Temperature-sensitive Liposomes Research Articles

Ultrasound-switchable fluorescence thermometry with dual detection channels using temperature-sensitive liposomes.

Temperature measurements in biological tissues play a crucial role in studying metabolic activities. In this study, we introduce a noninvasive thermometry technique based on two-color ultrasound-switchable fluorescence (USF). This innovative method allows for a local temperature mapping within a microtube filled with temperature-sensitive liposomes as nano imaging agents. By measuring the temperature-dependent fluorescence emission of the liposomes using a spectrometer, we identify four characteristic temperatures. The local background temperature can be estimated by analyzing the corresponding appearance time of these four characteristic temperatures in the dynamic USF signals captured by a camera-based USF system with two detection channels. Simultaneous measurements with an infrared (IR) camera showed a 0.38°C ± 0.27°C difference between USF thermometry and IR thermography in a physiological temperature range of 36.48°C-40.14°C. This shows that the two-color USF thermometry technique is a reliable, noninvasive tool with excellent spatial and thermal resolution.

Light-activatable and hyperthermia-sensitive "all-in-one" theranostics: NIR-II fluorescence imaging and chemo-photothermal therapy of subcutaneous glioblastoma by temperature-sensitive liposome-containing AIEgens and paclitaxel.

Nowadays, it is still quite difficult to combat glioblastoma, which is one of the most lethal cancers for human beings. Combinatory therapy, which could not only improve therapeutic efficacy and overcome multiple drug resistance but also decrease the threshold therapeutic drug dosage and minimize side effects, would be an appealing candidate for glioblastoma treatment. Herein, we report fluorescence imaging in the second near-infrared window (NIR-II)-guided combinatory photothermal therapy (PTT) and chemotherapy of glioblastoma with a newly formulated nanomedicine termed PATSL. It is composed of temperature-sensitive liposome (TSL) carriers, NIR-II emissive and photothermal aggregation-induced emission (AIE) dyes, and chemotherapeutic paclitaxel (PTX) as well. PATSL shows spherical morphology with diameters of approximately 55 and 85nm by transmission electron microscopy and laser light scattering, respectively, a zeta potential of -14.83 mV, good stability in both size and photoactivity, strong light absorption with a peak of approximately 770nm, and bright emission from 900nm to 1,200nm. After excitation with an 808-nm laser with good spatiotemporal controllability, PATSL emits bright NIR-II fluorescence signals for tumor diagnosis in vivo, exhibits high photothermal conversion efficiency (68.8%), and triggers drug release of PTX under hypothermia, which assists in efficient tumor ablation in vitro and in vivo. This research demonstrates that "all-in-one" theranostics with NIR-II fluorescence imaging-guided combinatory PTT and chemotherapy is an efficient treatment paradigm for improving the prognosis of brain cancers.

Co-Loading of Black Phosphorus Nanoflakes and Doxorubicin in Lysolipid Temperature-Sensitive Liposomes for Combination Therapy in Prostate Cancer.

Black phosphorus (BP) is one of the most promising nanomaterials for cancer therapy. This 2D material is biocompatible and has strong photocatalytic activity, making it a powerful photosensitiser for combined NIR photothermal and photodynamic therapies. However, the fast degradation of BP in oxic conditions (including biological environments) still limits its use in cancer therapy. This work proposes a facile strategy to produce stable and highly concentrated BP suspensions using lysolipid temperature-sensitive liposomes (LTSLs). This approach also allows for co-encapsulating BP nanoflakes and doxorubicin, a potent chemotherapeutic drug. Finally, we demonstrate that our BP/doxorubicin formulation shows per se high antiproliferative action against an in vitro prostate cancer model and that the anticancer activity can be enhanced through NIR irradiance.

NIR-II Regulation of Mitochondrial Potassium Channel with Dual-Targeted Conjugated Oligomer Nanoparticles for Efficient Cancer Theranostics In Vivo.

Cell fate can be efficiently modulated by switching ion channels. However, the precise regulation of ion channels in cells, especially in specific organelles, remains challenging. Herein, biomimetic second near-infrared (NIR-II) responsive conjugated oligomer nanoparticles with dual-targeted properties were designed and prepared to modulate the ion channels of mitochondria to selectively kill malignant cells in vivo. Upon 1060nm laser irradiation, the mitochondria-located nanoparticles photothermally released a specific ion inhibitor of the potassium channel via a temperature-sensitive liposome, thus altering the redox balance and pathways of mitochondria. NIR-II responsive nanoparticles can effectively regulate the potassium channels of mitochondria and fully suppress tumor growth. This work provides a new modality based on the NIR-II nanoplatform to regulate ion channels in specific organelles, and proposes an effective therapeutic mechanism for malignant tumors. This article is protected by copyright. All rights reserved.

Intelligent Responsive Nanoparticles with Multilevel Triggered Drug Penetration for Tumor Photochemotherapy.

Nanomedicines have contradictory size requirements to overcome systemic barriers and penetrate the tumor extracellular matrix (ECM). Larger-sized nanoparticles (50-200 nm) exhibit prolonged blood circulation half-life and improved tumor enrichment, while small-sized nanoparticles (4-20 nm) easily penetrate deep tumor tissues. Therefore, the development of intelligent responsive nanomedicine systems can not only increase nanodrug tumor accumulation but also improve their penetration into the ECM. Herein, we propose an intelligent responsive nanoparticle triggered by near-infrared light (NIR). The nanoparticle was constructed by a temperature-sensitive liposome (TSL) encapsulating ultrasmall melanin nanoparticles (MNPs) loaded with doxorubicin (MNP/doxorubicin (DOX)@TSL). When exposed to NIR irradiation, the tailor-made nanoparticles not only effectively ablated the tumor cells around blood vessels but also destroyed the structural integrity and released loaded ultrasmall MNP/DOX (<10 nm) to promote deep tumor penetration and enhance interior tumor cell killing. This NIR-triggered intelligent nanoparticle successfully integrated photothermal therapy (PTT) for perivascular tumor cells and chemotherapy for deep tumor cell inhibition. The in vivo results showed remarkable tumor regression in 4T1 breast tumor-bearing mice by 74.2%. This controllable size switchable nanosystem with efficient tumor accumulation and penetration has shown great potential in improving synergistic antitumor effects of photochemotherapy.

A NIR-Activated and Mild-Temperature-Sensitive Nanoplatform with an HSP90 Inhibitor for Combinatory Chemotherapy and Mild Photothermal Therapy in Cancel Cells.

Mild photothermal therapy (PTT) shows great potential to treat cancers while avoiding unwanted damage to surrounding normal cells. However, the efficacy of mild PTT is normally moderate because of the low hyperthermia temperature and limited light penetration depth. Chemotherapy has unlimited penetration but often suffers from unsatisfactory efficacy in view of the occurrence of drug resistance, suboptimal drug delivery and release profile. As a result, the combinatory of chemotherapy and mild PTT would integrate their advantages and overcome the shortcomings. Herein, we synthesized an NIR-activatable and mild-temperature-sensitive nanoplatform (BDPII-gel@TSL) composed of temperature-sensitive liposomes (TSL), heat shock protein 90 (HSP90) inhibitor (geldanamycin) and photothermal agent (BDPII), for dual chemotherapy and mild PTT in cancer cells. BDPII, constructed with donor-acceptor moieties, acts as an excellent near-infrared (NIR) photothermal agent (PTA) with a high photothermal conversion efficiency (80.75%). BDPII-containing TSLs efficiently produce a mild hyperthermia effect (42 °C) under laser irradiation (808 nm, 0.5 W cm-2). Importantly, the phase transformation of TSL leads to burst release of geldanamycin from BDPII-gel@TSL, and this contributes to down-regulation of the overexpression of HSP90, ensuring efficient inhibition of cancer cell growth. This research provides a dual-sensitive synergistic therapeutic strategy for cancer cell treatment.

Acoustic Forceps Based on Focused Acoustic Vortices with Different Topological Charges.

For enhanced energy concentration with improved flexibility for object manipulation, a focused acoustic vortex (FAV) is designed using a sector planar piston transducer array and acoustic lens that can produce the effective concentration of the acoustic field to perform the focusing function. Compared to the Gaussian beam, which tends to cause the object to deviate from the axis of acoustic propagation, FAVs can form a central valley region to firmly bind the objects, thus preventing off-target effects. The heat energy in the paraxial region is transferred to the vortex center in the form of heat transfer so that the temperature-sensitive liposomes captured can quickly release drugs, which has a good effect on targeted drug administration. The focused acoustic wave stopped acting on the tissue (gel) for 2 s, the temperature of the vortex center continued to rise, reaching 41.5 °C at the moment of 3.7 s, at which point the liposomes began to release the drug. The FAVs capture the drug and use its thermal effect to achieve accurate and rapid treatment. The simulation results show that the drug release temperature of temperature-sensitive liposomes can be achieved by controlling the action time of the vortices. This study provides a reliable theoretical basis for the clinical application of targeted drugs.

Temperature sensitive liposome based cancer nanomedicine enables tumour lymph node immune microenvironment remodelling

Targeting tumour immunosuppressive microenvironment is a crucial strategy in immunotherapy. However, the critical role of the tumour lymph node (LN) immune microenvironment (TLIME) in the tumour immune homoeostasis is often ignored. Here, we present a nanoinducer, NIL-IM-Lip, that remodels the suppressed TLIME via simultaneously mobilizing T and NK cells. The temperature-sensitive NIL-IM-Lip is firstly delivered to tumours, then directed to the LNs following pH-sensitive shedding of NGR motif and MMP2-responsive release of IL-15. IR780 and 1-MT induces immunogenic cell death and suppress regulatory T cells simultaneously during photo-thermal stimulation. We demonstrate that combining NIL-IM-Lip with anti-PD-1 significantly enhances the effectiveness of T and NK cells, leading to greatly suppressed tumour growth in both hot and cold tumour models, with complete response in some instances. Our work thus highlights the critical role of TLIME in immunotherapy and provides proof of principle to combine LN targeting with immune checkpoint blockade in cancer immunotherapy.

Thermosensitive Liposomal Drug Delivery Systems: A Review

When combined with local hyperthermia or high intensity focused ultrasound, thermosensitive liposomes are a promising technique for externally directing medications to solid tumours. To selectively focus drug delivery to diseased or damaged tissue while reducing drug distribution to vital normal tissues is the main goal of liposomal drug delivery. An overview of temperature-sensitive liposomes is provided in this review. The ability to heat tumours with external energy sources in a controlled and predictable manner makes temperature-sensitive liposomes an especially alluring alternative. The lipids used to make conventional thermosensitive liposomes experience a gel-to-liquid phase shift many degrees above physiological temperature. Lysolipids and artificial temperature-sensitive polymers have recently been used to show how liposomes can be made to be sensitive to temperature. Thermosensitive liposomes (TSL) and localized hyperthermia are potent delivery vehicles for tumor-specific drugs. In addition to chemotherapy, hyperthermia is given to cancer patients to help certain chemotherapeutic medications work more effectively. Using temperature-sensitive liposomes in conjunction with localized hyperthermia, which specifically releases the medicine contained in the heated tumor tissue, can significantly increase the temperature-dependent effect.

Preparation and Purification of Calcein Loaded Temperature-Sensitive Liposomes

Temperature-sensitive liposomes are drug carriers that can encapsulate drug molecules and carry them safely to their target sites for release. They ensure that the encapsulated drug is released for it to become cellularly internalized at the site of action. They also have a wide range of medical applications, however the most popular is chemotherapy.

Abstract No. 338 Novel drug device combination for rectal carcinoma: rectal heating and intraarterial delivery of doxorubicin-loaded low temperature sensitive liposomes in a swine feasibility study

To establish a rectal hyperthermia (HT) model and evaluate plasma and tissue pharmacokinetics following systemic IV vs intra-arterial trans-catheter delivery of low temperature sensitive liposomes (LTSLs) loaded with doxorubicin during rectal HT

TMZ magnetic temperature-sensitive liposomes-mediated magnetothermal chemotherapy induces pyroptosis in glioblastoma

Glioblastoma (GBM) is the most fatal and common type of primary malignant tumors in central nervous system. Chemotherapy drugs are difficult to reach the encephalic region effectively due to blood–brain barrier (BBB), but functional nanoparticle drug carriers can help to solve the problem. Herein, we developed a controllable drug carrier called temozolomide magnetic temperature-sensitive liposomes (TMZ/Fe-TSL) to investigate its feasibility and molecular mechanisms on GBM. Our research found TMZ/Fe-TSL exposed to alternating magnetic field (AMF) could induce significantly GBM cell death and promote the production of ROS. It also showed that the expression of NLRP3, CASP1 and N-GSDMD was upregulated compared to the control group, while the expression of CASP3 showed a reverse change. The results indicated that TMZ/Fe-TSL exposed to the AMF was capable of inducing GBM cells death. And the way and mechanisms of cell death may involve in ROS and pyroptosis, but not apoptosis.

Mild hyperthermia accelerates doxorubicin clearance from tumour-extravasated temperature-sensitive liposomes.

Mild hyperthermia (HT) (40-43 °C) has been combined with temperature-sensitive liposomes (TSL), offering on-demand drug release for increased drug bioavailability and reduced systemic toxicity. Different HT regimens have been applied to trigger liposome drug release in the blood vessels (intravascular) of heated tumours or following tumour extravasation (interstitial). The present study systematically assessed the in vivo doxorubicin (Dox) release and therapeutic efficacy of Dox-loaded TSL with different release profiles. Low temperature-sensitive liposomes (LTSL-Dox), traditional-temperature-sensitive liposomes (TTSL-Dox), and non-temperature-sensitive liposomes (NTSL-Dox) were combined with a single or two HT in different tumour models (murine melanoma B16F10 tumour and human breast MDA-MB-435). The efficacy of each treatment was assessed by monitor tumour growth and mice survival. The level of Dox in tumour tissues was quantified using 14C-Dox and liquid scintillation while Dox release was assessed using live imaging and confocal laser scanning microscopy. Applying a second HT to release Dox from extravasated TTSL-Dox was not therapeutically superior to single HT application due to Dox clearance from the extravasated TTSL-Dox. Our findings revealed that enhanced blood perfusion in heated tumours during the second water bath HT could be seen as a hurdle for TTSL-Dox's anticancer efficacy, where the systemic toxicity of the redistributed Dox from the tumour tissues could be potentiated.

Computational Modeling of Combination of Magnetic Hyperthermia and Temperature-Sensitive Liposome for Controlled Drug Release in Solid Tumor.

Combination therapy, a treatment modality that combines two or more therapeutic methods, provides a novel pathway for cancer treatment, as it targets the region of interest (ROI) in a characteristically synergistic or additive manner. To date, liposomes are the only nano-drug delivery platforms that have been used in clinical trials. Here, we speculated that it could be promising to improve treatment efficacy and reduce side effects by intravenous administration of thermo-sensitive liposomes loaded with doxorubicin (TSL-Dox) during magnetic hyperthermia (MHT). A multi-scale computational model using the finite element method was developed to simulate both MHT and temperature-sensitive liposome (TSL) delivery to a solid tumor to obtain spatial drug concentration maps and temperature profiles. The results showed that the killing rate of MHT alone was about 15%, which increased to 50% using the suggested combination therapy. The results also revealed that this combination treatment increased the fraction of killed cells (FKCs) inside the tumor compared to conventional chemotherapy by 15% in addition to reducing side effects. Furthermore, the impacts of vessel wall pore size, the time interval between TSL delivery and MHT, and the initial dose of TSLs were also investigated. A considerable reduction in drug accumulation was observed in the tumor by decreasing the vessel wall pore size of the tumor. The results also revealed that the treatment procedure plays an essential role in the therapeutic potential of anti-cancer drugs. The results suggest that the administration of MHT can be beneficial in the TSL delivery system and that it can be employed as a guideline for upcoming preclinical studies.

Encapsulation of doxorubicin prodrug in heat-triggered liposomes overcomes off-target activation for advanced prostate cancer therapy

L-377,202 prodrug consists of doxorubicin (Dox) conjugated to a prostate-specific antigen (PSA) peptide substrate that can be cleaved by enzymatically active PSA at the tumor site. Despite the initial promise in phase I trial, further testing of L-377,202 (herein called Dox-PSA) was ceased due to some degree of non-specific activation and toxicity concerns. To improve safety of Dox-PSA, we encapsulated it into low temperature-sensitive liposomes (LTSL) to bypass systemic activation, while maintaining its biological activity upon controlled release in response to mild hyperthermia (HT). A time-dependent accumulation of activated prodrug in the nuclei of PSA-expressing cells exposed to mild HT was observed, showing that Dox-PSA was efficiently released from the LTSL, cleaved by PSA and entering the cell nucleus as free Dox. Furthermore, we have shown that Dox-PSA loading in LTSL can block its biological activity at 37°C, while the combination with mild HT resulted in augmented cytotoxicity in both 2D and 3D PC models compared to the free Dox-PSA. More importantly, Dox-PSA encapsulation in LTSL prolonged its blood circulation and reduced Dox accumulation in the heart of C4-2B tumor-bearing mice over the free Dox-PSA, thus significantly improving Dox-PSA therapeutic window. Finally, Dox-PSA-loaded LTSL combined with HT significantly delayed tumor growth at a similar rate as mice treated with free Dox-PSA in both solid and metastatic PC tumor models. This indicates this strategy could block the systemic cleavage of Dox-PSA without reducing its efficacy in vivo, which could represent a safer option to treat patients with locally advanced PC. Statement of significanceThis study investigates a new tactic to tackle non-specific cleavage of doxorubicin PSA-activatable prodrug (L-377,202) to treat advanced prostate cancer. In the present study, we report a nanoparticle-based approach to overcome the non-specific activation of L-377,202 in the systemic circulation. This includes encapsulating Dox-PSA in low temperature-sensitive liposomes to prevent its premature hydrolysis and non-specific cleavage. This class of liposomes offers payload protection against degradation in plasma, improved pharmacokinetics and tumor targeting, and an efficient and controlled drug release triggered by mild hyperthermia (HT) (∼42°C). We believe that this strategy holds great promise in bypassing any systemic toxicity concerns that could arise from the premature activation of the prodrug whilst simultaneously being able to control the spatiotemporal context of Dox-PSA cleavage and metabolism.

Thermally tunable hydrogel crosslinking mediated by temperature sensitive liposome

Hydrogel crosslinking by external stimuli is a versatile strategy to control and modulate hydrogel properties. Besides photonic energy, thermal energy is one of the most accessible external stimuli and widely applicable for many biomedical applications. However, conventional thermal crosslinking systems require a relatively high temperature (over 100 °C) to initiate covalent bond formation. To our knowledge, there has not been a thermally tunable hydrogel crosslinking system suitable for biological applications. This work demonstrates a unique approach to utilize temperature sensitive liposomes to control and modulate hydrogel crosslinking over mild temperature range (below 50 °C). Temperature sensitive liposomes were used to control the release of chemical crosslinkers by moderate temperature changes. The thermally controlled crosslinker release resulted in tunable mechanical and transport properties of the hydrogel. No significant inflammable response observed in the histology results ensured the biocompatibility of the liposome-mediated crosslinkable hydrogel. This work opens new opportunities to implement thermal energy system for control and modulate hydrogel properties.

Drug transport kinetics of intravascular triggered drug delivery systems

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.g., temperature, light, ultrasound, electromagnetic fields, X-rays). We developed a computational model to simulate IV-DDS drug delivery, for which we quantified all model parameters in vivo in rodent tumors. The model was validated via quantitative intravital microscopy studies with unencapsulated fluorescent dye, and with two formulations of temperature-sensitive liposomes (slow, and fast release) encapsulating a fluorescent dye as example IV-DDS. Tumor intra- and extravascular dye concentration dynamics were extracted from the intravital microscopy data by quantitative image processing, and were compared to computer model results. Via this computer model we explain IV-DDS delivery kinetics and identify parameters of IV-DDS, of drug, and of target tissue for optimal delivery. Two parameter ratios were identified that exclusively dictate how much drug can be delivered with IV-DDS, indicating the importance of IV-DDS with fast drug release (~sec) and choice of a drug with rapid tissue uptake (i.e., high first-pass extraction fraction). The computational model thus enables engineering of improved future IV-DDS based on tissue parameters that can be quantified by imaging.

Theory and method of temperature control for drug release in hydrogel phantom of gastric mucosa in vitro

Unresectable tumors in the gastrointestinal tract are difficult to treat, and traditional radiotherapy combined with chemotherapy can easily induce severe side-effects due to the toxicities of anticancer drugs. Effective methods to enhance the concentration of local drug release in the narrow and hollow organs of the gastrointestinal tract are unavailable. To address this shortcoming, we propose a method to thermally trigger the release of Nile Red from temperature-sensitive liposomes (TSLs) in an in vitro hydrogel phantom of the gastric mucosa through ultrasound treatment by using a small, piezoelectric, single-crystal ultrasonic transducer with a diameter of 2.2 mm. To control the rise in temperature, we establish a model for ultrasound thermal calculation according to Helmholtz's equation, the equations of heat transfer, and the Navier–Stokes equations and validate it through an in vitro experiment. The results show that the temperature reached the melting-phase transition temperature of TSL (40–42 °C) when the duty ratio of the driving voltage of the ultrasonic transducer was 60%, and the amplitude was greater than 40 Vpp and less than 60 Vpp. Furthermore, the maximum rate of release of Nile Red was 2.9 × 10−3 mg/min when the ultrasonic transducer was activated with a driving voltage of 60 Vpp and a duty ratio of 60%. Thus, the proposed method for temperature control can be applied to improve local drug concentration in the gastrointestinal tract and reduce the number of anticancer drugs in the body.

Temperature-sensitive liposomes employ ultrasound for chemotherapy use

An ultrasonic transducer can initiate and control a temperature increase in a liposome drug-delivery system.

NEW PHARMACEUTICAL DOSAGE FORMS USED IN THE TREATMENT OF BREAST CANCER. LIPOSOMES

In order to obtain antineoplastic compounds and innovative formulations, new technologies and testing methods are continuously being developed. Unfortunately, besides cancer cells, chemotherapy also affects normal cells. An option to avoid toxicity is represented by the targeted cancer treatment using novel pharmaceutical dosage forms.&#x0D; Liposomes represent a relatively new pharmaceutical dosage form, used for their many advantages. In this article, the methods of liposomal preparation are mentioned, along with the classification and the latest improvements involving this pharmaceutical form. The bioavailability of conventional liposomes is currently improved by developing photodynamic liposomes, pH or temperature sensitive liposomes and targeted liposomes.