Thermosensitive Drug Delivery System Research Articles

Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma.

This study aimed to develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye. A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7 mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally into Dutch-belted pigmented rabbits after corneal alkali injury. Control rabbits received 2 mg of IgG-loaded DDS or 1.4 mg of aflibercept-loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug-release kinetics was assessed in vivo using an aqueous humor protein analysis. A single subconjunctival administration of dual anti-TNF-α/anti-VEGF DDS achieved a sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45+ immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect (combined: <1%; anti-VEGF: 15%; IgG: 10%, of cornea area), increased infiltration of CD45+ immune cells into the cornea (combined: 28 ± 20; anti-VEGF: 730 ± 178; anti-IgG: 360 ± 186, cells/section), and significant loss of RGCs (combined: 2.7%; anti-VEGF: 63%; IgG: 45%) and optic nerve axons at 3 months. The aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site. Concomitant inhibition of TNF-α and VEGF prevents corneal neovascularization and ameliorates subsequent irreversible damage to the retina and optic nerve after severe ocular injury. A single subconjunctival administration of this therapy, using a biodegradable, slow-release thermosensitive DDS, achieved the sustained elution of therapeutic levels of antibodies to all ocular tissues for 3 months. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients and improve the therapeutic outcomes in patients with retinal vascular diseases.

PNIPAM/Hexakis as a thermosensitive drug delivery system for biomedical and pharmaceutical applications

Many technologies ranging from drug delivery approaches to tissue engineering purposes are beginning to benefit from the unique ability of “smart polymers.” As a special case, thermo-sensitive hydrogels have great potential, e.g. in actuators, microfluidics, sensors, or drug delivery systems. Here, the loading of Doxorubicin (DOX) with novel thermo-sensitive polymer N-isopropyl acrylamide (PNIPAM) and its copolymers are investigated in order to increase the Doxorubicin’s drug efficacy on the targeted tumor site. Therefore, a rational design accurate based on the use of classical molecular dynamics (MD) and well-tempered metadynamics simulations allows for predicting and understanding the behavior of thermo-responsive polymers in the loading of DOX on Hexakis nano-channel at 298 and 320 K. Furthermore, this work investigates the efficacy of this drug carrier for the release of DOX in response to stimuli like variations in temperature and changes in the physiological pH. The study concludes that the Hexakis–polymer composite is capable of adsorbing the DOX at neutral pH and by increasing the temperature of the simulated systems from 298 to 320 K, the strength of intermolecular attraction decreases. In addition, the obtained results of MD simulation revealed that the dominant interaction between DOX and Hexakis in the DOX/polymer/Hexakis systems is the Lennard–Jones (LJ) term due to the formation of strong π–π interaction between the adsorbate and substrate surface. Obtained results show that a higher aggregation of DMA chains around the Hexakis and the formation of stronger bonds with DOX. The results of the well-tempered metadynamics simulations revealed that the order of insertion of drug and polymer into the system is a determining factor on the fate of the adsorption/desorption process. Overall, our results explain the temperature-dependent behavior of the PNIPAM polymers and the suitability of the polymer–Hexakis carrier for Doxorubicin delivery.

Thermosensitive Drug Delivery System SBA-15-PEI for Controlled Release of Nonsteroidal Anti-Inflammatory Drug Diclofenac Sodium Salt: A Comparative Study.

Mesoporous SBA-15 silica material was prepared by the sol–gel method and functionalized with thermosensitive polyethylenimine polymers with different molecular weight (g·mol−1): 800 (SBA-15(C)-800), 1300 (SBA-15(C)-1300) and 2000 (SBA-15(C)-2000). The nonsteroidal anti-inflammatory drug (NSAID) diclofenac sodium was selected as a model drug and encapsulated into the pores of prepared supports. Materials were characterized by the combination of infrared spectroscopy (IR), atomic force microscopy (AFM), transmission electron microscopy (TEM), photon cross-correlation spectroscopy (PCCS), nitrogen adsorption/desorption analysis, thermogravimetry (TG), differential scanning calorimetry (DSC) and small-angle X-ray diffraction (SA-XRD) experiments. The drug release from prepared matrixes was realized in two model media differing in pH, namely small intestine environment/simulated body fluid (pH = 7.4) and simulated gastric fluid (pH = 2), and at different temperatures, namely normal body temperature (T = 37 °C) and inflammatory temperature (T = 42 °C). The process of drug loading into the pores of prepared materials from the diclofenac sodium salt solutions with different concentrations and subsequent quantitative determination of released drugs was analyzed by UV-VIS spectroscopy. Analysis of prepared SBA-15 materials modified with polyethylenimines in solution showed a high ability to store large amounts of the drug, up to 230 wt.%. Experimental results showed their high drug release into the solution at pH = 7.4 for both temperatures, which is related to the high solubility of diclofenac sodium in a slightly alkaline environment. At pH = 2, a difference in drug release rate was observed between both temperatures. Indeed, at a higher temperature, the release rates and the amount of released drug were 2–3 times higher than those observed at a lower temperature. Different kinetic models were used to fit the obtained drug release data to determine the drug release rate and its release mechanism. Moreover, the drug release properties of prepared compounds were compared to a commercially available medicament under the same experimental conditions.

Ocular Drug Delivery: A Special Focus on the Thermosensitive Approach.

The bioavailability of ophthalmic therapeutics is reduced because of the presence of physiological barriers whose primary function is to hinder the entry of exogenous agents, therefore also decreasing the bioavailability of locally administered drugs. Consequently, repeated ocular administrations are required. Hence, the development of drug delivery systems that ensure suitable drug concentration for prolonged times in different ocular tissues is certainly of great importance. This objective can be partially achieved using thermosensitive drug delivery systems that, owing to their ability of changing their state in response to temperature variations, from room to body temperature, may increase drug bioavailability. In the case of topical instillation, in situ forming gels increase pre-corneal drug residence time as a consequence of their enhanced adhesion to the corneal surface. Otherwise, in the case of intraocular and periocular, i.e., subconjunctival, retrobulbar, peribulbar administration, among others, they have the undoubted advantage of being easily injectable and, owing to their sudden thickening at body temperature, have the ability to form an in situ drug reservoir. As a result, the frequency of administration can be reduced, also favoring the patient’s adhesion to therapy. In the main section of this review, we discuss some of the most common treatment options for ocular diseases, with a special focus on posterior segment treatments, and summarize the most recent improvement deriving from thermosensitive drug delivery strategies. Aside from this, an additional section describes the most widespread in vitro models employed to evaluate the functionality of novel ophthalmic drug delivery systems.

Synthesis and in vitro testing of thermoresponsive polymer-grafted core-shell magnetic mesoporous silica nanoparticles for efficient controlled and targeted drug delivery

In this work, thermoresponsive polymer grafted magnetic mesoporous silica nanoparticles were prepared, fully characterized and tested as controlled drug delivery systems. For this purpose, iron oxide nanoparticles coated with mesoporous silica shell were grafted with poly(N-isopropylacrylamide-co-3-(methacryloxypropyl)trimethoxysilane) (PNIPAM-co-MPS). The grafting and polymerization on the as-prepared nanoparticles were performed in one-step procedure. Using this methodology, the polymer was successfully grafted mainly onto the silica surface, leaving the mesopores empty for the drug loading. The prepared hybrid nanoparticles (MMSNP-PNIPAM-co-MPS) showed high magnetization saturation (19.5 emu g−1) and high specific surface area (505 m2 g−1) and pore volume (0.29 cm3 g−1). Ibuprofen was used as a model drug to test the performance of the hybrid particles as thermosensitive drug delivery systems. For this, in vitro drug delivery tests were conducted below (25 °C) and above (40 °C) the lower critical solution temperature (LCST) of the polymer (PNIPAM-co-MPS). Considerable difference (80%) in the ibuprofen release at these two temperatures and a fast and complete release of the drug at 40 °C was observed. These results suggest that the thermoresponsive copolymer acts as a gatekeeper for the temperature-controlled release of the drug loaded inside the mesopores. Therefore, MMSNP-PNIPAM-co-MPS are promising magnetic and thermoresponsive nanocarriers for targeted delivery of therapeutic substances.

Site-specific pharmaco-laser therapy: a novel treatment modality for refractory port wine stains

The current treatment options for PWS patients are limited in efficacy. Novel therapeutic modalities are needed to more effectively treat patients with recalcitrant PWSs. SSPLT is an experimental-stage treatment modality that could serve as an adjuvant to pulsed dye laser therapy for a selected group of patients whose PWS is ill-responsive to standard treatment. The expected clinical result of SSPLT is improved lesional blanching.

Thermo-Sensitive Nanomaterials: Recent Advance in Synthesis and Biomedical Applications.

Progress in nanotechnology has enabled us to open many new fronts in biomedical research by exploiting the peculiar properties of materials at the nanoscale. The thermal sensitivity of certain materials is a highly valuable property because it can be exploited in many promising applications, such as thermo-sensitive drug or gene delivery systems, thermotherapy, thermal biosensors, imaging, and diagnosis. This review focuses on recent advances in thermo-sensitive nanomaterials of interest in biomedical applications. We provide an overview of the different kinds of thermoresponsive nanomaterials, discussing their potential and the physical mechanisms behind their thermal response. We thoroughly review their applications in biomedicine and finally discuss the current challenges and future perspectives of thermal therapies.

A dual-targeting strategy for enhanced drug delivery and synergistic therapy based on thermosensitive nanoparticles

The functionalized nanoparticles have been widely studied and reported as carriers of drug transport recently. Furthermore, many groups have focused more on developing novel and efficient treatment methods, such as photodynamic therapy and photothermal therapy, since both therapies have shown inspiring potential in the application of antitumor. The mentioned treatments exhibited the superiority of cooperative manner and showed the ability to compensate for the adverse effects caused by conventional monotherapy in proposed strategies. In view of the above descriptions, we formulated a thermosensitive drug delivery system, which achieved the enhanced delivery of cisplatin and two photosensitizers (ICG and Ce6) by dual-targeting traction. Drawing on the thin film hydration method, cisplatin and photosensitizers were encapsulated inside nanoparticles. Meanwhile, the targeting peptide cRGD and targeting molecule folate can be modified on the surface of nanoparticles to realize the active identification of tumor cells. The measurements of dynamic light scattering showed that the prepared nanoparticles had an ideal dispersibility and uniform particle size of 102.6 nm. On the basis of the results observed from confocal laser scanning microscope, the modified nanoparticles were more efficient endocytosed by MCF-7 cells as a contrast to SGC-7901 cells. Photothermal conversion-triggered drug release and photo-therapies produced a significant apoptosis rate of 85.9% on MCF-7 cells. The distinguished results made it believed that the formulated delivery system had conducted great efforts and innovations for the realization of concise collaboration and provided a promising strategy for the treatment of breast cancer.

A thermosensitive drug delivery system prepared by blend electrospinning

In this study, the thermosensitive polymer poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA) was synthesized and electrospun into fibers by blending with ethyl cellulose (EC). Fibers were additionally prepared loaded with ketoprofen (KET) as a model drug. Smooth cylindrical fibers could generally be observed by electron microscopy, although there were some beads and fused fibers visible in the KET-loaded materials. KET was found to be amorphously distributed in the fibers on the basis of X-ray diffraction data. From water contact angle measurements, it was clear that the wettability of the EC/PDEGMA systems changed as the temperature increased, with the fibers becoming markedly more hydrophobic. In vitro drug release studies showed that KET was released over a prolonged period of time with the fibers having different profiles at 25 and 37°C, reflecting their thermosensitive properties. Furthermore, the materials were found to have good biocompatibility towards L929 fibroblasts. Thus, the fibers prepared in this work have potential as smart stimuli-responsive drug delivery systems.

A computational study on the usability of amino acid-functionalised nitrogen-doped graphene oxides as temperature-responsive drug delivery systems

The usability of amino acid–functionalised nitrogen-doped graphene oxide (GO) structures (AA-NGO) in drug delivery (DD) systems was studied using the computational approaches. Docking, molecular dynamic (MD) and molecular mechanics generalised born surface area studies were carried out. The calculations were done at 37 and 42 °C to study the usability of the mentioned structures in thermally induced DD systems. In this method, the drug is released by increasing the temperature. For the representative cases, studies at 32, 37, 42 and 47 °C were carried out, as well. Both one-to-one and two-to-one ratio between the AA-NGO and Taxol were studied. In the one-to-one system the Lys–NGO is the best structure to be used in the thermo-sensitive DD systems, based on the binding energy differences calculated at mentioned four temperatures. In the two-to-one systems, the Glu–NGO is leading to the most promising results. In this case, the longer distance between the two layers at higher temperature was regarded as the reason for the better release of the drug at a higher temperature. In this case, at a lower temperature, the Taxol is trapped between two layers of Glu–NGO and has interactions with both of them. At higher temperature, the interaction with just one of the layers is observable, which means lesser interactions and better release of the Taxol.

Near infrared laser-controlled drug release of thermoresponsive microgel encapsulated with Fe3O4 nanoparticles

One major issue in thermosensitive drug delivery systems is the remote, repeatable control of temperature in vivo through external stimuli such as light, ultrasound, and magnetic field.

Upper Critical Solution Temperature Polymer, Photothermal Agent, and Erythrocyte Membrane Coating: An Unexplored Recipe for Making Drug Carriers with Spatiotemporally Controlled Cargo Release.

"On-demand" drug release within target site is critical for targeted drug delivery systems. We herein integrate the advantages of upper critical solution temperature (UCST) polymers, photothermal agent, and red blood cell (RBC) membrane coating into a single drug delivery nanosystem and, for the first time, achieve remotely controlled UCST polymer-based drug delivery system that undergoes "on-demand" drug release within specified zone. When in laser-off state, the resulting nanosystem demonstrates significantly diminished drug self-leakage, owing to shielding by the RBC membrane coating. Upon laser irradiation, this system undergoes responsive drug release, likely because of particle swelling due to its UCST polymer component's hydrophobic-to-hydrophilic transition triggered by the rapid localized heating generated by its preloaded photothermal agent via photothermal effects. As a result, this drug delivery system exhibits spatiotemporally controlled cytotoxicity to cultured cells, efficiently eradicating irradiated cancerous cells without appreciably impacting nonirradiated ones, those ∼0.7 cm away from the irradiation zone. This work may open an avenue to thermosensitive drug delivery systems potentially "ideal" for intravenous administration and inspire future efforts on biomedical applications of UCST polymers.

Preparation and characterization of magnetic thermosensitive fluorouracil micelles

In this study, we synthesized P(NIPAM-co-DMAM)-b-PLA polymers with free radical polymerization and ring-opening addition polymerization, and immediately assembled ‘dextran magnetic layered double hydroxide fluorouracil’ (DMF) magnetic particles into the core of the amphiphilic polymer micelles with synchronous hydration and dialysis, to generate a magnetic thermosensitive fluorouracil drug delivery system. The basic properties of the micelle particles, such as the core–shell-type structure, size, and zeta potential, were studied with 1H-NMR, FTIR, TEM, TGA, laser nanoparticle size analysis, and other characterization techniques. The thermosensitivity of the micelles was investigated by measuring parameters such as the lower critical solution temperature (LCST) and the relationship between the particle size variation and temperature. The drug release curves for the micelles at different temperatures were constructed with a dialysis method. The LCST of the triblock polymers was 42 °C. The particle sizes of the blank micelles and DMF-loaded micelles were 493.6 ± 1.8 nm and 464.9 ± 4.1 nm, respectively, at 25 °C. When the temperature was higher than LSCT, a contraction phase change in the micelle structure occurred, a significant characteristic of the core–shell-type structure, and reversible phase transition phenomena. The release behavior of the drug-loaded micelles showed obvious variations with temperature. Therefore, the magnetic thermosensitive fluorouracil drug delivery system has a good magnetic response and excellent temperature controlled release characteristics, so it can be used as a drug delivery system in magnetically and thermally targeted chemotherapy for tumors.

Smart Cu1.75S nanocapsules with high and stable photothermal efficiency for NIR photo-triggered drug release

Thermosensitive drug delivery systems (DDSs) face major challenges, such as remote and repeatable control of in vivo temperature, although these can increase the therapeutic efficacy of drugs. To address this issue, we coated near-infrared (NIR) photothermal Cu1.75S nanocrystals with pH/thermos-sensitive polymer by in situ polymerization. The doxorubicine (DOX) loading content was up to 40 wt.%, with less than 8.2 wt.% of DOX being leaked under normal physiological conditions (pH = 7.4, 37 °C) for almost 48 h in the absence of NIR light. These nanocapsules demonstrate excellent photothermal stability by continuous longterm NIR irradiation. Based on the stable and high photothermal efficiency (55.8%), pre-loaded drugs were released as desired using 808-nm light as a trigger. Both in vitro and in vivo antitumor therapy results demonstrated that this smart nanoplatform is an effective agent for synergistic hyperthermia-based chemotherapy of cancer, demonstrating remote and noninvasive control.

Synthesis of hyperbranched polyglycidol-b-poly(N-isopropylacrylamide) using nitroxide-mediated polymerization for thermo-sensitive drug delivery system

Synthesis of hyperbranched polyglycidol-b-poly(N-isopropylacrylamide) using nitroxide-mediated polymerization for thermo-sensitive drug delivery system

Thermosensitive hydrogel drug delivery system containing doxorubicin loaded CS–GO nanocarriers for controlled release drug in situ

Local delivery of antitumour drugs provided a high local concentration, the intention of increased antitumour and decreased systemic therapy. An injectable thermosensitive hydrogel is commonly used as a local drug delivery system (DDS). In this paper, a novel local hydrophilic doxorubicin (DOX) DDS, chitosan functionalised graphene oxide (CS–GO) nanocarriers in polylactide (PLA)–poly(ethylene glycol) (PEG)–PLA thermosensitive hydrogel, was demonstrated. The DOX loaded CS–GO nanocarriers (DOX/CS–GO) were prepared via π–π stacking and hydrophobic interactions, which presented a superior loading capacity for DOX, and then DOX/CS–GO were incorporated into the thermosensitive hydrous matrix. The obtained injectable hydrophilic DOX delivery system was flowing sol at ambient temperature but became non-flowing gel at body temperature and can act as a depot for sustained release of DOX in situ. The in vitro cytotoxicity test showed that the PLA–PEG–PLA hydrogel and CS–GO nanocarriers were non-cytotoxic. The obtained CS–GO/DOX nanocarriers not only showed increased cellular uptake but also enhanced cytotoxicity. The in vitro release of PLA–PEG–PLA/(CS–GO/DOX) complexes was sustained for >200 h. These results suggested that this injectable composite hydrogel is a potential candidate as drug carrier and in clinical applications in situ.

Synthesis of a dextran based thermo-sensitive drug delivery system by gamma irradiation

Gamma radiation was used as the initiator/crosslinker agent for the synthesis of thermo-sensitive hydrogel networks, under the form of membranes, using dextran and N-isopropylacrylamide. The prepared membranes were loaded with Ondansetron™, a potent antiemetic drug and tested as drug delivery systems.The characterization of the materials was accomplished by: Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy, elemental analysis, lower critical solution temperature (LCST) determination, swelling behaviour evaluation, determination of surface energy by contact angle measurement and drug delivery kinetics studies. Also, the influence of irradiation time and temperature on the materials properties was evaluated.

Preparation and characterization of a novel thermosensitive nanoparticle for drug delivery in combined hyperthermia and chemotherapy.

In the present research, a novel thermal sensitive amphiphilic polymer was synthesized by modification of chitosan with hydrophilic hydroxybutyl groups and hydrophobic deoxycholic acid moieties. By finetuning the hydrophobic/hydrophilic balance of deoxycholic acid decorated hydroxybutyl chitosan (DAHBC), the lower critical solution temperature (LCST) of this novel polymer could be adjusted to 38.2 °C, which is an appropriate temperature in hyperthermia therapy. The polymer could self-assemble into approximately spherical nanoparticles in aqueous solutions with an average diameter of 399.6 nm and a zeta potential value of -33.8 mV. The controlled release properties of the thermosensitive drug delivery system were evaluated by using doxorubicin (DOX) as a model drug. Compared with the drug release behavior at a temperature below the LCST, the release of doxorubicin was significantly accelerated when the nanoparticles were in an environmental temperature above the LCST of the polymer. According to the results of MTT assays, blank DAHBC nanoparticles showed no significant toxicity on mouse embryo fibroblasts at a concentration as high as 1 mg ml-1, and DOX-loaded nanocarriers exhibited an improved drug uptake by MCF-7 cells with the incubation temperature rising from 37 °C to 43 °C, which indicated that thermoresponsive and biocompatible DAHBC nanoparticles might have practical applications as drug carriers in combined hyperthermia and chemotherapy.

Novel application of Eudragit RL and cholesteryl oleyl carbonate to thermo-sensitive drug delivery system

The Eudragit RL 100 and propylene glycol (PG) membranes with and without cholesteryl oleyl carbonate (COC) were prepared by the solvent casting method to pioneer a novel application of a thermo-sensitive drug delivery system. After that, the properties of these membranes were investigated by thermal, scanning, and porosity studies. Drug permeation studies through all membranes were carried out using salbuthamol sulphate (SBS) at constant temperatures (25°C and 37°C), respectively. The permeability of SBS through the membranes with COC has been shown to be a discontinuous function of temperature, that is, their permeability increased steeply above the phase transition temperature (37°C) of the COC. The thermo-sensitive permeation mechanism for the membranes might be based on the structure change of the membranes caused by the phase transition, so that the membranes could absorb more water. Considering the high biological safety of Eudragit RL 100 and PG membranes with and without COC might be used to develop a novel thermo-sensitive drug delivery system.

Zippered release from polymer-gated carbon nanotubes

A thermosensitive drug delivery system based on polymer-gated carbon nanotubes (CNTs) that are loaded with the anticancer drug doxorubicin (DOX) is herein reported. The development of carbon nanotubes for various biomedical applications is the research focus of many research groups and holds great promise. The major drawback of these materials is the toxicity that is associated with conjugated carbon systems. Functionalization of CNTs with polymers has proved very successful in lowering the toxicity and improving the pharmacokinetic profile. In this work, CNTs are coated with polyethylenimine (PEI) and polyvinyl alcohol (PVA) via the “zipper effect” that provides both support and control over drug release. PEI/PVA provides excellent support to increase DOX loading on the nanocarrier. The system is controlled by changes in temperature due to the complexation (low temperature) and decomplexation (high temperature) of PEI and PVA via hydrogen bonding. The release of DOX was tested in three cell lines (Lung fibroblast (LF), Breast Adenocarcinoma (BA), and HeLa). It was further tested in primary cell lines (Human Dermal Fibroblast adult (HDFa) and Human Dermal Fibroblast neonatal (HDFn)). When the bonds between PEI and PVA are decomplexed at high temperature (≥40 °C), drug release was observed as verified by fluorescence microscopy. There was no drug release at room temperature (25 °C) and a slow release at normal body temperature (37 °C). This system represents a promising method for incorporating stimuli triggered polymer-gated CNTs in future controlled release applications.