Magnetic Thermosensitive Liposomes Research Articles

Magnetic Thermosensitive Liposomes Loaded with Doxorubicin.

Liposome-mediated anticancer drug delivery has the advantage of limiting the massive cytotoxicity of chemotherapeutic agents. Doxorubicin (DOX) PEG-liposomal does however have a slow-release rate that hinders its therapeutic efficacy. In this study, an integrated therapeutic system based on magnetic thermosensitive liposomes was designed. The chelated gadolinium acquired magnetic properties in the liposomes. The hyperthermia induced by ultra-high-field magnetic resonance imaging (UHF-MRI) enhances the chemotherapeutic effects of DOX. The DOX release from liposomes was facilitated over a narrow range of temperatures owing to the phase transition temperature of the liposomes. The magnetic properties of the liposomes were evident by the elevation of contrast after the exposure to UHF-MRI. Moreover, triple-negative breast cancer (TNBC) cells showed a significant decrease in cellular viability reaching less than 40% viability after 1h of exposure to UHF-MRI. The liposomes demonstrated a physiological coagulation time and a minimal hemolytic potential in hemocompatibility studies; therefore, they were considered safe for physiological application. As a result, magnetic-thermosensitive liposomal guidance of local delivery of DOX could increase the therapeutic index, thereby reducing the amount of the drug required for systemic administration and the chance of affecting the adjacent tissues.

ADAM 8 as a novel target for doxorubicin delivery to TNBC cells using magnetic thermosensitive liposomes

Metastatic breast cancer is one of the most common causes of cancer-related death in women worldwide. The transmembrane metalloprotease-disintegrin (ADAM8) protein is highly overexpressed in triple-negative breast cancer (TNBC) cells and potentiates tumor cell invasion and extracellular matrix remodeling. Exploiting the high expression levels of ADAM8 in TNBC cells by delivering anti-ADAM8 antibodies efficiently to the targeted site can be a promising strategy for therapy of TNBC. For instance, a targeted approach with the aid of ultra-high field magnetic resonance imaging (UHF-MRI) activatable thermosensitive liposomes (LipTS–GD) could specifically increase the intracellular accumulation of cytotoxic drugs. The surface of doxorubicin-loaded LipTS–GD was modified by covalent coupling of MAB1031 antibody (LipTS–GD–MAB) in order to target the overexpressed ADAM8 in ADAM8 positive MDA-MB-231 cells. Physicochemical characterization of these liposomes was performed using size, surface morphology and UHF-MRI imaging analysis. In vitro cell targeting was investigated by the washing and circulation method. Intracellular trafficking and lysosomal colocalization were assessed by fluorescence microscopy. Cell viability, biocompatibility and in-ovo CAM assays were performed to determine the effectiveness and safety profiles of liposome formulations. Our results show specific binding and induction of doxorubicin release after LipTS–GD–MAB treatment caused a higher cytotoxic effect at the cellular target site.

Magnetic resonance activatable thermosensitive liposomes for controlled doxorubicin delivery.

To limit the massive cytotoxicity of chemotherapeutic agents, it is desirable to establish an appropriate subtle blend of formulation design based on a dual-responsive strategy. In this study, a combined therapeutic platform based on magnetic thermosensitive liposomes (LipTS-GD) was developed. The incorporation of chelated-gadolinium imparted magnetic properties to thermosensitive liposomes (LipTS). The application of an ultra high field magnetic resonance imaging (UHF-MRI) induced hyperthermia, thus provided an improved chemotherapeutic effect of Doxorubicin (DOX). The paramagnetic platform demonstrated thermal sensitivity over a narrow temperature range starting at 37.8°C, hence the release of DOX from LipTS-GD can be well triggered by inducing hyperthermia using UHF-MRI application. The prepared LipTS-GD were below 200nm in diameter and an adequate release of DOX reaching 68% was obtained after 1h UHF-MRI exposure. Profoundly, triple-negative breast cancer (TNBC) cells that were treated with LipTS-GD and subjected thereafter to UHF-MRI exposure for 60min showed 36% viability. Hemocompatibility studies of LipTS-GD showed a physiological coagulation time and minimal hemolytic potential. Conclusively, LipTS-GD guided local delivery of DOX to solid tumors will potentially raise the therapeutic index, thus reducing the required dose and frequency of DOX administered systemically without influencing the adjacent tissues.

Comprehensive Effects of Near-Infrared Multifunctional Liposomes on Cancer Cells.

Multifunctional theranostic systems are a recent important development of medical research. We combined the characteristics of near-infrared luminescent quantum dots and thermosensitive magnetoliposomes to develop a multifunctional nano-diagnostic material. This system is based on near-infrared magnetic thermosensitive liposomes, which encapsulate drugs and can control drug localization and release. After incubating cancer cells with the liposomes, the state of the cells was analyzed in real time by near-infrared imaging. Cell viability was significantly inhibited by heat treatment or alternating magnetic field treatment, which thus improved the anti-cancer properties of the liposomes. In the future, by combining near-infrared imaging technology and an external high-frequency alternating magnetic field, we could not only detect cancer cells noninvasively but also conduct image-guided treatments for cancer.

Thermosensitive magnetic liposomes for alternating magnetic field-inducible drug delivery in dual targeted brain tumor chemotherapy

The nonspecific distribution and non-targeted heating of chemotherapeutic agents in the human body commonly produce adverse side effects during brain cancer management. Even though an external magnetic field can partially gather extracellular magnetic drug carriers near brain tumor, magnetic guidance alone still cannot precisely identify and target either tumors or healthy tissues due to a lack of selectivity. In this study, we successfully developed thermal and magnetic dual-responsive thermosensitive magnetic liposomes (TML), which co-encapsulates Camptosar (CPT-11) and citric acid-coated magnetic Fe3O4 nanoparticles within the aqueous core and surface-conjugated with Cetuximab (CET) for recognizing over-expressed epidermal growth factor receptors on cancer cell surface. This drug carrier system can control the release of encapsulated drug when exposed to a high-frequency alternating magnetic field (AMF) that elevates the temperature of the liposomal membrane and triggers drug release from TML after their selective endocytosis by cancer cells. By detailed characterizing the physico-chemical and biological properties of liposomes, we demonstrated the liposomal formulation is with high biocompatibility and showed no hemolysis in vitro. Enhanced intracellular uptake of TML-CPT-11-CET by human primary glioblastoma cells (U87) also supported targeted delivery through CET-mediated endocytosis. The treatment of TML-CPT-11-CET solutions by AMF in vitro showed rise in solution temperature and enhanced drug release, which enhanced cytotoxicity of CPT-11 toward U87 though cell apoptosis as revealed from flow cytometry analysis of apoptotic cells and Western blot studies of marker proteins. Finally, the in vivo therapeutic efficacy was demonstrated in mice orthotopic xenograft brain tumor model from IVIS and PET/MRI studies.

Preparation of Folic Acid-Targeted Temperature-Sensitive Magnetoliposomes and their Antitumor Effects In Vitro and In Vivo.

Ovarian cancer is a common gynecologic malignancy with poor prognosis, requiring innovative new therapeutic strategies. Temperature-controlled drug delivery to cancer cells represents a novel, promising, targeted treatment approach. We prepared folate receptor-targeted thermosensitive liposomes wrapped with the HSP90 inhibitor 17-AAG and superparamagnetic material (17-AAG/MTSLs-FA), and tested the efficacy of these targeted magnetoliposomes in vitro and in vivo. Magnetic thermosensitive liposomes wrapped with 17-AAG were coprecipitated with Fe3O4 magnetic nanoparticles and prepared by a rotary evaporation method. Experiments were conducted with SKOV3 human ovarian cancer cells and MCF7 human breast carcinoma cells to evaluate the anti-tumor effects. 17-AAG/MTSLs-FA prepared in this study met the basic requirements for therapeutic application. The preparation method is relatively simple and the raw materials are readily available. The product exhibited strong magnetism, high encapsulation efficiencies, and satisfactory performance. The liposomes combined with hyperthermia significantly inhibited the proliferation of SKOV3 cells and induced apoptosis. Experiments using a mouse subcutaneous model as well as an ascites tumor xenograft model indicated that 17-AAG/MTSLs-FA was stable in vivo and effectively targeted tumor tissues expressing the folate receptor. Folic acid-conjugated 17-AAG magnetic thermosensitive liposomes in combination with an alternating magnetic field for heating can achieve a synergistic anti-tumor effect of chemotherapy and heat treatment, potentially offering a new method for ovarian cancer treatment.

Hydroxycamptothecin liposomes based on thermal and magnetic dual-responsive system: preparation, in vitro and in vivo antitumor activity, microdialysis-based tumor pharmacokinetics

Due to the absence of lactone form of hydroxycamptothecin, the commercially available hydroxycamptothecin injection exhibits inefficient therapeutic effects. In this study, we constructed a novel delivery system (thermosensitive magnetic liposomes) that protects lactone form of hydroxycamptothecin from blood or water. After hydroxycamptothecin was loaded into the thermosensitive magnetic liposome (HCPT/TML), its in vitro and in vivo antitumor activity and microdialysis-based tumour pharmacokinetics were determined. The results demonstrated that HCPT/TMLs possessed favourable physicochemical features and significant cytotoxicity against the Huh-7 cells in vitro. In the in vivo antitumor study and tumour pharmacokinetics, HCPT/TMLs displayed effective targeting delivery and antitumor effects, which corresponded to the determined hydroxycamptothecin concentration in tumour tissue. In conclusion, this thermal and magnetic dual-responsive system can efficiently deliver hydroxycamptothecin to tumour tissue and has great potential application in cancer treatment.

Thermosensitive magnetic liposomes with doxorubicin cell-penetrating peptides conjugate for enhanced and targeted cancer therapy

To specifically deliver cytotoxic drug to tumor cells and enhance cellular uptake is the key for effective cancer therapy. In this paper, we described a novel drug targeting system, which is designed to combine features of biological (cell-penetrating peptides, CPPs) and physical (magnetic) drug targeting for use in the magnetic hyperthermia-triggered release. A doxorubicin–CPPs conjugate (DOX-CPPs) was loaded into thermosensitive magnetic liposomes (TSMLs) (DOX-CPPs/TSMLs), and in vitro DOX-CPPs thermosensitive release activity, anti-proliferation effect, in vivo targeted delivery as well as in vivo antitumor activity were determined. The results demonstrated that the DOX-CPPs/TSMLs showed good physicochemical properties, effective anti-proliferation effect in MCF-7 cells in vitro. Additionally, in vivo study, DOX-CPPs/TSMLs under AC magnetic field displayed superior in vivo targeted delivery efficacy, antitumor efficacy in an MCF-7 xenograft murine model. In conclusion, the application of DOX-CPPs/TSMLs under AC magnetic field may provide a strategy for the selective and efficient delivery of drug.

Targeted temperature sensitive magnetic liposomes for thermo-chemotherapy

We describe folate receptor targeted thermosensitive magnetic liposomes, which are designed to combine features of biological and physical (magnetic) drug targeting for use in magnetic hyperthermia-triggered drug release. The optimized liposome formulation DPPC:cholesterol:DSPE-PEG 2000:DSPE-PEG 2000-Folate at 80:20:4.5:0.5 molar ratio showed calcein release of about 70% both in PBS and in 50% FBS (fetal bovine serum) at 43 °C and less than 5% release at 37 °C following 1 h incubation. Folate-targeted doxorubicin-containing magnetic liposomes of the above lipid composition (MagFolDox) showed encapsulation efficiencies of about 85% and 24% for doxorubicin and magnetic nanoparticles (mean crystallite size 10 nm), respectively. This magnetic formulation displayed the desired temperature sensitivity with 52% doxorubicin release in 50% fetal bovine serum (FBS) following 1 h incubation at 43 °C. MagFolDox, when physically targeted to tumor cells in culture by a permanent magnetic field yielded a substantial increase in cellular uptake of doxorubicin as compared to Caelyx® (a commercially available liposomal doxorubicin preparation), non-magnetic folate-targeted liposomes (FolDox) and free doxorubicin in folate receptor expressing tumor cell lines (KB and HeLa cells). This resulted in a parallel increase in cytotoxicity over Caelyx® and FolDox. Magnetic hyperthermia at 42.5 °C and 43.5 °C synergistically increased the cytotoxicity of MagFolDox. The results suggest that an integrated concept of biological and physical drug targeting, triggered drug release and hyperthermia based on magnetic field influence can be used advantageously for thermo-chemotherapy of cancers.

Preparation and characterization of Tegafur magnetic thermosensitive liposomes

The purpose was to study the preparation and properties of tegafur magnetic thermosensitive liposomes. The method was to employ an improved chemical coprecipitation method for preparing nano-magnetic particles and a reverse-phase evaporation and ultrasonic method for preparing tegafur magnetic thermosensitive liposomes. The results showed that tegafur magnetic thermosensitive liposomes were prepared successfully. They had comparatively strong magnetism and superparamagnetism, and their temperature showed a linear positive correlation with dosages and the field strength under a current value. The conclusion was that tegafur magnetic thermosensitive liposomes with comparatively small particle size, superparamagnetism and comparatively strong magnetism were prepared successfully.