Heat-triggered Drug Release Research Articles

Numerical evaluation of heat-triggered drug release via thermo-sensitive liposomes: A comparison between image-based vascularized tumor and volume-averaged porous media models

In this study, two numerical models for controlled drug delivery through thermo-sensitive liposomes under mild microwave hyperthermia are compared. The first model simulates blood flow directly in a realistic tumor vascular network. The second one, at the volume-averaged macro scale, employs the porous media model. Using the vascular-scale approach is helpful for these kind of applications since the porous media assumption does not allow to account for local vascular blood flow, which is a crucial variable to quantify outputs like local drug accumulations. In the present study, the vascularized tumor model is obtained from a photo-acoustic scan and used as computational domain. The vascular-scale model considers heat and drug transfer in vascular and intracellular spaces, employing energy equations for heat transfer and a three-compartment convection-diffusion model for drug diffusion. Blood flow is simulated using the momentum equation for non-Newtonian fluids. The volume-averaged model shows good agreement with the vascular-scale model even if provides less precise information about temperature field distribution and drug localization within the tumor tissue. Also, the volume-averaged model underestimates Fraction of Killed Cells by 3 % post-treatment, presenting a more uniform temperature field and drug distribution compared to the vascular-scale one. Despite these small limitations, the porous media model is reliable for obtaining average results, while the vascular-scale model is suitable when more accurate results are needed. This study's findings aid those who aim to predict hyperthermia-driven drug delivery, suggesting the vascular-scale approach for precision and accuracy and the volume-averaged approach for average outcomes.

Enhancement of brain hyperthermia via transcranial magnetic resonance imaging-guided focused ultrasound and microbubbles—Heating mechanism investigation using COMSOL

Noninvasive methods for enhancing the brain drug delivery has been pursued for years. Previously we developed a new MR-guided focused ultrasound (FUS)-based technique, which can achieve targeted brain hyperthermia for heat-triggered drug release and simultaneously open the blood–brain barrier safely for drug penetration. However, the underline mechanisms were unclear. This study aimed to explore the mechanisms for the enhanced FUS brain tissue hyperthermia with microbubbles via numerical modeling in COMSOL. The acoustic wave equation was employed to describe the FUS propagation. A bubble dynamics equation was adopted for calculating the stable bubble oscillations under FUS exposures. A modified bioheat transfer equation was utilized to compute the heating, with various heating sources including FUS, microbubble acoustic emission (MAE), and viscous dissipation (VD). The microbubbles were randomly distributed within the focal region. The sonication time was 6s with an initial temperature of 41°C. The average temperature in the focal region were 41.65°C, 42.24°C, 42.98°C, and 43.59°C for FUS alone, FUS + MAE, FUS + VD, and FUS + MAE + VD, respectively. Compared with the FUS alone, both MAE and VD made significant contributions to the heating with additional temperature increases of 47.6% and 67.2%, respectively.

Multifunctional Traceable Liposomes with Temperature-Triggered Drug Release and Neovasculature-Targeting Properties for Improved Cancer Chemotherapy.

Poor distribution of nanocarriers at the tumor site and insufficient drug penetration into the tissue are major challenges in the development of effective and safe cancer therapy. Here, we aim to enhance the therapeutic effect of liposomes by accumulating doxorubicin-loaded liposomes at high concentrations in and around the tumor, followed by heat-triggered drug release to facilitate low-molecular-weight drug penetration throughout the tumor. A cyclic RGD peptide (cRGD) was incorporated into liposomes decorated with a thermosensitive polymer that allowed precise tuning of drug release temperature (i.e., Polymer-lip) to develop a targeted thermosensitive liposome (cRGD-Polymer-lip). Compared with conventional thermosensitive liposomes, cRGD-Polymer-lip enhanced the binding of liposomes to endothelial cells, leading to their accumulation at the tumor site upon intravenous administration in tumor-bearing mice. Drug release triggered by local heating strongly inhibited tumor growth. Notably, tumor remission was achieved via multiple administrations of cRGD-Polymer-lip and heat treatments. Thus, combining the advantages of tumor neovascular targeting and heat-triggered drug release, these liposomes offer high potential for minimally invasive and effective cancer chemotherapy.

Smart gold nanocages for mild heat-triggered drug release and breaking chemoresistance

Chemotherapy is an important modality available for cancer treatment. However, the present chemotherapy is still far from being satisfactory mainly owing to the severe side effects of the chemotherapeutic agents and drug resistance of cancer cells. Thus, reversing drug resistance by constructing an ideal chemotherapeutic strategy with the least side effects and the best efficacy is greatly needed. Here, we designed a smart nanosystem of thermo-sensitive liposome coated gold nanocages with doxorubicin (DOX) loading (LAD) for near-infrared (NIR)-triggered drug release and chemo-photothermal combination therapy. The biocompatible liposomes coating facilitated the cellular uptake of LAD and meanwhile avoided drug leakage during the circulation. More importantly, LAD exhibited controllable photothermal conversion property and produced mild heat under NIR irradiation, which not only triggered DOX release and transferred DOX from lysosome to nucleus, but also elicited the mild heat cell killing effect to improve the curative efficiency. Further mechanism study revealed that mild heat could reverse drug resistance by down-regulation of the chemoresistance-related markers (e.g., HSF-1, p53, P-gp), and inhibited DOX export and increased drug sensitiveness, thereby prominently increased the anticancer efficiency. This versatile nanoplatform with enhanced curative efficacy and lower side effect is promising to apply in the field of drug controlled release and combination tumor therapy.

Experimental Evaluation on the Heating Efficiency of Magnetoferritin Nanoparticles in an Alternating Magnetic Field.

The superparamagnetic substance magnetoferritin is a potential bio-nanomaterial for tumor magnetic hyperthermia because of its active tumor-targeting outer protein shell, uniform and tunable nanosized inner mineral core, monodispersity and good biocompatibility. Here, we evaluated the heating efficiency of magnetoferritin nanoparticles in an alternating magnetic field (AMF). The effects of core-size, Fe concentration, viscosity, and field frequency and amplitude were investigated. Under 805.5 kHz and 19.5 kA/m, temperature rise (ΔT) and specific loss power (SLP) measured on magnetoferritin nanoparticles with core size of 4.8 nm at 5 mg/mL were 14.2 °C (at 6 min) and 68.6 W/g, respectively. The SLP increased with core-size, Fe concentration, AMF frequency, and amplitude. Given that: (1) the SLP was insensitive to viscosity of glycerol-water solutions and (2) both the calculated effective relaxation time and the fitted relaxation time were closer to Néel relaxation time, we propose that the heating generation mechanism of magnetoferritin nanoparticles is dominated by the Néel relaxation. This work provides new insights into the heating efficiency of magnetoferritin and potential future applications for tumor magnetic hyperthermia treatment and heat-triggered drug release.

Understanding Plasmonic Heat-triggered drug release from gold based nanostructure

Targeted drug delivery in a spatiotemporal fashion with high specificity could aid numerous therapeutic applications having reduced nonspecific cytotoxicity. In a typical nanoconstruct, gold nanoparticle synthesized using folic acid as reducing agent is conjugated with stearic acid coupled Pluronic F-127. The pluronic F-127 can hold 5-FU on its hydrophilic corona of the micelle, acting as a drug reservoir and the folic acid reduced Au NPs on its outer surface ensures the targeting ability as well as provides surface plasmon resonance induced plasmonic heating required for triggered drug release. Thus, engineered nanostructure has high stability and ability to load 73.07% of 5-FU. In-vitro drug release profile with and without laser irradiation at plasmonic resonance wavelength of 532 nm (50 mW commercial laser) was studied and found the nanoconstruct was effective for controlled drug release via laser induced plasmonic heating from Au NPs. In-vitro biocompatible studies proves the nanocarrier was nontoxic and the drug loaded nanocarrier was effective towards A549 lung cancer cells. The overall results of the study reveals that the multifunctional nanoconstruct based on gold nanoparticle can find promising therapeutic application in targeted triggered drug release and has the potential application during oncosurgical procedures via (i) laser triggered targeted drug release, (ii) Photothermal therapy, (iii) SERS based onsite detection and imaging of cancer cells.

Thermally triggered theranostics for pancreatic cancer therapy.

Hybrid iron oxide-gold nanoparticles (HNPs) show the ability to bind drugs onto their surface with a triggered release at elevated temperatures. The iron oxide core allows for diagnostic imaging whilst heating of the gold shell upon laser irradiation reverses drug binding. This study exploits the reversible binding of novel polyamine based drugs in order to provide a specific and effective method for pancreatic cancer treatment. Here we used a novel bisnaphthalamido (BNIP) based drug series. Our hybrid nanoparticles (50 nm) showed the ability to load drugs onto their surface (3 : 1 : 0.25, drug : Fe : Au). By exploiting the surface-to-drug electrostatic interaction of a range of BNIP agents, heat triggered drug release was achieved. A 12-fold reduction in IC50 after 24 h in vitro and a 5-fold reduction of tumour retardation in vivo compared with free drug in pancreatic models after treatment were achieved with the HNP-formulation and laser irradiation. This heat activated system could provide a key platform for future therapeutic strategies.

Engineering thermosensitive liposome-nanoparticle hybrids loaded with doxorubicin for heat-triggered drug release

The engineering of responsive multifunctional delivery systems that combine therapeutic and diagnostic (theranostic) capabilities holds great promise and interest. We describe the design of thermosensitive liposome-nanoparticle (NP) hybrids that can modulate drug release in response to external heating stimulus. These hybrid systems were successfully engineered by the incorporation of gold, silver, and iron oxide NPs into the lipid bilayer of lysolipid-containing thermosensitive liposomes (LTSL). Structural characterization of LTSL-NP hybrids using cryo-EM and AFM revealed the incorporation of metallic NPs into the lipid membranes without compromising doxorubicin loading and retention capability. The presence of metallic NPs in the lipid bilayer reinforced bilayer retention and offered a nanoparticle concentration-dependent modulation of drug release in response to external heating. In conclusion, LTSL-NP hybrids represent a promising versatile platform based on LTSL liposomes that could further utilize the properties of the embedded NPs for multifunctional theranostic applications.

Chemical Components for the Design of Temperature-Responsive Vesicles as Cancer Therapeutics.

In this Review, we attempt to offer a thorough description of all of the chemical components and the rationale behind the design of temperature-sensitive vesicle systems, as well as the critical pharmacological parameters that need to be combined to achieve their successful clinical translation. The focus of this Review will be predominantly on the design principles around the construction of temperature-sensitive liposomes (TSL) and their use in combination with external local hyperthermia to achieve heat-triggered drug release. The emphasis lies on the chemical components synthesized and incorporated in the design and engineering of TSL. We conclude that the development of TSL with ultrafast drug release capabilities needs to progress in parallel with vesicle pharmacokinetic profiling, imaging, and monitoring capacity and technologies for accurate temperature elevation and control. The development of heat-triggered liposome systems offer the greatest opportunity for clinical translation of the next generation, nanoscale "smart" vesicle systems of enhanced functionality, following from the successful legacy and rich clinical history from multiple earlier liposome technologies.

Enhanced Specificity and Drug Delivery in Tumors by cRGD-Anchoring Thermosensitive Liposomes.

PurposeTo develop RGD-targeted thermosensitive liposomes with increased tumor retention, improving drug release efficiency upon mild hyperthermia (HT) in both tumor and angiogenic endothelial cells.MethodsStandard termosensitive liposomes (TSL) and TSL containing a cyclic Arg-Gly-Asp (cRGD) pentapeptide with the sequence Arg-Cys-D-Phe-Asp-Gly (RGDf[N-Met]C) were synthetized, loaded with Dox and characterized. Temperature- and time-dependent drug release profiles were assessed by fluorometry. Intracellular Dox delivery was studied by flow cytometry and confocal microscopy. Cytotoxic effect of TSL and RGD-TSL was studied on B16Bl6 melanoma, B16F10 melanoma and HUVEC. Intravital microscopy was performed on B16Bl6 tumors implanted in dorsal-skin fold window-bearing mice. Pharmacokinetic and biodistribution of Dox-TSL and Dox-RGD-TSL were followed in B16Bl6 tumor bearing mice upon normothermia or initial hyperthermia conditions.ResultsDLS and cryo-TEM revealed particle homogeneity and size of around 85 nm. Doxorubicin loading efficiency was >95%as assessed by spectrofluorometry. Flow cytometry and confocal microscopy showed a specific uptake of RGD-TSL by melanoma and endothelial cells when compared to TSL and an increased doxorubicin delivery. High resolution intravital microscopy demonstrated specific accumulation of RGD-TSL to the tumor vasculature. Moreover, application of hyperthermia resulted in massive drug release from RGD-TSL. Biodistribution studies showed that initial hyperthermia increases Dox uptake in tumors from TSL and RGD-TSL.ConclusionRGD-TSL have potency to increase drug efficacy due to higher uptake by tumor and angiogenic endothelial cells in combination with heat-triggered drug release.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-015-1746-7) contains supplementary material, which is available to authorized users.

Formulation and pharmacokinetics of thermosensitive stealth® liposomes encapsulating 5-Fluorouracil.

We optimize the encapsulation and investigate the pharmacokinetics of 5-Fluorouracil (5-FU) delivered by thermosensitive stealth(®) liposomes (TSLs) designed to trigger drug release upon hyperthermia using focused ultrasound (FUS). 5-FU was encapsulated into liposomes made of 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol/1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG2000 either as a free molecule or complexed with copper-polyethylenimine. Heat-triggered drug release was evaluated using either a water bath or FUS. Formulation cytotoxicity was assessed on HT-29 cell line by MTS assay. Pharmacokinetics and biodistribution of 5-FU were evaluated in HT-29-tumor bearing mice. 5-FU was easily encapsulated using the lipid hydration method (encapsulation efficacy of 13%) but poorly retained upon dilution. 5-FU complexation with copper-polyethylenimine improved 5-FU retention into liposomes and allowed to obtain an encapsulation efficacy of 37%. At 42°C, heat-triggered 5-FU release from TSLs was 63% using a water bath and 68% using FUS, within 10 min, whereas it remained below 20% for the non-thermosensitive formulation. The MTS assay revealed that formulation toxicity arose from 5-FU and not from the excipients. In addition, 5-FU complex encapsulation into TSLs induces a reduction of the IC50 from 115 down to 49 μM. Pharmacokinetics reveals a longer circulation of encapsulated 5-FU and a more important body exposure, although tumor passive targeting is not significantly higher than free 5-FU. Complexation of 5-FU with copper-polyethylenimine appears an interesting strategy to improve 5-FU retention into TSLs in vitro and in vivo. TSLs allow heat-triggered release of the drug within 10 min at 42°C, a reasonable time for future in vivo experiments.

Evaluation of thermo-triggered drug release in intramuscular-transplanted tumors using thermosensitive polymer-modified liposomes and MRI

Multi-modal thermo-sensitive polymer-modified liposomes (MTPLs) containing an anticancer drug, MR contrast agent, and fluorescent dye have been investigated as “theranostic” nanodevices that can be used to monitor drug delivery in cancer therapy. Here, we measured the physical characteristics of MTPLs, observed the dynamics of MTPLs in vivo, visualized heat-triggered drug release using MRI, and evaluated the treatment effects of the MTPLs with and without heating. In vitro experiments demonstrated that the MTPLs released drugs at temperatures above 41°C. In vivo MTPLs accumulated in tumor tissue, with the accumulation maximized for 4-12hours. MR signal in the tumor was significantly elevated after mild heating for 15 minutes, indicating release of the contrast agent from the MTPLs was facilitated by heat-triggering. Tumor size after treatment with MTPLs and heating was significantly smaller than those of the control groups. In conclusion, MTPLs with MRI are useful for low-invasive cancer theranostics. From the Clinical EditorThis team of investigators measured the physical characteristics of multi-modal thermo-sensitive polymer-modified liposomes, observed their dynamics in vivo, visualized drug release after heat-triggering using MRI, and evaluated the treatment effects of the MTPLs with and without heating, concluding that their approach may be useful in low-invasive cancer therapy.

Targeted and heat-triggered doxorubicin delivery to tumors by dual targeted cationic thermosensitive liposomes

Liposomal nanoparticles can circumvent toxicity of encapsulated chemotherapeutic drugs, but fall short in tumor-specific and efficient intracellular drug delivery. To overcome these shortcomings, we designed a multifunctional dual targeted, heat-responsive nanocarrier encapsulating doxorubicin (Dox) as a chemotherapeutic content. Dox-loaded cationic thermosensitive liposomes (Dox-CTSL) carry targeting functions addressing tumor cells and tumor vasculature and have a heat-responsive lipid bilayer. Targeted Dox-CTSL demonstrated superior uptake by and toxicity to different tumor cell lines and endothelial cells compared to non-targeted TSL. Heat triggered intracellular Dox release in acidic cell compartments was visualized as fluorescent Dox nanobursts by live cell confocal microscopy. In vivo, using high resolution intravital microscopy, we demonstrated that Dox-CTSL upon an external heat-trigger delivered 3-fold higher Dox quantity to tumors than TSL. Dox-CTSL bound specifically to tumor vasculature, which in combination with the heat-triggered drug release caused significant tumor vessel damage, which was not observed when non-targeted TSL were administered. Therefore, Dox-CTSL have strong potency to increase drug efficacy due to targeted delivery and heat-triggered drug release in tumors.

Heat-triggered drug release systems based on mesoporous silica nanoparticles filled with a maghemite core and phase-change molecules as gatekeepers

Core-shell nanoparticles made of a maghemite core and a mesoporous silica shell were developed as drug delivery systems (DDS). Doxorubicin® (DOX, DNA intercalating drug) was loaded within the mesoporous cavities, while phase-change molecules (PCMs), e.g. 1-tetradecanol (TD) with a melting temperature (Tm) of 39 °C, were introduced as gatekeepers to regulate the release behaviours. An overall loading amount of ca. 20 wt% (TD/DOX ca. 50/50 wt/wt) was confirmed. Heat-triggered release of DOX evidenced a "zero premature release" (<3% of the entire payload in 96 h release) under physiological conditions (37 °C), and however, a sustainable release (ca. 40% of the entire payload in 96 h) above Tm of TD (40 °C). It also demonstrated the possibility to deliver drug payloads in small portions (pulsatile release mode) via multiple heating on/off cycles, due to the reversible phase change of the PCMs. In vitro heat-triggered release of DOX within cell culture of the MEL-5 melanoma cell line was also tested. It was found that DOX molecules were trapped efficiently within the mesopores even after internalization within the cytoplasm of MEL-5 cells at 37 °C, with the potential toxicity of DOX strongly quenched (>95% viability after 72 h incubation). However, continuous cell apoptosis was detected at cell culture temperature above Tm of TD, due to the heat-triggered release of DOX (<50% viability after 72 h incubation at 40 °C). Moreover, due to the presence of a maghemite core within the DDS, T2-weighted magnetic resonance imaging performance was also confirmed. These as-designed core-shell nanoparticles are envisaged to become promising DDS for "on-demand" heat-triggered release.