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Multifunctional Thermosensitive Liposomes Based on Natural Phase Change Material: Near-Infrared Light-Triggered Drug Release and Multimodal Imaging Guided Cancer Combination Therapy
摘要： Multifunctional theranostic nanoplatforms (NPs) in response to environment stimulations for on-demand drug release are highly desirable. Herein, the near-infrared (NIR)-absorbing dye, indocyanine green (ICG) and the antitumor drug, doxorubicin (DOX) were efficiently co-encapsulated into the thermosensitive liposomes based on natural phase change material (PCM). Folate and conjugated gadolinium chelate-modified liposome shells enhance active targeting and magnetic resonance (MR) performance of the NPs while maintaining the size of the NPs. The ICG/DOX loaded and gadolinium chelates conjugated temperature-sensitive liposomes nanoplatforms (ID@TSL-Gd NPs) exhibited NIR-triggered drug release and prominent chemo-, photothermal, photodynamic therapy properties. With the co-encapsulated ICG, DOX and the conjugated gadolinium chelates, the ID@TSL-Gd NPs can be used for triple-modal imaging (fluorescence/photoacoustic/magnetic resonance imaging, FL/PAI/MRI) guided combination tumor therapy (chemotherapy, photothermotherapy and photodynamic therapy, Chemo/PTT/PDT). After tail vein injection, the ID@TSL-Gd NPs accumulated effectively in subcutaneous HeLa tumor of mice. The tumor was effectively suppressed by accurate imaging guided NIR triggered phototherapy and chemotherapy, and no tumor regression and side effects were observed. In summary, the prepared ID@TSL-Gd NPs achieved multimodal imaging-guided cancer combination therapy, providing a promising platform for improving diagnosis and treatment of cancer.
关键词： Multimodal imaging,Liposomes,Thermosensitive,Combination therapy,Phase change material
更新于2025-11-21 11:08:12
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Evaluation of various tissue-clearing techniques for the three-dimensional visualization of liposome distribution in mouse lungs at the alveolar scale
摘要： Purpose: To develop a three-dimensional visualization method for evaluating the distribution of pulmonary drug delivery systems and compare four tissue-clearing techniques (ClearT2, CUBIC, ScaleS, and SeeDB2) using intrapulmonary liposomes as drug carriers. Methods: Rhodamine B-labeled liposomes were administered intrapulmonarily to mice using a MicroSprayer, and then fluorescent-labeled tomato lectin was administered intravenously to visualize the general lung structure. Tissue-clearing treatment of the mouse lungs was performed using the standard protocols of the ClearT2, CUBIC, ScaleS, and SeeDB2 techniques. Lung clearing was clarified using laser-scanning confocal microscopy, and three-dimensional images were reconstructed. Results: Fluorescent-labeled tomato lectin was preserved using ClearT2 and SeeDB2 but not using CUBIC and ScaleS. In addition, the liposomes were stable in ClearT2 reagent, but they were mostly degraded in other reagents by surface-active agents. ClearT2 treatment enabled the three-dimensional visualization of intrapulmonary rhodamine B-labeled liposomes at the alveolar scale. Conclusions: These results suggest that the ClearT2 tissue-clearing technique was appropriate for the three-dimensional visualization of intrapulmonary liposomes at the alveolar scale. This study provides important information for selecting and optimizing suitable optical tissue-clearing techniques in lungs for evaluating the distribution of pulmonary drug delivery systems.
关键词： fluorescence preservation,Intrapulmonary distribution,inhalation,liposomes,drug delivery systems,laser-scanning confocal microscopy
更新于2025-11-21 11:08:12
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Magnesium tetrapyrazinoporphyrazines: tuning of the pKa of red-fluorescent pH indicators
摘要： Magnesium (II) tetrapyrazinoporphyrazines (TPyzPzs) are excellent red fluorophores (λF ~ 663 nm, ΦF ~ 0.53 in THF). In this work, a series of magnesium (II) complexes of unsymmetrical TPyzPzs bearing one or two phenol substituents was prepared. Suitable substitutions on the phenolic moiety tuned its pKa in the range of 5.5 to 13. Deprotonation of the phenolic group at higher pH induced a strong donor (phenolate) in the macrocycle that led to pH-dependent quenching of the red fluorescence of these indicators. pH sensing was proven in water solutions after incorporation of TPyzPs into two delivery systems – microemulsions and liposomes. The latter also serves as a simple model of biomembranes. Finally, a wavelength-ratiometric probe was constructed by incorporation of a TPyzPz indicator and lipophilic pH-nonsensitive BODIPY dye into liposomes. Synthetic precursors for TPyzPzs, substituted pyrazine-2,3-dicarbonitriles, also represent donor-acceptor system and the pH-dependent changes in absorption spectra may be easily visible to the naked eye.
关键词： pH indicators,microemulsions,fluorescence,BODIPY,wavelength-ratiometric probe,liposomes,tetrapyrazinoporphyrazines,magnesium complexes
更新于2025-11-20 15:33:11
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Blood Interactions, Pharmacokinetics and Depth-Dependent Ablation of Rat Mammary Tumors with Photoactivatable, Liposomal Doxorubicin
摘要： Photosensitizers can be integrated with drug delivery vehicles to develop chemophototherapy agents with anti-tumor synergy between chemo- and photo- components. Long-circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) incorporates a phospholipid-like photosensitizer (2 mole %) in the bilayer of Dox-loaded stealth liposomes. Hematological effects of endotoxin-minimized LC-Dox-PoP were characterized via standardized assays. In vitro interaction with erythrocytes, platelets, and plasma coagulation cascade were generally unremarkable while complement activation was found to be similar to that of commercial Doxil. Blood partitioning suggested both the Dox and PoP components of LC-Dox-PoP were stably entrapped or incorporated in liposomes. This was further confirmed with pharmacokinetic studies in Fischer rats, which showed the PoP and Dox components of the liposomes both had nearly identical, long circulation half-lives (25-26 hours). In a large orthotopic mammary tumor model in Fischer rats, following intravenous dosing (2 mg/kg Dox), the depth of enhanced Dox delivery in response to 665 nm laser irradiation was over 1 cm. LC-Dox-PoP with laser treatment cured or potently suppressed tumor growth, with greater efficacy observed in tumors 0.8-1.2 cm compared to larger ones. The skin at the treatment site healed within approximately 30 days. Taken together, these data provide insight into nanocharacterization and photo-ablation parameters for a chemophototherapy agent.
关键词： doxorubicin,chemophototherapy,ablation,nanocharacterization,Liposomes
更新于2025-09-23 15:23:52
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Highly-Soluble Cyanine J-aggregates Entrapped by Liposomes for <i>In Vivo</i> Optical Imaging around 930 nm
摘要： Near infrared (NIR) dyes are useful for in vivo optical imaging. Liposomes have been used extensively for delivery of diverse cargos, including hydrophilic cargos which are passively loaded in the aqueous core. However, most currently available NIR dyes are only slightly soluble in water, making passive entrapment in liposomes challenging for achieving high optical contrast. Methods: We modified a commercially-available NIR dye (IR-820) via one-step Suzuki coupling with dicarboxyphenylboronic acid, generating a disulfonated heptamethine; dicarboxyphenyl cyanine (DCP-Cy). DCP-Cy was loaded in liposomes and used for optical imaging. Results: Owing to increased charge in mildly basic aqueous solution, DCP-Cy had substantially higher water solubility than indocyanine green (by an order of magnitude), resulting in higher NIR absorption. Unexpectedly, DCP-Cy tended to form J-aggregates with pronounced spectral red-shifting to 934 nm (from 789 nm in monomeric form). J-aggregate formation was dependent on salt and DCP-Cy concentration. Dissolved at 20 mg/mL, DCP-Cy J-aggregates could be entrapped in liposomes. Full width at half maximum absorption of the liposome-entrapped dye was just 25 nm. The entrapped DCP-Cy was readily detectable by fluorescence and photoacoustic NIR imaging. Upon intravenous administration to mice, liposomal DCP-Cy circulated substantially longer than the free dye. Accumulation was largely in the spleen, which was visualized with fluorescence and photoacoustic imaging. Conclusions: DCP-Cy is simple to synthesize and exhibits high aqueous solubility and red-shifted absorption from J-aggregate formation. Liposomal dye entrapment is possible, which facilitates in vivo photoacoustic and fluorescence imaging around 930 nm.
关键词： liposomes,photoacoustic,cyanine,J-aggregate
更新于2025-09-23 15:22:29
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Polymer Dots Compartmentalized in Liposomes as Photocatalyst for In Situ Hydrogen Therapy
摘要： Semiconducting polymer dots (Pdots) have recently attracted considerable attention because of their photocatalytic activity as well as tunable optical band gap. In this contribution, we describe the therapeutic application of Pdots through in situ photocatalytic hydrogen generation. A liposome was employed as a nanoreactor to confine the Pdot photocatalyst, reactants, intermediates, and by-products. Upon photon absorption by the Pdots, the catalytic cycle is initiated and repeated within the aqueous interior, while the H2 product diffuses across the lipid bilayer to counteract reactive oxygen species (ROS) overexpressed in diseased tissues. Ensemble and single-particle F?rster resonance energy transfer microscopy confirmed the proposed nanoreactor model. We demonstrate that a liposomal nanoreactor containing Pdots and a sacrificial electron donor is a potential photocatalytic nanoreactor for in situ hydrogen therapy.
关键词： compartmentalization,hydrogen therapy,photocatalysis,polymer dots,liposomes
更新于2025-09-23 15:22:29
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Fluorescence Microscopy of Single Liposomes with Incorporated Pigment–Proteins
摘要： Reconstitution of transmembrane proteins into liposomes is a widely used method to study their behavior under conditions closely resembling the natural ones. However, this approach does not allow precise control of the liposome size, reconstitution efficiency and the actual protein-to-lipid ratio in the formed proteoliposomes, which might be critical for some applications and/or interpretation of data acquired during the spectroscopic measurements. Here we present a novel strategy employing methods of proteoliposome preparation, fluorescent labelling, purification, and surface immobilization that allow us to quantify these properties using fluorescence microscopy at the single-liposome level and for the first time apply it to study photosynthetic pigment–protein complexes LHCII. We show that LHCII proteoliposome samples, even after purification with a density gradient, always contain a fraction of non-reconstituted protein and are extremely heterogeneous in both protein density and liposome sizes. This strategy enables quantitative analysis of the reconstitution efficiency of different protocols and precise fluorescence spectroscopic study of various transmembrane proteins in a controlled native-like environment.
关键词： Fluorescence Microscopy,Proteoliposomes,Pigment–Proteins,LHCII,Single Liposomes
更新于2025-09-23 15:21:01
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Effect of Laser Irradiation on Reversibility and Drug Release of Light-Activatable Drug-Encapsulated Liposomes
摘要： Although several studies have demonstrated repetitive drug release using light-activatable liposomes, inconsistent drug release at each activation limits widespread usage. Here, we report reversible plasmonic material-coated encapsulated liposomes for proportional controlled delivery of methotrexate (MTX), which is a common drug for cancer and autoimmune diseases, using repetitive laser irradiation. Our results suggest a proportional increase in total drug release after repetitive laser irradiation. We hypothesize that the drug is released via “melted” lipid bilayers when the plasmonic materials on the liposome surface are heated by laser irradiation followed by reversible formation of the liposome. To evaluate our hypothesis, the number density of liposomes after laser irradiation was measured using single-particle (liposome) collision experiments at an ultramicroelectrode. Collisional frequency data suggest that the number density of liposomes remains unaltered even after 60 s of laser irradiation at 1.1 and 1.8 W, indicating that the liposome structure is reversible. The results were further compared with gold nanorod-coated nanodroplets where drug is released via irreversible phase transition. In contrast to what was observed with the liposome particles, the number density of the nanodroplets decreased with increasing laser irradiation duration. The structure reversibility of our liposome particles may be responsible for repetitive drug release with laser heating. We also studied the temperature rise in the lipid bilayer by incorporating polymerized 10,12-pentacosadiynoic acid (PCDA) in the lipid composition. The red shift in the UV?vis spectrum due to the structural change in PCDA lipids after laser irradiation indicates a rise in temperature above 75 °C, which is also above the chain-melting temperature of the main lipid used in the liposomes. All these results indicate that drug is released from the light-activatable liposomes due to reversible nanostructural alteration in the lipid bilayer by plasmonic resonance heating. The liposomes have potential to be a drug carrier for dose-controlled repetitive drug delivery.
关键词： drug release,reversible nanostructural alteration,light-activatable liposomes,plasmonic materials,laser irradiation,methotrexate
更新于2025-09-23 15:19:57
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Photodynamic therapy – hypericin tetraether liposome conjugates and their antitumor and antiangiogenic activity
摘要： Photodynamic therapy (PDT) is an established noninvasive tumor treatment. The hydrophobic natural occurring pigment hypericin shows a lot of attractive properties for the application in PDT. Hence, the administration to biological systems or patients requires the formulation in drug carriers enabling sufficient bioavailability. Therefore, free hypericin was encapsulated by the thin film hydration method or a hypericin-hydroxypropyl-b-cyclodextrin inclusion complex (Hyp-HPbCD) was incorporated by dehydration-rehydration vesicle method in either conventional or ultra-stable tetraether lipid (TEL) liposomes. The hydrodynamic diameter of the prepared nanoformulations ranged between 127 and 212 nm. These results were confirmed by atomic force microscopy. All liposomes showed a good stability under physiological conditions. TEL liposomes which tend to build more rigid bilayers, generate higher encapsulation efficiencies than their conventional counterparts. Furthermore, the suitability for intravenous application was confirmed by hemocompatibility studies resulting in a hemolytic potential less than 20% and a coagulation time less than 50 sec. The uptake of liposomal hypericin into human ovarian carcinoma cells (SK-OV-3) was confirmed using confocal microscopy and further characterized by pathway studies. It was demonstrated that the lipid composition and intraliposomal hypericin localization influenced the anti-vascular effect in the chorioallantoic membrane (CAM). While hypericin TEL liposomes exhibit substantial destruction of the microvasculature drug-in-cyclodextrin TEL liposomes showed no effect. Nevertheless, both formulations yielded severe photocytotoxicity in SK-OV-3 cells in a therapeutic dosage range. Conclusively, hypericin TEL liposomes would be perfectly suited for anti-vascular targeting while Hyp-HPbCD TEL liposomes could deliver the photosensitizer to the tumor site in a more protected manner.
关键词： Antitumor,hypericin,antiangiogenic,photodynamic therapy,liposomes
更新于2025-09-19 17:15:36
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Formation of lipid bilayers on the pore walls of macroporous silicon
摘要： Electron paramagnetic resonance (EPR) spectroscopy was used to study the pore filling of macroporous silicon with lipid vesicles (liposomes), added with a spin label. Different EPR spectra were obtained with the magnetic field parallel and perpendicular to the macroporous silicon sample surface. These spectra could be well simulated with an admixture of the isotropic spectrum of liposomes, plus a simulated spectrum corresponding to a cylindrical distribution of lipid bilayers. This means that a portion of the liposomes were disrupted, and supported lipid bilayers were formed covering the inner surface of the pores. Diverse protocols can be explored in order to optimize the lipid covering of the pore walls, and to achieve an adequate lipid hydration. This system can be used as a platform to study lipid phase transitions in a confined environment, and to characterize membrane proteins.
关键词： Liposomes,Electron paramagnetic resonance/electron spin resonance,Supported lipid bilayers,Porous silicon,Spin labels
更新于2025-09-19 17:15:36