designed for the controlled and targeted release of therapeutic payload. These systems exploit hyperthermic temperatures (>39°C), which may be applied by some external means or due to an encountered symptom in inflammatory diseases such as cancer and arthritis. The objective of this paper was to provide some solid evidence in support of the hypothesis that solid lipid nanoparticles (SLNs) can be used for thermoresponsive targeting by undergoing solid–liquid phase transition at their melting point (MP). Thermoresponsive lipid mixtures were prepared by mixing solid and liquid natural fatty acids, and their MP was measured by differential scanning calorimetry (DSC). SLNs (MP 39°C) containing 5-fluorouracil (5-FU) were synthesized by hot melt encapsulation method, and were found to have spherical shape (transmission electron microscopy studies), desirable size (<200 nm), and enhanced physicochemical stability (Fourier transform infrared spectroscopy analysis). We observed a sustained release pattern (22%–34%) at 37°C (5 hours). On the other hand, >90% drug was released at 39°C after 5 hours, suggesting that the SLNs show thermoresponsive drug release, thus confirming our hypothesis. Drug release from SLNs at 39°C was similar to oleic acid and linoleic acid nanoemulsions used in this study, which further confirmed that thermoresponsive drug release is due to solid–liquid phase transition. Next, a differential pulse voltammetry-based electrochemical chemical detection method was developed for quick and real-time analysis of 5-FU release, which also confirmed thermoresponsive drug release behavior of SLNs. Blank SLNs were found to be biocompatible with human gingival fibroblast cells, although 5-FU-loaded SLNs showed some cytotoxicity after 24 hours. 5-FU-loaded SLNs showed thermoresponsive cytotoxicity to breast cancer cells (MDA-MB-231) as cytotoxicity was higher at 39°C (cell viability 72%–78%) compared to 37°C (cell viability >90%) within 1 hour. In conclusion, this study presents SLNs as a safe, simple, and effective platform for thermoresponsive targeting.

Effect of Moisture on the Thermoresponsive Properties of Binary Mixtures of Monoglycerides for Triggerable Drug Delivery Systems.

The crystallization behavior and temperature-dependent phase transition of monoglycerides have been utilized to develop thermal-sensitive drug delivery systems. The presence of excess water has been reported to influence the phase transition. The present study investigates the effect of moisture on the thermal behavior of binary blends of monoglycerides. Various compositions (0-100wt%) of glyceryl monooleate (GMO) and glyceryl monostearate (GMS) were prepared by fusion method, and exposed to varying relative humidity (RH) levels (0-100%). The moisture uptakes, sorption isotherm, and the thermal behavior of GMO-GMS samples were analyzed using differential scanning calorimeter (DSC), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The in vitro nifedipine (NF) release was studied at 37 and 42°C. Samples of GMO-GMS (25:75, 50:50, and 75:25wt%) stored at 97%RH at 25°C for 3weeks increased in weight by 14.0, 14.7, and 15.8%, respectively. Despite such high moisture uptake, the GMO-GMS matrices maintained crystalline structure. The melting point (T m) and heat of fusion (ΔH f) of the samples were reduced as the amount of moisture in the matrices increased. However, the heat of fusion calculated on dry basis remained constant at 139.4 ± 1.25, 102.7 ± 1.14, and 46.7 ± 1.16J/g for GMO-GMS 25:75, 50:50, and 75:25wt%, respectively. The comparison of the XRD measurements of the dry samples with those containing 30% water confirmed the preserved crystalline arrangement in the matrices. This study indicates that despite the high moisture uptakes, the GMO-GMS matrices retained their crystalline properties and provided temperature-dependent drug release indicating the potential application for thermoresponsive local drug delivery systems.

Enhanced blood brain barrier permeability and glioblastoma cell targeting via thermoresponsive lipid nanoparticles.

Thermoresponsive targeting is used to deliver therapeutic agents at hyperthermic conditions (39-45 °C). However, available thermoresponsive drug delivery systems (TDDS), including liposomes, have a complex method of preparation involving toxic solvents and reagents. The objective of this in vitro study was to prepare and characterize thermoresponsive lipid nanoparticles (TLN) for treating glioblastoma, the most aggressive brain tumor whose treatment is limited by a low blood brain barrier (BBB) permeability of drugs. Thermoresponsive lipids were prepared by mixing liquid and solid fatty acids (0.1 : 1 to 2 : 1 ratio) and lipid mixtures exhibiting a solid-liquid phase transition at 39 °C were identified by plotting melting point against liquid contents. TLN were prepared by a hot melt encapsulation method using mono- or double-surfactant systems. TLN showed desirable size (<270 nm), zeta potential (-35 to -50 mV), spherical morphology and stability by FTIR studies. In the drug release studies, paclitaxel release was slow at 37 °C, however, it was released abruptly at 39 °C due to the faster diffusion rate from liquid state nanoparticles. During cytotoxicity studies, the unloaded TLN were non-toxic whereas paclitaxel loaded TLN showed higher cytotoxicity to glioblastoma cells at 39 °C (69% cell viability after one hour) compared to 37 °C (82% cell viability). The TLN showed higher permeability across an in vitro model of BBB at 39 °C due to a deformable liquid state which can squeeze through the tight junctions of the BBB. In conclusion, this study demonstrated that the TLN can be used as a safe and effective alternative to traditional TDDS with higher potential to target glioblastoma cells across the BBB.

Electrospun Poly(N-isopropylacrylamide)/Ethyl Cellulose Nanofibers as Thermoresponsive Drug Delivery Systems

Fibers of poly(N-isopropylacrylamide) (PNIPAAm), ethyl cellulose (EC), and a blend of both were successfully fabricated by electrospinning. Analogous drug-loaded fibers were prepared loaded with ketoprofen (KET). Scanning and transmission electron microscopy showed that the fibers were largely smooth and cylindrical, with no phase separation observed. The addition of KET to the spinning solutions did not affect the morphology of resultant fibers, and no drug particles could be observed to separate from the polymer matrix. X-ray diffraction demonstrated that the drug was present in the amorphous physical form in the fiber matrix. There are significant intermolecular interactions between KET and polymers, as evidenced by IR spectroscopy and molecular modeling. Water contact angle measurements proved that the PNIPAAm and PNIPAAm/EC fibers switched from being hydrophilic to hydrophobic when the temperature was increased through the lower critical solution temperature of 32°C. In vitro drug release studies found that the PNIPAAm/EC blend nanofibers were able to synergistically combine the properties of the 2 polymers, giving temperature-sensitive systems with sustained release properties. In addition, they were established to be nontoxic and suitable for cell growth. This study demonstrates that electrospun-blend PNIPAAm/EC fibers comprise effective and biocompatible materials for drug delivery systems and tissue engineering.

Binary Blend of Glyceryl Monooleate and Glyceryl Monostearate for Magnetically Induced Thermo-Responsive Local Drug Delivery System

To develop a novel monoglycerides-based thermal-sensitive drug delivery system, specifically for local intracavitary chemotherapy. Lipid matrices containing mixtures of glyceryl monooleate (GMO) and glyceryl monostearate (GMS) were evaluated for their potential application as magnetically induced thermo-responsive local drug delivery systems using a poorly water-soluble model drug, nifedipine (NF). Oleic acid-modified iron oxide (OA-Fe3O4) nanoparticles were embedded into the GMO-GMS matrix for remote activation of the drug release using an alternating magnetic field (AMF). The crystallization behavior of binary blends of GMO and GMS as characterized by DSC did show temperature dependent phase transition. GMO-GMS (75:25wt%) blend showed a melting (T m ) and crystallization (T c ) points at 42°C and 37°C, respectively indicating the potential of the matrix to act as an 'on-demand' drug release. The matrix released only 35% of the loaded drug slowly in 10days at 37°C whereas 96% release was obtained at 42°C. A concentration of 0.5% OA-Fe3O4 heated the matrix to 42.3 and 45.5°C within 5min and 10min of AMF exposure, respectively. The in vitro NF release profiles form the monoglycerides matrix containing 0.5% OA-Fe3O4 nanoparticles after AMF activation confirmed the thermo-responsive nature of the matrix that could provide pulsatile drug release 'on-demand'.

Actively targeting solid tumours with thermoresponsive drug delivery systems that respond to mild hyperthermia

A diverse range of drug delivery vehicles have been developed to specifically target chemotherapeutics to solid tumours while avoiding systemic dose-limiting toxicity. Many of these active targeting strategies display limited efficacy because they rely on subtle differences in expression patterns between pathogenic tissue and healthy tissue. In contrast, drug delivery systems that exploit thermoresponsive behaviour allow a clinician to spatially and temporally control the accumulation and/or release of the toxic agents within tumour tissue by simply applying mild hyperthermia (defined as 39–43 °C) to the desired site. Although thermally sensitive materials comprise a significant portion of the literature on novel drug delivery systems, only a few systems have been methodically tuned to respond within this narrowly defined physiological temperature range in an in vivo environment. This review discusses the materials and strategies developed to control the primary tumour through the combined application of hyperthermia and chemotherapy.

Lower critical solution temperature versus volume phase transition temperature in thermoresponsive drug delivery systems

One of the most subtle problem in the characterization of thermoresponsive polymers is the evaluation of the relationship between the lower critical solution temperature (LCST) of the linear polymer and the volume phase transition temperature (VPTT) of the corresponding hydrogel. Here, the LCST and the onset temperature of linear poly(N-isopropy- lacrylamide-co-N-hydroxymethyl acrylamide) has been determined under pseudo-physiological conditions by cloud point (CP) measurements and by microcalorimetric analysis. The LCSTs, as well as the onset temperatures, determined by the CP method, decrease with increasing the concentration of the polymer solution. On the contrary, microcalorimetric analyses give almost the same values for LCSTs and the onset temperatures regardless of polymer concentration. The VPTT of the hydrogel, determined by the blue dextran method, was found to be closely similar to the LCST of the concentrated polymer solution (10%, w/v), determined by the CP method. In fact, the hydrogel could be considered as a concentrated polymer solution whose concentration could be related to the amount of water retained by the hydrogel. Hydrogel microspheres have been also reported to release diclofenac, a drug model system, in a pulsating way at temperatures slightly below and above the VPTT.

SCKs as nanoparticle carriers of doxorubicin: investigation of core composition on the loading, release and cytotoxicity profiles.

SCK nanoparticles having differing core thermal characteristics were designed and evaluated as thermoresponsive drug delivery systems of doxorubicin for the killing of cancerous cells.

温度感応物質を用いたｏｎ‐ｏｆｆ機能を有するニトログリセリン経皮吸収製剤の調製と評価

New liquid crystal-immobilized membrane (LC-membrane) was prepared to develop the thermo-responsive drug delivery systems, This LC-membrane has high compatibility to a variety of drugs because of its electrical neutrality and the LC can sharply control the membrane permeation of drugs in response to temperature. The application of thermo-responsive LC-membrane to transdermal delivery of glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) was studied to achieve the on-off switching release of the vasodilators which reguire “wash-out” from the body to avoid drug tolerance. The permeability of GTN and ISDN through LC-membrane increased above the gel-liquid crystal phase trandition temperature (Tc) of LC(38°C), The LC-membrane suppressed GTN and ISDN permeation through the excised abdominal skin of hairless rat at 32°C to about one-half of that at 38°C Similar tendency was found in the plasma level of GTN and ISDN in hairless rat. It was suggested from these results that the LC-membrane might enable Transdermal Therapeutic Systems to achieve the on-off switching release.