Search

Quercetin (QU) faces challenges in its therapeutic efficacy due to its hydrophobic nature and limited oral bioavailability. Using a Box–Behnken design (BBD) approach, we developed QU‐loaded magnetoliposomes (QMLs) to address these limitations. By encapsulating QU within iron oxide nanoparticles (IONPs) and liposomes (LPs), we enhanced its hydrophilicity and improved its potential for drug delivery. Through systematic adjustments of phosal, polyvinyl alcohol, and magnetic/IONPs, we optimized the particle size, zeta potential, and iron content of the QMLs. The formulations underwent comprehensive structural characterization using techniques, such as Fourier transform infrared spectroscopy, X‐Ray diffraction, differential scanning calorimetry–thermogravimetric analysis, and energy‐dispersive X‐ray analysis, whereas their morphology was examined through field emission scanning electron microscopy. Furthermore, we evaluated the in vitro drug release of the QMLs and antioxidant activity of QU, QU‐loaded LPs, and QMLs using DPPH, 2,2′‐azino‐bis(3‐ethylbenzthiazoline‐6‐sulfonic acid), and H2O2 scavenging assays, enabling us to compare their antioxidant potential and the efficiency of QU encapsulation within the magneto LPs. Practical Applications: This research holds significant practical implications, particularly in targeted drug delivery using magnetic liposomes. The developed system shows promise in enhancing cancer therapy, providing localized treatment for inflammation‐related conditions, delivering drugs to the brain to address neurological disorders, promoting wound healing, and incorporating quercetin into skincare products for its antioxidant and antiaging benefits. [ABSTRACT FROM AUTHOR]

In cancer therapy, new therapeutic nanoformulations able to mediate targeted chemotherapy are required. Recently, biomimetic magnetic nanoparticles (BMNPs) mediated by MamC, a magnetosome protein from Magnetococcus marinus MC-1, have proven, in vitro and in vivo, to be effective drug nanocarriers (following the application of an external gradient magnetic field) and to allow combination with hyperthermia. However, these nanoassemblies require further optimization to improve cytocompatibility, stability and active targeting ability. Herein, we describe the production of the magnetoliposomes (LP) embedding BMNPs functionalized (or not) with doxorubicin (DOXO), [LP(+/−DOXO-BMNPs)], and their surface modification with the DO-24 mAb, which targets the human Met/HGF receptor's ectodomain (overexpressed in many cancers). Nanoformulations were extensively characterized using TEM, DLS, FTIR and when tested in vitro, the lipid coating increased the colloidal stability and their biocompatibility, favoring the cellular uptake in cells overexpressing the cognate receptor. Indeed, the magnetoliposomes mAb-LP(+/−DOXO-BMNPs) exerted a specific active targeting ability by the presence of the mAb that preserved its immunocompetence. Both LP(BMNPs) and mAb-LP(BMNPs) were not toxic to cells, while +/−mAb-LP(DOXO-BMNPs) nanoformulations were indeed cytotoxic. Therefore, this study represents a proof of concept for the development of promising drug carriers for cancer therapy based on local chemotherapy directed by mAbs. [ABSTRACT FROM AUTHOR]

The use of magnetite nanoparticles in biology and medicine is steadily growing, while some questions regarding their safety remain unclear. For example, nanomagnetite-based magnetoliposomes are a promising basis for the creation of new drugs. In this work, using hematological methods, a comparative assessment of changes in the number of hematopoietic cells in the bone marrow in sexually mature outbred rats was carried out for 120 days after intravenous administration of a suspension of unmodified magnetite nanoparticles and magnetoliposomes based on them. The features of the structure of hematopoietic cells of the main differons of bone marrow (erythrocyte, granulocytic, lymphocytic, monocytic, and platelet) are described, as well as the dynamics of changes in their number during the experiment. Single intravenous administration of a suspension of magnetoliposomes based on magnetite nanoparticles at a dose of 0.14 g (Fe3O4) per 1 kg of body weight (injection volume 3 mL) does not cause changes in the structure and number of hematopoietic cells of the studied rat bone-marrow differons. The absence of a negative effect of magnetoliposomes based on magnetite nanoparticles on the structure of hematopoietic cells of the bone marrow allows us to consider these nanostructures as a promising magnetically controlled carrier for creating modern systems for the targeted delivery of diagnostic and therapeutic drugs. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. Therefore, development of novel technologies and strategies to treat PD is a global health priority. Current treatments include administration of Levodopa, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, and anticholinergic drugs. However, the effective release of these molecules, due to the limited bioavailability, is a major challenge for the treatment of PD. As a strategy to solve this challenge, in this study we developed a novel multifunctional magnetic and redox-stimuli responsive drug delivery system, based on the magnetite nanoparticles functionalized with the high-performance translocating protein OmpA and encapsulated into soy lecithin liposomes. The obtained multifunctional magnetoliposomes (MLPs) were tested in neuroblastoma, glioblastoma, primary human and rat astrocytes, blood brain barrier rat endothelial cells, primary mouse microvascular endothelial cells, and in a PD-induced cellular model. MLPs demonstrated excellent performance in biocompatibility assays, including hemocompatibility (hemolysis percentages below 1%), platelet aggregation, cytocompatibility (cell viability above 80% in all tested cell lines), mitochondrial membrane potential (non-observed alterations) and intracellular ROS production (negligible impact compared to controls). Additionally, the nanovehicles showed acceptable cell internalization (covered area close to 100% at 30 min and 4 h) and endosomal escape abilities (significant decrease in lysosomal colocalization after 4 h of exposure). Moreover, molecular dynamics simulations were employed to better understand the underlying translocating mechanism of the OmpA protein, showing key findings regarding specific interactions with phospholipids. Overall, the versatility and the notable in vitro performance of this novel nanovehicle make it a suitable and promising drug delivery technology for the potential treatment of PD.

Cancer represents a very grave and quickly growing public health problem worldwide. Despite the breakthroughs in treatment and early detection of the disease, an increase is projected in the incidence rate and mortality during the next 30 years. Thus, it is important to develop new treatment strategies and diagnostic tools. One alternative is magnetic hyperthermia, a therapeutic approach that has shown promising results, both as monotherapy and in combination with chemo- and radiotherapy. However, there are still certain limitations and questions with respect to the safety of the systemic administration of magnetic nanoparticles. To deal with these issues, magnetoliposomes were conceived as a new generation of liposomes that incorporate superparamagnetic nanoparticles and oncological pharmaceuticals within their structure. They have the advantage of targeted and selective drug delivery to the diseased organs and tissues. Some of them can avoid the immune response of the host. When exposed to a magnetic field of alternating current, magnetoliposomes produce hyperthermia, which acts synergistically with the released drug. The aim of the present review is to describe the most recent advances in the use of magnetoliposomes and point out what research remains to be done for their application to chemo-thermal therapy in cancer patients. [ABSTRACT FROM AUTHOR]

In cancer therapy, new therapeutic nanoformulations able to mediate targeted chemotherapy are required. Recently, biomimetic magnetic nanoparticles (BMNPs) mediated by MamC, a magnetosome protein from Magnetococcus marinus MC-1, have proven, in vitro and in vivo, to be effective drug nanocarriers (following the application of an external gradient magnetic field) and to allow combination with hyperthermia. However, these nanoassemblies require further optimization to improve cytocompatibility, stability and active targeting ability. Herein, we describe the production of the magnetoliposomes (LP) embedding BMNPs functionalized (or not) with doxorubicin (DOXO), [LP(+/−DOXO-BMNPs)], and their surface modification with the DO-24 mAb, which targets the human Met/HGF receptor’s ectodomain (overexpressed in many cancers). Nanoformulations were extensively characterized using TEM, DLS, FTIR and when tested in vitro, the lipid coating increased the colloidal stability and their biocompatibility, favoring the cellular uptake in cells overexpressing the cognate receptor. Indeed, the magnetoliposomes mAb-LP(+/−DOXO-BMNPs) exerted a specific active targeting ability by the presence of the mAb that preserved its immunocompetence. Both LP(BMNPs) and mAb-LP(BMNPs) were not toxic to cells, while +/−mAb-LP(DOXO-BMNPs) nanoformulations were indeed cytotoxic. Therefore, this study represents a proof of concept for the development of promising drug carriers for cancer therapy based on local chemotherapy directed by mAbs.

Biodistribution and tumour agglomeration of chemotherapeutic drugs are improved by nanoparticles augmenting the ratio of efficacy and toxicity. Iron oxide nanoparticles have attracted growing attention in diagnosis, cancer therapy, and smart drug delivery. To simplify the combined therapy and targeting drug delivery such as using ultrasound, we developed magnetoliposome-encapsulated doxorubicin. Superparamagnetic iron oxide nanoparticles and magnetoliposome-encapsulated doxorubicin were well synthesised without any remarkable mitigation of the saturation magnetisation. Doxorubicin and the synthesised iron oxide nanoparticles were passively encapsulated into PEGylated liposomes leading to stable soluble magnetoliposomes with a size of about 485 nm. The cytotoxicity of doxorubicin-loaded magnetoliposomes was examined on MCF-7 cells. Compared with chemotherapy alone, the combined therapy employing ultrasound showed a synergistic effect, giving rise to more robust cytotoxicity and higher therapeutic efficacy. Hence, the multifunctional doxorubicin-loaded magnetoliposomes permit them to selectively deliver a combinatorial therapeutic load with increased therapeutic effectiveness. [ABSTRACT FROM AUTHOR]

Multicore magnetic nanoparticles of manganese ferrite were prepared using carboxymethyl dextran as an agglutinating compound or by an innovative method using melamine as a cross-coupling agent. The nanoparticles prepared using melamine exhibited a flower-shape structure, a saturation magnetization of 6.16 emu/g and good capabilities for magnetic hyperthermia, with a specific absorption rate (SAR) of 0.14 W/g. Magnetoliposome-like structures containing the multicore nanoparticles were prepared, and their bilayer structure was confirmed by FRET (Förster Resonance Energy Transfer) assays. The nanosystems exhibited sizes in the range of 250–400 nm and a low polydispersity index. A new antitumor thienopyridine derivative, 7-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]thieno[3,2-b]pyridine, active against HeLa (cervical carcinoma), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small-cell lung carcinoma) and HepG2 (hepatocellular carcinoma) cell lines, was loaded in these nanocarriers, obtaining a high encapsulation efficiency of 98 ± 2.6%. The results indicate that the new magnetoliposomes can be suitable for dual cancer therapy (combined magnetic hyperthermia and chemotherapy). [ABSTRACT FROM AUTHOR]

Liposomes provide high biocompatibility with the cells of the human body due to the prevalence of membrane lipids in their composition. They can be used as an effective tool for targeted delivery of drugs against diseases of different etiology. Interactions between liposomes and target cells can be different, i.e., adsorption on the cell surface, endocytosis, and fusion of liposomes with cell membranes. The incorporation of magnetic nanoparticles into liposomes for active control using an external magnetic field makes it possible to enhance the efficiency and rate of drug release. To create magnetically controlled liposomes, we have chosen nanostructured magnetite created in our laboratory. We used nanoparticles with a diameter of 4.23 ± 1.19 nm. The surface of synthesized magnetite nanoparticles was covered with molecules of cetyltrimethylammonium bromide (CTAB), followed by inclusion into phosphatidylcholine-based liposomes. The quantitative analysis of magneto-sensitive nanoparticles embedded in the lipid bilayer was carried out by spectral methods and transmission electron microscopy. This study has shown that modification of nanostructured magnetite with CTAB increases the efficiency of the incorporation of magnetite nanoparticles into the lipid bilayer by 31.6%. [ABSTRACT FROM AUTHOR]

Stimuli-responsive liposomes are a class of nanocarriers whose drug release occurs, preferentially, when exposed to a specific biological environment, to an external stimulus, or both. This work is focused on the design of solid magnetoliposomes (SMLs) as lipid-based nanosystems aiming to obtain multi-stimuli-responsive vesicles for doxorubicin (DOX) controlled release in pathological areas under the action of thermal, magnetic, and pH stimuli. The effect of lipid combinations on structural, colloidal stability, and thermodynamic parameters were evaluated. The results confirmed the reproducibility for SMLs synthesis based on nine lipid formulations (combining DPPC, DSPC, CHEMS, DOPE and/or DSPE-PEG), with structural and colloidal properties suitable for biological applications. A loss of stability and thermosensitivity was observed for formulations containing dioleoylphosphatidylethanolamine (DOPE) lipid. SMLs PEGylation is an essential step to enhance both their long-term storage stability and stealth properties. DOX encapsulation (encapsulation efficiency ranging between 87% and 96%) in the bilayers lowered its pKa, which favors the displacement of DOX from the acyl chains to the surface when changing from alkaline to acidic pH. The release profiles demonstrated a preferential release at acidic pH, more pronounced under mimetic mild-hyperthermia conditions (42 °C). Release kinetics varied with the lipid formulation, generally demonstrating hyperthermia temperatures and acidic pH as determining factors in DOX release; PEGylation was shown to act as a diffusion barrier on the SMLs surface. The integrated assessment and characterization of SMLs allows tuning lipid formulations that best respond to the needs for specific controlled release profiles of stimuli-responsive nanosystems as a multi-functional approach to cancer targeting and therapy. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is a chemotherapeutic agent commonly used for the treatment of solid tumors. However, the cardiotoxicity associated with its prolonged use prevents further adherence and therapeutic efficacy. By encapsulating DOX within a PEGylated liposome, Doxil® considerably decreased DOX cardiotoxicity. By using thermally sensitive lysolipids in its bilayer composition, ThermoDox® implemented a heat-induced controlled release of DOX. However, both ThermoDox® and Doxil® rely on their passive retention in tumors, depending on their half-lives in blood. Moreover, ThermoDox® ordinarily depend on invasive radiofrequency-generating metallic probes for local heating. In this study, we prepare, characterize, and evaluate the antitumoral capabilities of DOX-loaded folate-targeted PEGylated magnetoliposomes (DFPML). Unlike ThermoDox®, DOX delivery via DFPML is mediated by the heat released through dynamic hysteresis losses from magnetothermal converting systems composed by MnFe2O4 nanoparticles (NPs) under AC magnetic field excitation—a non-invasive technique designated magnetic hyperthermia (MHT). Moreover, DFPML dismisses the use of thermally sensitive lysolipids, allowing the use of simpler and cheaper alternative lipids. MnFe2O4 NPs and DFPML are fully characterized in terms of their size, morphology, polydispersion, magnetic, and magnetothermal properties. About 50% of the DOX load is released from DFPML after 30 min under MHT conditions. Being folate-targeted, in vitro DFPML antitumoral activity is higher (IC50 ≈ 1 μg/ml) for folate receptor-overexpressing B16F10 murine melanoma cells, compared to MCF7 human breast adenocarcinoma cells (IC50 ≈ 4 μg/ml). Taken together, our results indicate that DFPML are strong candidates for folate-targeted anticancer therapies based on DOX controlled release. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is a chemotherapeutic agent commonly used for the treatment of solid tumors. However, the cardiotoxicity associated with its prolonged use prevents further adherence and therapeutic efficacy. By encapsulating DOX within a PEGylated liposome, Doxil® considerably decreased DOX cardiotoxicity. By using thermally sensitive lysolipids in its bilayer composition, ThermoDox® implemented a heat-induced controlled release of DOX. However, both ThermoDox® and Doxil® rely on their passive retention in tumors, depending on their half-lives in blood. Moreover, ThermoDox® ordinarily depend on invasive radiofrequency-generating metallic probes for local heating. In this study, we prepare, characterize, and evaluate the antitumoral capabilities of DOX-loaded folate-targeted PEGylated magnetoliposomes (DFPML). Unlike ThermoDox®, DOX delivery via DFPML is mediated by the heat released through dynamic hysteresis losses from magnetothermal converting systems composed by MnFe2O4 nanoparticles (NPs) under AC magnetic field excitation—a non-invasive technique designated magnetic hyperthermia (MHT). Moreover, DFPML dismisses the use of thermally sensitive lysolipids, allowing the use of simpler and cheaper alternative lipids. MnFe2O4 NPs and DFPML are fully characterized in terms of their size, morphology, polydispersion, magnetic, and magnetothermal properties. About 50% of the DOX load is released from DFPML after 30 min under MHT conditions. Being folate-targeted, in vitro DFPML antitumoral activity is higher (IC50 ≈ 1 μg/ml) for folate receptor-overexpressing B16F10 murine melanoma cells, compared to MCF7 human breast adenocarcinoma cells (IC50 ≈ 4 μg/ml). Taken together, our results indicate that DFPML are strong candidates for folate-targeted anticancer therapies based on DOX controlled release.

Aggregates of superparamagnetic colloids confined in liposomes in the presence of a controllable external magnetic field are studied here by computer simulation. A model of a hard sphere with a central dipole has been used to simulate secondary particles of colloids confined to move within a liposome, which is modelled as a hard spherical cavity. We focus our study on the structure of aggregates created by secondary particles, which in turn are formed by superparamagnetic particles. This study was performed by using the conventional Monte Carlo simulations and the cluster-moving Monte Carlo method. The results obtained with both methods show a dependence on the number of particles and on the ratio cavity-colloid diameters. However, the usual Monte Carlo method does not allow the collective movement of the aggregates. The simulation results show, that for the particular case of the liposome diameter obtained from the experiments σ c = 30 , the formation of a single ribbons located at the centre of the cavity for N = 30 and N = 60. In addition, we analyse the structure formation for different values of σ c = N σ , the equilibrium structures are chains for systems for lower σ c ∗ < 30 , whereas ribbons formation are structures of equilibrium for σ c ≳ σ c ∗ . [ABSTRACT FROM AUTHOR]

Claudia Geanina Farcas,1,2,* Cristina Dehelean,2,* Iulia Andreea Pinzaru,2 Marius Mioc,2 Vlad Socoliuc,3,4 Elena-Alina Moaca,2 Stefana Avram,2 Roxana Ghiulai,2 Dorina Coricovac,2 Ioana Pavel,5 Praveen Kumar Alla,5 Octavian Marius Cretu,6 Codruta Soica,2 Felicia Loghin1 1Faculty of Pharmacy, Department of Toxicology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania; 2Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Timisoara, Romania; 3Laboratory of Magnetic Fluids, Center for Fundamental and Advanced Technical Research, Romanian Academy – Timisoara Branch, Timisoara, Romania; 4Research Center for Complex Fluids Systems Engineering, Politehnica University of Timisoara, Timisoara, Romania; 5Department of Chemistry, Wright State University, Dayton, OH, USA; 6Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Timisoara, Romania*These authors contributed equally to this workCorrespondence: Iulia Andreea Pinzaru; Marius Mioc Email iuliapinzaru@umft.ro; marius.mioc@umft.roPurpose: Breast cancer presents one of the highest rates of prevalence around the world. Despite this, the current breast cancer therapy is characterized by significant side effects and high risk of recurrence. The present work aimed to develop a new therapeutic strategy that may improve the current breast cancer therapy by developing a heat-sensitive liposomal nano-platform suitable to incorporate both anti-tumor betulinic acid (BA) compound and magnetic iron nanoparticles (MIONPs), in order to address both remote drug release and hyperthermia-inducing features. To address the above-mentioned biomedical purposes, the nanocarrier must possess specific features such as specific phase transition temperature, diameter below 200 nm, superparamagnetic properties and heating capacity. Moreover, the anti-tumor activity of the developed nanocarrier should significantly affect human breast adenocarcinoma cells.Methods: BA-loaded magnetoliposomes and corresponding controls (BA-free liposomes and liposomes containing no magnetic payload) were obtained through the thin-layer hydration method. The quality and stability of the multifunctional platforms were physico-chemically analysed by the means of RAMAN, scanning electron microscopy-EDAX, dynamic light scattering, zeta potential and DSC analysis. Besides this, the magnetic characterization of magnetoliposomes was performed in terms of superparamagnetic behaviour and heating capacity. The biological profile of the platforms and controls was screened through multiple in vitro methods, such as MTT, LDH and scratch assays, together with immunofluorescence staining. In addition, CAM assay was performed in order to assess a possible anti-angiogenic activity induced by the test samples.Results: The physico-chemical analysis revealed that BA-loaded magnetoliposomes present suitable characteristics for the purpose of this study, showing biocompatible phase transition temperature, a diameter of 198 nm, superparamagnetic features and heating capacity. In vitro results showed that hyperthermia induces enhanced anti-tumor activity when breast adenocarcinoma MDA-MB-231 cells were exposed to BA-loaded magnetoliposomes, while a low cytotoxic rate was exhibited by the non-tumorigenic breast epithelial MCF 10A cells. Moreover, the in ovo angiogenesis assay endorsed the efficacy of this multifunctional platform as a good strategy for breast cancer therapy, under hyperthermal conditions. Regarding the possible mechanism of action of this multifunctional nano-platform, the immunocytochemistry of the MCF7 and MDA-MB-231 breast carcinoma cells revealed a microtubule assembly modulatory activity, under hyperthermal conditions.Conclusion: Collectively, these findings indicate that BA-loaded magnetoliposomes, under hyperthermal conditions, might serve as a promising strategy for breast adenocarcinoma treatment.Keywords: magnetoliposomes, hyperthermia, betulinic acid, breast adenocarcinoma

Cutaneous administration has advantages over the oral or intravenous route, such as convenience for the patient, avoiding hepatic metabolism, and providing sustained administration of the active component over long periods of time. A major challenge in this route is the administration of drugs that are difficult to penetrate. For these, it is necessary to design delivery vehicles that help increase the stability of the active components and facilitate transport across the skin barrier. In this work, magnetoliposomes (MLPs) immobilizing magnetite nanoparticles (MNPs) have been realized. MNPs act as a nanocarrier for hydrophobic drugs, such as doxorubicin (DOX). To facilitate topical application, MLPs were dispersed in photoresponsive methacrylated chitosan hydrogels. For this purpose, the MLPs were synthesized by coprecipitation of FeCl3 and FeCl2. Subsequently, they were silanized and functionalized by a PEG spacer to bind DOX. The success of each functionalization step was evaluated by Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). The size and morphology of the PEG-DOX-MNPs were analyzed by DLS and TEM. Then, the MNPs-PEG-DOX MNPs were encapsulated in liposomes synthesized by the layer hydration method. Dispersion of MLPs in the hydrogel, followed by crosslinking with visible blue light, was performed. Preliminary FTIR results indicate a correct synthesis and functionalization of the MNPs, as indicated by the presence of bands corresponding to the Si-O stretching vibration at 1029 cm−1 and Fe-O absorption bands around 560 cm−1. TGA results showed a weight loss of 3.5% for MNPs from 200 to 400 °C, which was attributed to silane ligands. The hydrodynamic diameter of the MNPs was 140 nm with polydispersity indices of 0.16. In a future work, DOX will be conjugated to MNPs and MLPs will be synthesized for dispersion in the hydrogel. Subsequently, drug release kinetics tests will be performed under relevant conditions.

Cancer represents a very grave and quickly growing public health problem worldwide. Despite the breakthroughs in treatment and early detection of the disease, an increase is projected in the incidence rate and mortality during the next 30 years. Thus, it is important to develop new treatment strategies and diagnostic tools. One alternative is magnetic hyperthermia, a therapeutic approach that has shown promising results, both as monotherapy and in combination with chemo- and radiotherapy. However, there are still certain limitations and questions with respect to the safety of the systemic administration of magnetic nanoparticles. To deal with these issues, magnetoliposomes were conceived as a new generation of liposomes that incorporate superparamagnetic nanoparticles and oncological pharmaceuticals within their structure. They have the advantage of targeted and selective drug delivery to the diseased organs and tissues. Some of them can avoid the immune response of the host. When exposed to a magnetic field of alternating current, magnetoliposomes produce hyperthermia, which acts synergistically with the released drug. The aim of the present review is to describe the most recent advances in the use of magnetoliposomes and point out what research remains to be done for their application to chemo-thermal therapy in cancer patients.

The combination of magnetic hyperthermia with chemotherapy is considered a promising strategy in cancer therapy due to the synergy between the high temperatures and the chemotherapeutic effects, which can be further developed for targeted and remote-controlled drug release. In this paper we report a simple, rapid, and reproducible method for the preparation of thermosensitive magnetoliposomes (TsMLs) loaded with doxorubicin (DOX), consisting of a lipidic gel formation from a previously obtained water-in-oil microemulsion with fine aqueous droplets containing magnetic nanoparticles (MNPs) dispersed in an organic solution of thermosensitive lipids (transition temperature of ~43 °C), followed by the gel hydration with an aqueous solution of DOX. The obtained thermosensitive magnetoliposomes (TsMLs) were around 300 nm in diameter and exhibited 40% DOX incorporation efficiency. The most suitable MNPs to incorporate into the liposomal aqueous lumen were Zn ferrites, with a very low coercive field at 300 K (7 kA/m) close to the superparamagnetic regime, exhibiting a maximum absorption rate (SAR) of 1130 W/gFe when dispersed in water and 635 W/gFe when confined inside TsMLs. No toxicity of Zn ferrite MNPs or of TsMLs was noticed against the A459 cancer cell line after 48 h incubation over the tested concentration range. The passive release of DOX from the TsMLs after 48h incubation induced a toxicity starting with a dosage level of 62.5 ug/cm2. Below this threshold, the subsequent exposure to an alternating magnetic field (20–30 kA/m, 355 kHz) for 30 min drastically reduced the viability of the A459 cells due to the release of incorporated DOX. Our results strongly suggest that TsMLs represent a viable strategy for anticancer therapies using the magnetic field-controlled release of DOX.

The structure of blood neutrophils, eosinophils, monocytes, and lymphocytes and differential white blood count in adult rats were studied over 120 days after a single intravenous injection of magnetoliposomes based on nanomagnetite. Magnetoliposomes had no effect on the structure of neutrophils, eosinophils, monocytes, and lymphocytes. At the same time, injection of a suspension of magnetoliposomes based on magnetite nanoparticles led to a decrease in lymphocyte count and an increase in the count of monocytes and band and segmented neutrophils in the blood. These changes were transient and the parameters returned to normal by day 40-60 after injection. [ABSTRACT FROM AUTHOR]

The potential use of magnetic nanoparticles (MNPs) in biomedicine as magnetic resonance, drug delivery, imagenology, hyperthermia, biosensors, and biological separation has been studied in different laboratories. One of the challenges on MNP elaboration for biological applications is the size, biocompatibility, heat efficiency, stabilization in physiological conditions, and surface coating. Magnetoliposome (ML), a lipid bilayer of phospholipids encapsulating MNPs, is a system used to reduce toxicity. Encapsulated MNPs can be used as a potential drug and a gene delivery system, and in the presence of magnetic fields, MLs can be accumulated in a target tissue by a strong gradient magnetic field. Here, we present a study of the effects of DC magnetic fields on encapsulated MNPs inside liposomes. Despite their widespread applications in biotechnology and environmental, biomedical, and materials science, the effects of magnetic fields on MLs are unclear. We use a modified coprecipitation method to synthesize superparamagnetic nanoparticles (SNPs) in aqueous solutions. The SNPs are encapsulated inside phospholipid liposomes to study the interaction between phospholipids and SNPs. Material characterization of SNPs reveals round-shaped nanoparticles with an average size of 12 nm, mainly magnetite. MLs were prepared by the rehydration method. After formation, we found two types of MLs: one type is tense with SNPs encapsulated and the other is a floppy vesicle that does not show the presence of SNPs. To study the response of MLs to an applied DC magnetic field, we used a homemade chamber. Digitalized images show encapsulated SNPs assembled in chain formation when a DC magnetic field is applied. When the magnetic field is switched off, it completely disperses SNPs. Floppy MLs deform along the direction of the external applied magnetic field. Solving the relevant magnetostatic equations, we present a theoretical model to explain the ML deformations by analyzing the forces exerted by the magnetic field over the surface of the spheroidal liposome. Tangential magnetic forces acting on the ML surface result in a press force deforming MLs. The type of deformations will depend on the magnetic properties of the mediums inside and outside the MLs. The model predicts a coexistence region of oblate–prolate deformation in the zone where χ = 1. We can understand the chain formation in terms of a dipole–dipole interaction of SNP.

Rita Sofia Garcia Ribeiro,1,* Sarah Belderbos,1,* Pierre Danhier,2 Juan Gallo,2 Bella B Manshian,1 Bernard Gallez,2 Manuel Bañobre,3 Marcel de Cuyper,4 Stefaan J Soenen,1 Willy Gsell,1 Uwe Himmelreich11Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, Leuven B-3000, Belgium; 2Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique De Louvain, Brussels B-1200, Belgium; 3Diagnostic Tools and Methods/Advanced (Magnetic) Theranostic Nanostructures Lab, International Iberian Nanotechnology Laboratory (INL), PT-Braga 4715-330, Portugal; 4Laboratory of Bionanocolloids, Interdisciplinary Research Centre, KULAK/KU Leuven, Kortrijk B-8500, Belgium*These authors contributed equally to this workPurpose: Magnetoliposomes (MLs) have shown great potential as magnetic resonance imaging contrast agents and as delivery vehicles for cancer therapy. Targeting the MLs towards the tumor cells or neovascularization could ensure delivery of drugs at the tumor site. In this study, we evaluated the potential of MLs targeting the αvβ3 integrin overexpressed on tumor neovascularization and different tumor cell types, including glioma and ovarian cancer.Methods: MLs functionalized with a Texas Red fluorophore (anionic MLs), and with the fluorophore and the cyclic Arginine-Glycine-Aspartate (cRGD; cRGD-MLs) targeting the αvβ3 integrin, were produced in-house. Swiss nude mice were subcutaneously injected with 107 human ovarian cancer SKOV-3 cells. Tumors were allowed to grow for 3 weeks before injection of anionic or cRGD-MLs. Biodistribution of MLs was followed up with a 7T preclinical magnetic resonance imaging (MRI) scanner and fluorescence imaging (FLI) right after injection, 2h, 4h, 24h and 48h post injection. Ex vivo intratumoral ML uptake was confirmed using FLI, electron paramagnetic resonance spectroscopy (EPR) and histology at different time points post injection.Results: In vivo, we visualized a higher uptake of cRGD-MLs in SKOV-3 xenografts compared to control, anionic MLs with both MRI and FLI. Highest ML uptake was seen after 4h using MRI, but only after 24h using FLI indicating the lower sensitivity of this technique. Furthermore, ex vivo EPR and FLI confirmed the highest tumoral ML uptake at 4 h. Last, a Perl’s stain supported the presence of our iron-based particles in SKOV-3 xenografts.Conclusion: Uptake of cRGD-MLs can be visualized using both MRI and FLI, even though the latter was less sensitive due to lower depth penetration. Furthermore, our results indicate that cRGD-MLs can be used to target SKOV-3 xenograft in Swiss nude mice. Therefore, the further development of this particles into theranostics would be of interest.Keywords: tumor targeting, SKOV-3, cRGD, magnetoliposomes, MRI, FLI

Multicore magnetic nanoparticles of manganese ferrite were prepared using carboxymethyl dextran as an agglutinating compound or by an innovative method using melamine as a cross-coupling agent. The nanoparticles prepared using melamine exhibited a flower-shape structure, a saturation magnetization of 6.16 emu/g and good capabilities for magnetic hyperthermia, with a specific absorption rate (SAR) of 0.14 W/g. Magnetoliposome-like structures containing the multicore nanoparticles were prepared, and their bilayer structure was confirmed by FRET (Förster Resonance Energy Transfer) assays. The nanosystems exhibited sizes in the range of 250–400 nm and a low polydispersity index. A new antitumor thienopyridine derivative, 7-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]thieno[3,2-b]pyridine, active against HeLa (cervical carcinoma), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small-cell lung carcinoma) and HepG2 (hepatocellular carcinoma) cell lines, was loaded in these nanocarriers, obtaining a high encapsulation efficiency of 98 ± 2.6%. The results indicate that the new magnetoliposomes can be suitable for dual cancer therapy (combined magnetic hyperthermia and chemotherapy).

Stimuli-responsive liposomes are a class of nanocarriers whose drug release occurs, preferentially, when exposed to a specific biological environment, to an external stimulus, or both. This work is focused on the design of solid magnetoliposomes (SMLs) as lipid-based nanosystems aiming to obtain multi-stimuli-responsive vesicles for doxorubicin (DOX) controlled release in pathological areas under the action of thermal, magnetic, and pH stimuli. The effect of lipid combinations on structural, colloidal stability, and thermodynamic parameters were evaluated. The results confirmed the reproducibility for SMLs synthesis based on nine lipid formulations (combining DPPC, DSPC, CHEMS, DOPE and/or DSPE-PEG), with structural and colloidal properties suitable for biological applications. A loss of stability and thermosensitivity was observed for formulations containing dioleoylphosphatidylethanolamine (DOPE) lipid. SMLs PEGylation is an essential step to enhance both their long-term storage stability and stealth properties. DOX encapsulation (encapsulation efficiency ranging between 87% and 96%) in the bilayers lowered its pKa, which favors the displacement of DOX from the acyl chains to the surface when changing from alkaline to acidic pH. The release profiles demonstrated a preferential release at acidic pH, more pronounced under mimetic mild-hyperthermia conditions (42 °C). Release kinetics varied with the lipid formulation, generally demonstrating hyperthermia temperatures and acidic pH as determining factors in DOX release; PEGylation was shown to act as a diffusion barrier on the SMLs surface. The integrated assessment and characterization of SMLs allows tuning lipid formulations that best respond to the needs for specific controlled release profiles of stimuli-responsive nanosystems as a multi-functional approach to cancer targeting and therapy.

This study investigates the effect of PD1 blockade on the therapeutic efficacy of novel doxorubicin-loaded temperature-sensitive liposomes. Herein, we report photothermally-activated, low temperature-sensitive magnetoliposomes (mLTSL) for efficient drug delivery and magnetic resonance imaging (MRI). The mLTSL were prepared by embedding small nitrodopamine palmitate (NDPM)-coated iron oxide nanoparticles (IO NPs) in the lipid bilayer of low temperature-sensitive liposomes (LTSL), using lipid film hydration and extrusion. Doxorubicin (DOX)-loaded mLTSL were characterized using dynamic light scattering, differential scanning calorimetry, electron microscopy, spectrofluorimetry, and atomic absorption spectroscopy. Photothermal experiments using 808 nm laser irradiation were conducted. In vitro photothermal DOX release studies and cytotoxicity was assessed using flow cytometry and resazurin viability assay, respectively. In vivo DOX release and tumor accumulation of mLTSL(DOX) were assessed using fluorescence and MR imaging, respectively. Finally, the therapeutic efficacy of PD1 blockade in combination with photothermally-activated mLTSL(DOX) in CT26-tumor model was evaluated by monitoring tumor growth, cytokine release and immune cell infiltration in the tumor tissue. Interestingly, efficient photothermal heating was obtained by varying the IO NPs content and the laser power, where on-demand burst DOX release was achievable in vitro and in vivo. Moreover, our mLTSL exhibited promising MR imaging properties with high transverse r 2 relaxivity (333 mM−1 s−1), resulting in superior MR imaging in vivo. Furthermore, mLTSL(DOX) therapeutic efficacy was potentiated in combination with anti-PD1 mAb, resulting in a significant reduction in CT26 tumor growth via immune cell activation. Our study highlights the potential of combining PD1 blockade with mLTSL(DOX), where the latter could facilitate chemo/photothermal therapy and MRI-guided drug delivery. PD1 blockade potentiates the therapeutic efficacy of photothermally-activated and MRI-guided low temperature-sensitive magnetoliposomes. [Display omitted] [ABSTRACT FROM AUTHOR]

The development of stimuli-sensitive drug delivery systems is a very attractive area of current research in cancer therapy. The deep knowledge on the microenvironment of tumors has supported the progress of nanosystems’ ability for controlled and local fusion as well as drug release. Temperature and pH are two of the most promising triggers in the development of sensitive formulations to improve the efficacy of anticancer agents. Herein, magnetic liposomes with fusogenic sensitivity to pH and temperature were developed aiming at dual cancer therapy (by chemotherapy and magnetic hyperthermia). Magnetic nanoparticles of mixed calcium/manganese ferrite were synthesized by co-precipitation with citrate and by sol–gel method, and characterized by X-ray diffraction (XRD), scanning electron microscopy in transmission mode (STEM), and superconducting quantum interference device (SQUID). The citrate-stabilized nanoparticles showed a small-sized population (around 8 nm, determined by XRD) and suitable magnetic properties, with a low coercivity and high saturation magnetization (~54 emu/g). The nanoparticles were incorporated into liposomes of dipalmitoylphosphatidylcholine/cholesteryl hemisuccinate (DPPC:CHEMS) and of the same components with a PEGylated lipid (DPPC:CHEMS:DSPE-PEG), resulting in magnetoliposomes with sizes around 100 nm. Dynamic light scattering (DLS) and electrophoretic light scattering (ELS) measurements were performed to investigate the pH-sensitivity of the magnetoliposomes’ fusogenic ability. Two new antitumor thienopyridine derivatives were efficiently encapsulated in the magnetic liposomes and the drug delivery capability of the loaded nanosystems was evaluated, under different pH and temperature conditions.

Magnetite nanoparticles (MNPs) have gained significant attention in several applications for drug delivery. However, there are some issues related to cell penetration, especially in the transport of cargoes that show limited membrane passing. A widely studied strategy to overcome this problem is the encapsulation of the MNPs into liposomes to form magnetoliposomes (MLPs), which are capable of fusing with membranes to achieve high delivery rates. This study presents a low-cost microfluidic approach for the synthesis and purification of MLPs and their biocompatibility and functional testing via hemolysis, platelet aggregation, cytocompatibility, internalization, and endosomal escape assays to determine their potential application in gastrointestinal delivery. The results show MLPs with average hydrodynamic diameters ranging from 137 ± 17 nm to 787 ± 45 nm with acceptable polydispersity index (PDI) values (below 0.5). In addition, we achieved encapsulation efficiencies between 20% and 90% by varying the total flow rates (TFRs), flow rate ratios (FRRs), and MNPs concentration. Moreover, remarkable biocompatibility was attained with the obtained MLPs in terms of hemocompatibility (hemolysis below 1%), platelet aggregation (less than 10% with respect to PBS 1×), and cytocompatibility (cell viability higher than 80% in AGS and Vero cells at concentrations below 0.1 mg/mL). Additionally, promising delivery results were obtained, as evidenced by high internalization, low endosomal entrapment (AGS cells: PCC of 0.28 and covered area of 60% at 0.5 h and PCC of 0.34 and covered area of 99% at 4 h), and negligible nuclear damage and DNA condensation. These results confirm that the developed microfluidic devices allow high-throughput production of MLPs for potential encapsulation and efficient delivery of nanostructured cell-penetrating agents. Nevertheless, further in vitro analysis must be carried out to evaluate the prevalent intracellular trafficking routes as well as to gain a detailed understanding of the existing interactions between nanovehicles and cells.

Liposome-like nanoarchitectures containing manganese ferrite nanoparticles covered or decorated with gold were developed for application in dual cancer therapy, combining chemotherapy and photothermia. The magnetic/plasmonic nanoparticles were characterized using XRD, UV/Visible absorption, HR-TEM, and SQUID, exhibiting superparamagnetic behavior at room temperature. The average size of the gold-decorated nanoparticles was 26.7 nm for MnFe2O4 with 5–7 nm gold nanospheres. The average size of the core/shell nanoparticles was 28.8 nm for the magnetic core and around 4 nm for the gold shell. Two new potential antitumor fluorescent drugs, tricyclic lactones derivatives of thienopyridine, were loaded in these nanosystems with very high encapsulation efficiencies (higher than 98%). Assays in human tumor cell lines demonstrate that the nanocarriers do not release the antitumor compounds in the absence of irradiation. Moreover, the nanosystems do not cause any effect on the growth of primary (non-tumor) cells (with or without irradiation). The drug-loaded systems containing the core/shell magnetic/plasmonic nanoparticles efficiently inhibit the growth of tumor cells when irradiated with red light, making them suitable for a triggered release promoted by irradiation.

Magnetic hyperthermia therapy may be combined with controlled release of multiple chemotherapeutic agents to effectively treat cancerous tumors. This study describes the preparation and characteristics of gemcitabine- and paclitaxel-loaded magnetoliposomes to investigate the in vitro potential of this formulation in association with magnetic hyperthermia therapy to control drug delivery. Magnetic nanoparticles, gemcitabine, and paclitaxel were encapsulated into thermosensitive liposomes with efficiency of 84%, 57%, and 68%, respectively. The hydrodynamics and distribution of the magnetoliposome formulations were determined, showing ideal characteristics for accumulation in the tumor tissue: mean size less than 100 nm, polydispersity index < 0.2, and stability in aqueous suspension for at least 15 days. At physiological temperature, only 9% of the gemcitabine and 1% of the paclitaxel were released after 72 h, but the formulations exposed to an alternating magnetic field (AMF) dissipated energy sufficient to increase mean temperature to 43 °C in just 5 min and delivered 94% of the gemcitabine and 43% of the paclitaxel after 30 min. In vitro cytotoxicity and magnetic hyperthermia studies were then carried out using human primary breast cancer cells (MGSO-3) and MTT assay. The viability of cells exposed to the loaded magnetoliposomes and AMF for 30 min fell to 27%; the cells treated with the loaded magnetoliposomes but not exposed to AMF exhibited viability over 60%, while hyperthermia alone (with unloaded magnetoliposomes) reduced cell viability to 50%. This study consequently suggests that gemcitabine- and paclitaxel-loaded magnetoliposomes may present potential for combined treatments involving hyperthermia and controlled release of chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

Stimuli-sensitive nanocarriers have recently been developed as a powerful tool in biomedical applications such as drug delivery, detection, and gene transfer techniques. Among the external triggers investigated, low intensity magnetic fields represent a non-invasive way to remotely control the release of compounds from a magneto-sensitive carrier. Magnetoliposomes (MLs), i.e., liposomes entrapping magnetic nanoparticles (MNPs), are studied due to their capacity to transport hydrophobic and hydrophilic agents, their easy production, and due to the ability of MNPs to respond to a magnetic actuation determining the triggered release of the encapsulated compounds. Here we investigated the design and optimization of the MLs to obtain an efficient on-demand release of the transported compounds, due to the magneto-mechanical actuation induced by applying low-intensity pulsed electromagnetic fields (PEMFs). In particular we studied the effect of the bilayer packing on the ability of MLs, with oleic acid-coated MNPs encapsulated in the bilayer, to respond to PEMFs application. Three kinds of MLs are produced with an increasing rigidity of the bilayer, defined as Liquid Disorder, Liquid Order, and Gel MLs and the delivery of a hydrophilic dye (as a model drug) is investigated. Results demonstrate the efficacy of the magnetic trigger on high-ordered bilayers, which are unable to dampen the perturbation produced by MNPs motion.

Multifunctional lipid nanocarriers are a promising therapeutic approach for controlled drug release in cancer therapy. Combining the widely used liposome structure with magnetic nanoparticles in magnetoliposomes allies, the advantages of using liposomes include the possibility to magnetically guide, selectively accumulate, and magnetically control the release of drugs on target. The effectiveness of these nanosystems is intrinsically related to the individual characteristics of the two main components—lipid formulation and magnetic nanoparticles—and their physicochemical combination. Herein, shape-anisotropic calcium-substituted magnesium ferrite nanoparticles (Ca0.25Mg0.75Fe2O4) were prepared for the first time, improving the magnetic properties of spherical counterparts. The nanoparticles revealed a superparamagnetic behavior, high saturation magnetization (50.07 emu/g at 300 K), and a large heating capacity. Furthermore, a new method for the synthesis of solid magnetoliposomes (SMLs) was developed to enhance their magnetic response. The manufacturing technicalities were optimized with different lipid compositions (DPPC, DPPC/Ch, and DPPC/DSPE-PEG) originating nanosystems with optimal sizes for biomedical applications (around or below 150 nm) and low polydispersity index. The high encapsulation efficiency of doxorubicin in these magnetoliposomes was proven, as well as the ability of the drug-loaded nanosystems to interact with cell membrane models and release DOX by fusion. SMLs revealed to reduce doxorubicin interaction with human serum albumin, contributing to a prolonged bioavailability of the drug upon systemic administration. Finally, the drug release kinetic assays revealed a preferable DOX release at hyperthermia temperatures (42 °C) and acidic conditions (pH = 5.5), indicating them as promising controlled release nanocarriers by either internal (pH) and external (alternate magnetic field) stimuli in cancer therapy.

This study was focused on the estimation of the targeted modification of 1,4-DHP core with (1) different alkyl chain lengths at 3,5-ester moieties of 1,4-DHP (C12, C14 and C16); (2) N-substituent at position 1 of 1,4-DHP (N-H or N-CH3); (3) substituents of pyridinium moieties at positions 2 and 6 of 1,4-DHP (H, 4-CN and 3-Ph); (4) substituent at position 4 of 1,4-DHP (phenyl and napthyl) on physicochemical properties of the entire molecules and on the characteristics of the obtained magnetoliposomes formed by them. It was shown that thermal behavior of the tested 1,4-DHP amphiphiles was related to the alkyl chains length, the elongation of which decreased their transition temperatures. The properties of 1,4-DHP amphiphile monolayers and their polar head areas were determined. The packing parameters of amphiphiles were in the 0.43–0.55 range. It was demonstrated that the structure of 1,4-DHPs affected the physicochemical properties of compounds. “Empty” liposomes and magnetoliposomes were prepared from selected 1,4-DHP amphiphiles. It was shown that the variation of alkyl chains length or the change of substituents at positions 4 of 1,4-DHP did not show a significant influence on properties of liposomes.

The compartmentalization of colloids into topologically closed, vesicular, microphases offers an attractive mean to concentrate a functional cargo in aqueous solutions for a range of biomedical, cosmetic, and biotechnological applications. In this paper, we develop a simple, phospholipid‐free, phase change method employing a pH‐responsive glycolipid. The method is applied to the encapsulation of a sonicated, metastable, aqueous dispersion of functional colloids in the lumen of lipid vesicles: uncoated magnetic maghemite γ‐Fe2O3 and oleic‐acid coated upconverting NaYF4 : Yb/Ln (Ln=Er or Tm) nanoparticles (NPs). We find a stable liposomal dispersion containing a sub‐population of crowded liposomes with high concentrations of NPs. The encapsulated NPs, formed at nearly neutral pH and room temperature, are stable over time and towards extrusion. The vesicular microphase is entirely composed of pH‐responsive glycolipids, which undergo a pH‐mediated mesoscopic structural transition from an open lamellar (24). We also show that encapsulation successfully works with a stable colloidal aqueous dispersion of iron clusters stabilized in ferritin cages. This compartmentalization approach combining self‐assembly with an orthogonal nonequilibrium dispersion of nanoparticles shows untapped potential for synthesizing unusual classes of mixed matter. [ABSTRACT FROM AUTHOR]

The structure of the testicles was studied in adult rats in 120 days after a single intravenous injection of chitosan-modified (magnetic nanospheres) and lipid-modified (magnetoliposomes) nanosized magnetite particles. Perls histochemical reaction detected in the testicular interstitial connective tissue the cells which absorbed and accumulated magnetite nanoparticles. The dynamics of spermatogenesis index and the count of Perls+ cells in the rat testicles were traced throughout the experiment. The studied modified nanosized magnetite particles did not penetrate through the blood—testicle barrier in rats. [ABSTRACT FROM AUTHOR]

Superparamagnetic iron oxide nanoparticles are used in a rapidly expanding number of research and practical applications in biotechnology and biomedicine. Recent developments in iron oxide nanoparticle design and understanding of nanoparticle membrane interactions have led to applications in magnetically triggered, liposome delivery vehicles with controlled structure. Here we study the effect of external physical stimuli—such as millimeter wave radiation—on the induced movement of giant lipid vesicles in suspension containing or not containing iron oxide maghemite (γ-Fe2O3) nanoparticles (MNPs). To increase our understanding of this phenomenon, we used a new microscope image-based analysis to reveal millimeter wave (MMW)-induced effects on the movement of the vesicles. We found that in the lipid vesicles not containing MNPs, an exposure to MMW induced collective reorientation of vesicle motion occurring at the onset of MMW switch "on." Instead, no marked changes in the movements of lipid vesicles containing MNPs were observed at the onset of first MMW switch on, but, importantly, by examining the course followed; once the vesicles are already irradiated, a directional motion of vesicles was induced. The latter vesicles were characterized by a planar motion, absence of gravitational effects, and having trajectories spanning a range of deflection angles narrower than vesicles not containing MNPs. An explanation for this observed delayed response could be attributed to the possible interaction of MNPs with components of lipid membrane that, influencing, e.g., phospholipids density and membrane stiffening, ultimately leads to change vesicle movement. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Quercetin-loaded magnetoliposomes (ML_QC) are promising antitumoral systems. • ML_QC have superparamagnetic behavior, being advantageous for antitumoral therapy. • Quercetin ordered the lipid polar region of magnetoliposomes. • Quercetin disordered interfacial and hydrophobic portions of magnetoliposomes. • Quercetin improved in vitro effect of the magnetoliposomes on rat glioma cells viability. Abstract The bioflavonoid quercetin may prevent magnetoliposomes oxidation, preserving their stability. In this work, the interaction between quercetin and asolectin-based magnetoliposomes was investigated by monitoring the hydration degree, vibrational, rotational and translational mobility parameters of the system as well as its thermodynamic properties. The efficiency of the encapsulation of maghemite magnetic nanoparticles was detected by high resolution-continuum source flame atomic absorption spectrometry (HR-CS FAAS). The magnetic behavior of the system was studied by vibrating sample magnetometry (VSM) technique. The size and surface charge of magnetoliposomes were detected by dynamic light scattering (DLS) and zeta potential (ζ-potential) measurements. The influence of quercetin on the physico-chemical parameters of the magnetoliposomes was evaluated by Fourier transform infrared spectroscopy (FTIR), 31P and 1H nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC) techniques. In vitro antioxidant and antitumoral assays were also performed for the magnetoliposomes. An insertion of quercetin into magnetoliposomes reduced the efficiency of the encapsulation of maghemite nanoparticles by 11%, suggesting a significant interaction between flavonoid and nanoparticles in a specific region of the system. Quercetin discreetly decreased the saturation magnetization of magnetoliposomes, but did not affect the superparamagnetic behavior of the system. 31P and 1H NMR results showed that quercetin did not alter the inverted hexagonal system phase state but decreased lipid polar head mobility. The flavonoid also seems to reorient the choline group above the bilayer phosphate membrane plane, as indicated by ζ-potential system values. FTIR, NMR and DSC responses showed that quercetin disordered the carbonyl and the methylene regions of the magnetoliposomes. Quercetin, as the nanoparticles, seems to be located in the polar head regions of magnetoliposomes, ordering it and diminishing the lipid intermolecular communication in the membrane carbonyl and non-polar regions. The lipid peroxidation of the magnetoliposomes was prevented 8-fold by the presence of quercetin in the system. Also, the flavonoid was responsible for a 45% reduction in the viability of glioma cells. Location and interactions between quercetin and magnetoliposomes components were discussed in order to be correlated with the results of biological activity, contributing to the design of more stable and efficient magnetoliposomes to be applied as contrast and antitumoral agents. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • New γ-Fe2O3 magnetoliposomes suitable for parenteral administration were synthesized. • Magnetoliposomes were no-toxic in normal and tumor -derived cell lines from colon. • Magnetoliposomes accumulated preferentially in mitochondria of colon cancer cells. • Cells in suspension treated with magnetoliposomes migrated under a magnet field. • Magnetoliposomes are promising platform for chemo/thermotherapy of cancer. Abstract Magnetoliposomes (MLPs) offer many new possibilities in cancer therapy and diagnosis, including the transport of antitumor drugs, hyperthermia treatment, detection using imaging techniques, and even cell migration. However, high biocompatibility and functionality after cell internalization are essential to their successful application. We synthesized maghemite nanoparticles (γ -Fe 2 O 3) by oxidizing magnetite cores (Fe 3 O 4) and coating them with phosphatidylcholine (PC) liposomes, obtained using the thin film hydration method, to generate MLPs. The MLPs were tested in vitro , using human tumor and non-tumor colon cell lines, for cytotoxicity, cell uptake and cellular distribution, and magnetically-induced cell mobility. In addition, blood cells biocompatibility studies were performed. The mean size of the MLPs, with a core of γ -Fe 2 O 3 completely surrounded by PC liposomes, was 90 ± 20 nm, showing a soft magnetic character and a great biocompatibility in all the cell lines assayed including blood cells. Prussian blue staining showed a high MLP cell uptake with maximum internalization at 24 h. TEM analysis showed the MLPs surrounded by the cell membrane and in the cell periphery, suggesting internalization by endocytosis and/or macropinocytosis. Interestingly, the mitochondria presented MLP accumulations, particularly in tumor cells. Finally, MLPs within colon cancer cells were able to induce cell migration when a magnetic field was applied in vitro , indicating the functionality of our nanoformulation. A promising biomedical application of these MLPs is anticipated based on their physical, chemical and biological properties. [ABSTRACT FROM AUTHOR]

A major problem with magnetogels is the encapsulation of hydrophobic drugs. Magnetoliposomes not only provide these domains but also improve drug stability and avert the aggregation of the magnetic nanoparticles. In this work, two magnetoliposome architectures, solid and aqueous, were combined with supramolecular peptide-based hydrogels, which are of biomedical interest owing to their biocompatibility, easy tunability, and wide array of applications. This proof-of-concept was carried out through combination of magnetoliposomes (loaded with the model drug curcumin and the lipid probe Nile Red) with the hydrogels prior to pH triggered gelation, and fluorescence spectroscopy was used to assess the dynamics of the encapsulated molecules. These systems allow for the encapsulation of a wider array of drugs. Further, the local environment of the encapsulated molecules after gelation is unaffected by the used magnetoliposome architecture. This system design is promising for future developments on drug delivery as it provides a means to independently modify the components and adapt and optimize the design according to the required conditions.

Despite the promising pharmacological properties of curcumin, the transport and effective release of curcumin is still a challenge. The advances in functionalized nanocarriers for curcumin have also been motivated by the anticancer activity of this natural compound, aiming at targeted therapies. Here, stealth (aqueous and solid) magnetoliposomes containing calcium-substituted magnesium ferrite nanoparticles, CaxMg1−xFe2O4 (with x = 0.25, 0.50, 0.75) were developed as nanocarriers for curcumin. The magnetic nanoparticles exhibit superparamagnetic properties and crystalline structure, with sizes below 10 nm. The magnetoliposomes based on these nanoparticles have hydrodynamic diameters around or below 150 nm and a low polydispersity. The influence of an alternating magnetic field (AMF) on drug release over time was evaluated and compared with curcumin release by diffusion. The results suggest the potential of drug-loaded magnetoliposomes as nanocarriers that can be magnetically guided to the tumor sites and act as agents for a synergistic effect combining magnetic hyperthermia and controlled drug release.

Multifunctional nanosystems combining magnetic and plasmonic properties are a promising approach for cancer therapy, allowing magnetic guidance and a local temperature increase. This capability can provide a triggered drug release and synergistic cytotoxic effect in cancer cells. In this work, nickel ferrite/gold nanoparticles were developed, including nickel ferrite magnetic nanoparticles decorated with plasmonic gold nanoparticles and core/shell nanostructures (with a nickel ferrite core and a gold shell). These nanoparticles were covered with a surfactant/lipid bilayer, originating liposome-like structures with diameters below 160 nm. The heating capacity of these systems, upon excitation with light above 600 nm wavelength, was assessed through the emission quenching of rhodamine B located in the lipid layer. The developed nanosystems show promising results for future applications in thermotherapy.

Magnesium ferrite nanoparticles, with diameters around 25 nm, were synthesized by coprecipitation method. The magnetic properties indicate a superparamagnetic behaviour, with a maximum magnetization of 16.2 emu g−1, a coercive field of 22.1 Oe and a blocking temperature of 183.2 K. These MgFe2O4 nanoparticles were used to produce aqueous and solid magnetoliposomes, with sizes below 130 nm. The potential drug curcumin was successfully incorporated in these nanosystems, with high encapsulation efficiencies (above 89%). Interaction by fusion between both types of drug-loaded magnetoliposomes (with or without PEGylation) and models of biological membranes was demonstrated, using FRET or fluorescence quenching assays. These results point to future applications of magnetoliposomes containing MgFe2O4 nanoparticles in cancer therapy, allowing combined magnetic hyperthermia and chemotherapy.

In this review, we discuss the recent advances in and problems with the use of magnetically-guided and magnetically-responsive nanoparticles in drug delivery and magnetofection. In magnetically-guided nanoparticles, a constant external magnetic field is used to transport magnetic nanoparticles loaded with drugs to a specific site within the body or to increase the transfection capacity. Magnetofection is the delivery of nucleic acids under the influence of a magnetic field acting on nucleic acid vectors that are associated with magnetic nanoparticles. In magnetically-responsive nanoparticles, magnetic nanoparticles are encapsulated or embedded in a larger colloidal structure that carries a drug. In this last case, an alternating magnetic field can modify the structure of the colloid, thereby providing spatial and temporal control over drug release.

Abstract Multifunctional magnetoliposomes (MLs) with active and magnetic targeting potential are evaluated as platform systems for drug targeting applications. USPIO-encapsulating MLs are prepared by freeze drying/extrusion, decorated with one or two ligands for brain or cancer targeting (t-MLs), and actively loaded with Doxorubicin (DOX). MLs have mean diameters between 117 and 171 nm. Ligand attachment yields and DOX-loading efficiency are sufficiently high, 78–95% and 89–92%, respectively, while DOX loading and retention is not affected by co-entrapment of USPIOs, and USPIO loading/retention is not modulated by DOX. Attachment of ligands, also does not affect DOX or USPIO loading. Interestingly, MLs have high magnetophoretic mobility (MM) compared to free USPIOs, which is not affected by surface coating with PEG (up to 8 mol%), but is slightly reduced by Chol incorporation in their membrane, or when functional groups are immobilized on their surface. ML size, (directly related to number of USPIOs entrapped per vesicle), is the most important MM-determining factor. MM increases by 570% when ML size increases from 69 to 348 nm. Targeting potential of t-MLs is verified by enhanced: (i) transport across a cellular model of the blood-brain-barrier, and (ii) anti-proliferative effect towards B16 melanoma cells. The potential of further enhancing t-ML targeting magnetically is verified by additional enhancements of (i) and (ii), when experiments are performed under a permanent magnetic field. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

A simple and effective method based on magnetic separation has been developed for the extraction of organochlorine pesticides (OCPs) from river water samples using magnetoliposomes as adsorbents. This method avoided the time-consuming column passing process of loading large volume samples in traditional SPE through the rapid isolation of magnetoliposomes with an adscititious magnet. Lipid bilayers formed on the surface of Fe 3 O 4 showed great adsorptive tendency towards analytes through hydrophobic interactions, and zwitterions headgroups endowed the outer surface of magnetoliposomes with hydrophilicity to improve the dispersing property of adsorbents in the sample matrix. The target analytes were detected by gas chromatography-tandem mass spectrometry, and the limits of detection obtained are in the range of 0.04–0.35 ng L − 1 . The relative standard deviations of intra- and inter-day are in the range of 2–5% and 4–7%, respectively. The proposed method was employed for analysis of six OCPs in the surface water samples from two cities along the Songhua River in different seasons. Compared with the traditional methods, the proposed method could reduce the consumption of the organic solvent and shorten the sample preparation time. [ABSTRACT FROM AUTHOR]

Pancreatic islets (PIs) transplantation is an alternative approach for the treatment of severe forms of type 1 diabetes (T1D). To monitor the success of transplantation, it is desirable to follow the location of engrafted PIs non-invasively. In vivo magnetic resonance imaging (MRI) of transplanted PIs is a feasible cell tracking method; however, this requires labeling with a suitable contrast agent prior to transplantation. We have tested the feasibility of cationic magnetoliposomes (MLs), compared to commercial contrast agents (Endorem and Resovist), by labeling insulinoma cells and freshly isolated rat PIs. It was possible to incorporate Magnetic Ressonance (MR)-detectable amounts of MLs in a shorter time (4 h) when compared to Endorem and Resovist. MLs did not show negative effects on the PIs' viability and functional parameters in vitro. Labeled islets were transplanted in the renal sub-capsular region of healthy mice. Hypointense contrast in MR images due to the labeled PIs was detected in vivo upon transplantation, while MR detection of PIs labeled with Endorem and Resovist was only possible after the addition of transfection agents. These findings indicate that MLs are suitable to image PIs, without affecting their function, which is promising for future longitudinal pre-clinical and clinical studies involving the assessment of PI transplantation. [ABSTRACT FROM AUTHOR]

Precise delivery of antineoplastic drugs to specific tumor region has drawn much attention in recent years. Herein, a light/magnetic hyperthermia triggered drug delivery with multiple functionality is designed based on methotrexate (MTX) modified thermo-sensitive magnetoliposomes (MTX-MagTSLs). In this system, MTX and oleic acid modified magnetic nanoparticles (MNPs) can be applied in biological and magnetic targeting. Meanwhile, lipophilic fluorescent dye Cy5.5 and MNPs are encapsulated into the bilayer of liposomes, which can not only achieve dual-imaging effect to verify the MTX-MagTSLs accumulation in tumor region, but also provide an appropriate laser irradiation region to release Doxorubicin (Dox) under alternating magnetic field (AMF). Both in vitro and in vivo results revealed that MTX-MagTSLs possessed an excellent targeting ability towards HeLa cells and HeLa tumor-bearing mice. Furthermore, the heating effect of MTX-MagTSLs was amplified 4.2-fold upon combination with AMF and local precise near-infrared laser irradiation (808 nm) (DUAL-mode) to rapidly reach the phase change temperature (Tm) of MTX-MagTSLs in 5 min compared with either AMF or laser stimulation alone, resulting in a significantly enhanced release of Dox at tumor region and precise cancer synergetic theranostics. [ABSTRACT FROM AUTHOR]