Microscale optoelectronic infrared-to-visible upconversion devices and their use as injectable light sources.

Optical upconversion that converts infrared light into visible light is of significant interest for broad applications in biomedicine, imaging, and displays. Conventional upconversion materials rely on nonlinear light-matter interactions, exhibit incidence-dependent efficiencies, and require high-power excitation. We report an infrared-to-visible upconversion strategy based on fully integrated microscale optoelectronic devices. These thin-film, ultraminiaturized devices realize near-infrared (∼810 nm) to visible [630 nm (red) or 590 nm (yellow)] upconversion that is linearly dependent on incoherent, low-power excitation, with a quantum yield of ∼1.5%. Additional features of this upconversion design include broadband absorption, wide-emission spectral tunability, and fast dynamics. Encapsulated, freestanding devices are transferred onto heterogeneous substrates and show desirable biocompatibilities within biological fluids and tissues. These microscale devices are implanted in behaving animals, with in vitro and in vivo experiments demonstrating their utility for optogenetic neuromodulation. This approach provides a versatile route to achieve upconversion throughout the entire visible spectral range at lower power and higher efficiency than has previously been possible.

Non-Magnetic Injectable Implant for Magnetic Field-Driven Thermochemotherapy and Dual Stimuli-Responsive Drug Delivery: Transformable Liquid Metal Hybrid Platform for Cancer Theranostics.

Transformable liquid metal (LM)-based materials have attracted considerable research interest in biomedicine. However, the potential biomedical applications of LMs have not yet been fully explored. Herein, for the first trial, the inductive heating property of gallium-indium eutectic alloy (EGaIn) under alterative magnetic field is systematically investigated. By virtue of its inherent metallic nature, LM possesses excellent magnetic heating property as compared to the conventional magnetite nanoparticles, therefore enabling its unique application as non-magnetic agents in magnetic hyperthermia. Moreover, the extremely high surface tension of LM could be dramatically lowered by a rather facile PEGylation approach, making LM an ideal carrier for other theranostic cargos. By incorporating doxorubicin (DOX)-loaded mesoporous silica (DOX-MS) within PEGylated LM, a magnetic field-driven transformable LM hybrid platform capable of pH/AFM dual stimuli-responsive drug release and magnetic thermochemotherapy are successfully fabricated. The potential application for breast cancer treatment is demonstrated. Furthermore, the large X-ray attenuation ability of LM endows the hybrid with the promising ability for CT imaging. This work explores a new biomedical use of LM and a promising cancer treatment protocol based on LM hybrid for magnetic hyperthermia combined with dual stimuli-responsive chemotherapy and CT imaging.

Fabrication of Antimicrobial Peptide-Loaded PLGA/Chitosan Composite Microspheres for Long-Acting Bacterial Resistance.

An antimicrobial decapeptide, KSL-W (KKVVFWVKFK-CONH2), which could maintain stable antimicrobial activity in saliva, has therefore been widely used to inhibit biofilm formation on teeth and prevent the growth of oral microorganisms for related infectious diseases treatment. In order to control the release of KSL-W for long-term bacterial resistance, KSL-W-loaded PLGA/chitosan composite microspheres (KSL/PLGA/CS MSs) were prepared by electrospraying and combined crosslinking-emulsion methods. Different formulations of microspheres were characterized as to surface morphology, size distribution, encapsulation efficiency, in vitro drug release, and antimicrobial activity. Antibacterial experiment demonstrated the prolonged antimicrobial and inhibitory effects of KSL/PLGA/CS MSs on oral bacteria. Moreover, the cell proliferation assay proved that the released KSL-W antibacterial dosage had no cytotoxicity to the growth of osteoblast MC3T3-E1. Thus, our study suggested that the KSL-W-loaded PLGA/CS composite microspheres may have potentially therapeutic applications as an effective drug delivery system in the treatment of oral infectious diseases such as periodontitis and periodontitis, and also within bone graft substitutes for alveolar bone augmentation.

FePd Nanozyme- and SKN-Encapsulated Functional Lipid Nanoparticles for Cancer Nanotherapy via ROS-Boosting Necroptosis.

Cell necroptosis has presented great potential, acting as an effective approach against tumor apoptotic resistance, and it could be further enhanced via accompanying reactive oxygen species (ROS) overexpression. However, whether overproduced ROS assists the necroptotic pathway remains unclear. Thus, iron-palladium nanozyme (FePd NZ)- and shikonin (SKN)-encapsulated functional lipid nanoparticles (FPS-LNPs) were designed to investigate the ROS overexpression-enhanced SKN-induced necroptosis. In this system, SKN acts as an effective necroptosis inducer for cancer cells, and FePd NZ, a sensitive Fenton reaction catalyst, produces extra-intracellular ROS to reinforce the necroptotic pathway. Both in vitro and in vivo antitumor evaluation revealed that FPS-LNPs presented the best tumor growth inhibition efficacy compared with FP-LNPs or SKN-LNPs alone. Meanwhile, induced necroptosis by FPS-LNPs can further trigger the release of damage-associated molecular patterns (DAMPs) and antigens from dying tumor cells to activate the innate immune response. Taking biosafety into consideration, this study has provided a potential nanoplatform for cancer nanotherapy via inducing necroptosis to avoid apoptosis resistance and activate CD8+ T cell immune response.

Planted Graphene Quantum Dots for Targeted, Enhanced Tumor Imaging and Long-Term Visualization of Local Pharmacokinetics.

While photoluminescent graphene quantum dots (GQDs) have long been considered very suitable for bioimaging owing to their protein-like size, superhigh photostability and in vivo long-term biosafety, their unique and crucial bioimaging applications in vivo remain unreachable. Herein, planted GQDs are presented as an excellent tool for in vivo fluorescent, sustainable and multimodality tumor bioimaging in various scenarios. The GQDs are in situ planted in the poly(ethylene glycol) (PEG) layer of PEGylated nanoparticles via a bottom-up molecular approach to obtain the NPs-GQDs-PEG nanocomposite. The planted GQDs show more than four times prolonged blood circulation and 7-8 times increased tumor accumulation than typical GQDs in vivo. After accessible specificity modification, the multifunctional NPs-GQDs-PEG provides targeted, multimodal molecular imaging for various tumor models in vitro or in vivo. Moreover, the highly photostable GQDs enable long-term, real-time visualization of the local pharmacokinetics of NPs in vivo. Planting GQDs in PEGylated nanomedicine offers a new strategy for broad in vivo biomedical applications of GQDs.

Acidity-Triggered Charge-Convertible Conjugated Polymer for Dihydroartemisinin Delivery and Tumor-Specific Chemo-Photothermal Therapy.

Since the nonspecificity and nonselectivity of traditional treatment models lead to the difficulty of cancer treatment, nanobased strategies are needed to fill in the gaps of current approaches. Herein, a tumor microenvironment (TME)-responsive chemo-photothermal treatment model was developed based on dihydroartemisinin (DHA)-loaded conjugated polymers (DHA@PLGA-PANI). The synthesized DHA@PLGA-PANI exhibited enhanced photothermal properties under mild-acidic conditions and thus triggered local heat at the tumor site. Meanwhile, these iron-doped conjugated polymers of PLGA-PANI were used as the source of Fe, and benefiting from the Fe-dependent cytotoxicity of DHA, the burst of free radicals could be generated in tumors. Therefore, the combination of TME-responsive chemo-photothermal therapy could achieve effective tumor efficacy.

Magnetic Self-Healing Hydrogel from Difunctional Polymers Prepared via the Kabachnik-Fields Reaction.

The development of high quality magnetic self-healing hydrogels containing well-dispersed magnetic nanoparticle has been a challenging procedure due to unavailable methods of facilely introducing groups that can efficiently stabilize these magnetic nanoparticles in the self-healing hydrogels. In this research, a polymer containing both phenylboronic acid (PBA) and phosphonic acid (PA) groups has been developed by the Kabachnik-Fields (KF) reaction. This polymer well disperses iron oxide nanoparticles (IONPs) through the strong interactions between the PA groups and the surface of the IONPs; thus, this polymer effectively mixed IONPs and poly(vinyl alcohol) (PVA) to form a hydrogel containing well-dispersed IONPs. The resulting hydrogel is self-healing, owing to the dynamic borate ester linkages. Moreover, the presence of the IONPs endowed the hydrogel with magnetic properties, also making it heat-responsive in an alternating magnetic field and expanding its application as a contrast agent for magnetic resonance imaging. The magnetic self-healing hydrogel showed excellent biosafety properties in animal experiments, suggesting its potential as an injectable implant material for biological and medical applications. This research exploits a biocompatible magnetic self-healing hydrogel with well-dispersed IONPs, demonstrating the value of the KF reaction in the development of functional polymers and smart materials, which might prompt a broad study of multicomponent reactions in interdisciplinary fields.

Local Destruction of Tumors for Systemic Immunoresponse: Engineering Antigen-Capturing Nanoparticles as Stimulus-Responsive Immunoadjuvants.

Immunotherapy has established a new paradigm for cancer treatment and made many breakthroughs in clinical practice. However, the rarity of immune response suggests that additional intervention is necessary. In recent years, it has been reported that local tumor destruction (LTD) can cause cancer cell death and induce an immunologic response. Thus, the combination of immunotherapy and LTD methods will be a promising approach to improve immune efficiency for cancer treatment. Herein, a nanobiotechnology platform to achieve high-precision LTD for systemic cancer immunotherapy has been successfully constructed. Possessing radio-sensitizing and photothermal properties, the engineered immunoadjuvant-loaded nanoplatform, which could precisely induce radiotherapy (RT)/photothermal therapy (PTT) to eliminate local tumor and meanwhile lead to the release of tumor-derived protein antigens (TDPAs), has been facilely fabricated by commercialized SPG membrane emulsification technology. Further on, the TDPAs could be captured and form personal nanovaccines in situ to serve as both reservoirs of antigen and carriers of immunoadjuvant, which can effectively improve the immune response. The investigations suggest that the combination of RT/PTT and improved immunotherapy using adjuvant-encapsulated antigen-capturing nanoparticles holds tremendous promise in cancer treatments.

Metal-phenolic networks: facile assembled complexes for cancer theranostics.

In recent years, metal-phenolic networks (MPNs) have attracted increasing attention for the engineering of multi-functional platforms because of their easy fabrication processes, excellent physicochemical properties, outstanding biocompatibility, and promising theranostic applications. In this review, we summarize recent progress in the design, synthesis, shape-control, biocompatibility evaluation, and potential theranostic applications of MPNs, especially for cancer theranostics. First, we provide an overview of various MPN systems, relevant self-assembly procedures, and shape-controllable preparation. The in vitro and in vivo biocompatibility evaluation of MPNs is also discussed, including co-incubation viability, adhesion, bio-distribution, and inflammation. Finally, we highlight the significant achievements of various MPNs for cancer theranostics, such as tumor imaging, drug delivery, photothermal therapy, radiotherapy, and chemo- and photo-dynamic therapy. This review provides a comprehensive background on the design and controllable synthesis, in vitro and in vivo biocompatibility evaluation, applications of MPNs as cancer theranostic agents, and presents an overview of the most up-to-date achievements in this field.

Biodegradable Flexible Electronic Device with Controlled Drug Release for Cancer Treatment.

Nowadays, controllable drug release is a vitally important strategy for cancer treatment and usually realized using implanting biocompatible devices. However, these devices need to be removed by another surgery after the function fails, which brings the risks of inflammation or potential death. In this article, a biodegradable flexible electronic device with controllable drug (paclitaxel) release was proposed for cancer treatment. The device is powered by an external alternating magnetic field to generate internal resistance heat and promote drug release loaded on the substrate. Moreover, the device temperature can even reach to 65 °C, which was sufficient for controllable drug release. This device also has similar mechanical properties to human tissues and can autonomously degrade due to the structure design of the circuit and degradable compositions. Finally, it is confirmed that the device has a good inhibitory effect on the proliferation of breast cancer cells (MCF-7) and could be completely degraded in vitro. Thus, its great biodegradability and conformity can relieve patients of second operation, and the device proposed in this paper provides a promising solution to complete conquest of cancer in situ.

Three-Dimensional Printing and Injectable Conductive Hydrogels for Tissue Engineering Application.

The goal of tissue engineering scaffolds is to simulate the physiological microenvironment, in which the electrical microenvironment is an important part. Hydrogel is an ideal material for tissue engineering scaffolds because of its soft, porous, water-bearing, and other extracellular matrix-like properties. However, the hydrogel matrix is usually not conductive and can hinder the communication of electrical signals between cells, which promotes researchers' attention to conductive hydrogels. Conductive hydrogels can promote the communication of electrical signals between cells and simulate the physiological microenvironment of electroactive tissues. Hydrogel formation is an important step for the application of hydrogels in tissue engineering. In situ forming of injectable hydrogels and customized forming of three-dimensional (3D) printing hydrogels represent two most potential advanced forming processes, respectively. In this review, we discuss (i) the classification, properties, and advantages of conductive hydrogels, (ii) the latest development of conductive hydrogels applied in myocardial, nerve, and bone tissue engineering, (iii) advanced forming processes, including injectable conductive hydrogels in situ and customized 3D printed conductive hydrogels, (iv) the challenges and opportunities of conductive hydrogels for tissue engineering. Impact Statement Biomimetic construction of electro-microenvironment is a challenge of tissue engineering. The development of conductive hydrogels provides possibility for the construction of biomimetic electro-microenvironment. However, the importance of conductive hydrogels in tissue engineering has not received enough attention so far. Herein, various conductive hydrogels and their tissue engineering applications are systematically reviewed. Two potential methods of conductive hydrogel forming, in situ forming of injectable conductive hydrogels and customized forming of three-dimensional printing conductive hydrogels, are introduced. The current challenges and future development directions of conductive hydrogels are comprehensively overviewed. This review provides a guideline for tissue engineering applications of conductive hydrogels.

Nonmagnetic Hypertonic Saline-Based Implant for Breast Cancer Postsurgical Recurrence Prevention by Magnetic Field/pH-Driven Thermochemotherapy.

Magnetic-mediated hyperthermia (MMT) is emerging as one of the promising techniques, which could synergistically treat cancer along with current treatment techniques such as chemotherapy and radiotherapy and trigger on-demand release of therapeutic macromolecules. However, the low specific absorption rate and potential in vivo toxicity of magnetic nanomaterials as the MMT mediators restrict the new advancements in MMT treatment. Herein, for the first trial, the unique inductive heating property of hypertonic saline (HTS), a clinically applied solution exhibiting several physiological effects under alternative magnetic field (AMF), was systematically investigated. Though without magnetic property, due to the dipolar polarization under the electromagnetic radiation, HTS can induce enough high and rapid temperature increase upon exposure under AMF. Based on such an observation, PEG-based HTS hydrogel was fabricated for the inhibition of unwanted diffusion of ions so as to ensure the ideal temperature rise at the targeted region for a longer time. Furthermore, an anticancer drug (doxorubicin) was also incorporated into the hydrogel to achieve the magnetic field/pH stimuli-responsive drug-sustainable release as well as synergistic thermochemotherapy. The potential application of the drug-loaded HTS-PEG-injectable hydrogel for breast cancer postsurgical recurrence prevention is demonstrated. Significant in vivo suppression of two kinds of breast cancer models was achieved by the hybrid hydrogel system. This work explores a new biomedical use of clinical HTS and a promising cancer treatment protocol based on HTS-PEG hydrogel for magnetic hyperthermia combined with stimuli-responsive chemotherapy for breast cancer postsurgical recurrence prevention.

Magnetic Reactive Oxygen Species Nanoreactor for Switchable Magnetic Resonance Imaging Guided Cancer Therapy Based on pH-Sensitive Fe5C2@Fe3O4 Nanoparticles.

Reactive oxygen species (ROS) are crucial molecules in cancer therapy. Unfortunately, the therapeutic efficiency of ROS is unsatisfactory in clinic, primarily due to their rigorous production conditions. By taking advantage of the intrinsic acidity and overproduction of H2O2 in the tumor environment, we have reported an ROS nanoreactor based on core-shell-structured iron carbide (Fe5C2@Fe3O4) nanoparticles (NPs) through the catalysis of the Fenton reaction. These NPs are able to release ferrous ions in acidic environments to disproportionate H2O2 into •OH radicals, which effectively inhibits the proliferation of tumor cells both in vitro and in vivo. The high magnetization of Fe5C2@Fe3O4 NPs is favorable for both magnetic targeting and T2-weighted magnetic resonance imaging (MRI). Ionization of these NPs simultaneously decreases the T2 signal and enhances the T1 signal in MRI, and this T2/T1 switching process provides the visualization of ferrous ions release and ROS generation for the supervision of tumor curing. These Fe5C2@Fe3O4 NPs show great potential in endogenous environment-excited cancer therapy with high efficiency and tumor specificity and can be guided further by MRI.

Self-Adapting Hydrogel to Improve the Therapeutic Effect in Wound-Healing.

Smart materials that can respond to multistimuli have been broadly studied. However, the smart materials that can spontaneously answer the ever-changing inner environment of living bodies have not been reported. Here, we report a strategy based on the dynamic chemistry to develop possible self-adapting solid materials that can automatically change shape without external stimuli, as organisms do. The self-adapting property of a chitosan-based self-healing hydrogel has been rediscovered since its dynamic Schiff-base network confers the unique mobility to that solid gel. As a result, the hydrogel can move slowly, like an octopus climbing through a narrow channel, only following the natural forces of surface tension and gravity. The fascinating self-adapting feature enables this hydrogel as an excellent drug carrier for the in vivo wound treatment. In a healing process of the rat-liver laceration, this self-adapting hydrogel demonstrated remarkable superiority over traditional drug delivery methods, suggesting the great potential of this self-adapting hydrogel as a promising new material for biomedical applications. We believe the current research revealed a possible strategy to achieve self-adapting materials and may pave the way toward the further development, study, and application of new-generation smart materials.

Effect of nanoheat stimulation mediated by magnetic nanocomposite hydrogel on the osteogenic differentiation of mesenchymal stem cells.

Hyperthermia has been considered as a promising healing treatment in bone regeneration. We designed a tissue engineering hydrogel based on magnetic nanoparticles to explore the characteristics of hyperthermia for osteogenic regeneration. This nanocomposite hydrogel was successfully fabricated by incorporating magnetic Fe3O4 nanoparticles into chitosan/polyethylene glycol (PEG) hydrogel, which showed excellent biocompatibility and were able to easily achieve increasing temperatures under an alternative magnetic field (AMF). With uniformly dispersed nanoparticles, the composite hydrogel resulted in high viability of mesenchymal stem cells (MSCs), and the elevated temperature contributed to the highest osteogenic differentiation ability compared with direct heat treatment applied under equal temperatures. Therefore, the nanoheat stimulation method using the magnetic nanocomposite hydrogel under an AMF may be considered as an alternative candidate in bone tissue engineering regenerative applications.

Enhanced colloidal stability and protein resistance of layered double hydroxide nanoparticles with phosphonic acid-terminated PEG coating for drug delivery.

Conjugating nanoparticles with polyethylene glycol (PEG) is a useful strategy to improve the colloidal and biological stability of nanoparticles. However, studies on PEGylation of two-dimensional layered double hydroxide (LDH) nanoparticles are very limited. The present work reported two functionalization approaches to synthesize PEG-conjugated LDH nanoparticles by introducing phosphonic acid terminated PEG before and after LDH aging. The successful PEGylation was confirmed and suggested to be via electrostatic interaction and a ligand exchange process. Different functionalization approaches resulted in different binding types of PEG on/in LDH nanoparticles. The PEG coating maintained the dispersity of LDH nanoparticles in water and saline with the feeding mass ratio of 1:1. Further colloidal stability tests of PEGylated LDHs revealed that the PEGylated LDH dispersity was affected by the feeding mass ratio of PEG/LDH, the molar weight of PEG and anions intercalated in the LDHs. In a test to determine the extent of non-specific protein adsorption, the PEGylation was effective at resisting non-specific bovine serum albumin adsorption on LDH nanoparticles with both functionalization methods investigated. Moreover, PEGylated LDH nanoparticles had no effect on cell viability up to 500 µg/mL, and demonstrated enhanced cellular uptake in a SK-MEL-28 cell culture. The results in this work indicate that conjugating phosphonic acid-terminated PEG on LDH nanoparticles is a promising strategy to improve the colloidal and biological stability of LDHs for biomedical applications.

Hierarchically aligned fibrin nanofiber hydrogel accelerated axonal regrowth and locomotor function recovery in rat spinal cord injury.

BACKGROUND: Designing novel biomaterials that incorporate or mimic the functions of extracellular matrix to deliver precise regulatory signals for tissue regeneration is the focus of current intensive research efforts in tissue engineering and regenerative medicine. METHODS AND RESULTS: To mimic the natural environment of the spinal cord tissue, a three-dimensional hierarchically aligned fibrin hydrogel (AFG) with oriented topography and soft stiffness has been fabricated by electrospinning and a concurrent molecular self-assembling process. In this study, the AFG was implanted into a rat dorsal hemisected spinal cord injury model to bridge the lesion site. Host cells invaded promptly along the aligned fibrin hydrogels to form aligned tissue cables in the first week, and then were followed by axonal regrowth. At 4 weeks after the surgery, neurofilament (NF)-positive staining fibers were detected near the rostral end as well as the middle site of defect, which aligned along the tissue cables. Abundant NF- and GAP-43-positive staining indicated new axon regrowth in the oriented tissue cables, which penetrated throughout the lesion site in 8 weeks. Additionally, the abundant blood vessels marked with RECA-1 had reconstructed within the lesion site at 4 weeks after surgery. Basso-Beattie-Bresnahan scoring showed that the locomotor performance of the AFG group recovered much faster than that of blank control group or the random fibrin hydrogel (RFG) group from 2 weeks after surgery. Furthermore, diffusion tensor imaging tractography of MRI confirmed the optimal axon fiber reconstruction compared with the RFG and control groups. CONCLUSION: Taken together, our results suggested that the AFG scaffold provided an inductive matrix for accelerating directional host cell invasion, vascular system reconstruction, and axonal regrowth, which could promote and support extensive aligned axonal regrowth and locomotor function recovery.

Increased recruitment of endogenous stem cells and chondrogenic differentiation by a composite scaffold containing bone marrow homing peptide for cartilage regeneration.

Even small cartilage defects could finally degenerate to osteoarthritis if left untreated, owing to the poor self-healing ability of articular cartilage. Stem cell transplantation has been well implemented as a common approach in cartilage tissue engineering but has technical complexity and safety concerns. The stem cell homing-based technique emerged as an alternative promising therapy for cartilage repair to overcome traditional limitations. In this study, we constructed a composite hydrogel scaffold by combining an oriented acellular cartilage matrix (ACM) with a bone marrow homing peptide (BMHP)-functionalized self-assembling peptide (SAP). We hypothesized that increased recruitment of endogenous stem cells by the composite scaffold could enhance cartilage regeneration. Methods: To test our hypothesis, in vitro proliferation, attachment and chondrogenic differentiation of rabbit mesenchymal stem cells (MSCs) were tested to confirm the bioactivities of the functionalized peptide hydrogel. The composite scaffold was then implanted into full-thickness cartilage defects on rabbit knee joints for cartilage repair, in comparison with microfracture or other sample groups. Stem cell recruitment was monitored by dual labeling with CD29 and CD90 under confocal microcopy at 1 week after implantation, followed by chondrogenic differentiation examined by qRT-PCR. Repaired tissue of the cartilage defects was evaluated by histological and immunohistochemistry staining, microcomputed tomography (micro-CT) and magnetic resonance imaging (MRI) at 3 and 6 months post-surgery. Macroscopic and histological scoring was done to evaluate the optimal in vivo repair outcomes of this composite scaffold. Results: The functionalized SAP hydrogels could stimulate rabbit MSC proliferation, attachment and chondrogenic differentiation during in vitro culture. At 7 days after implantation, increased recruitment of MSCs based on CD29+ /CD90+ double-positive cells was found in vivo in the composite hydrogel scaffold, as well as upregulation of cartilage-associated genes (aggrecan, Sox9 and type II collagen). After 3 and 6 months post-surgery, the articular cartilage defect in the composite scaffold-treated group was fully covered with cartilage-like tissue with a smooth surface, which was similar to the surrounding native cartilage, according to the results of histological and immunohistochemistry staining, micro-CT and MRI analysis. Macroscopic and histological scoring confirmed that the quality of cartilage repair was significantly improved with implantation of the composite scaffold at each timepoint, in comparison with microfracture or other sample groups. Conclusion: Our findings demonstrated that the composite scaffold could enhance endogenous stem cell homing and chondrogenic differentiation and significantly improve the therapeutic outcome of chondral defects. The present study provides a promising approach for in vivo cartilage repair without cell transplantation. Optimization of this strategy may offer great potential and benefits for clinical application in the future.

DSC and EPR investigations on effects of cholesterol component on molecular interactions between paclitaxel and phospholipid within lipid bilayer membrane.

Differential scanning calorimetry (DSC) and electron paramagnetic resonance spectroscopy (EPR) were applied to investigate effects of cholesterol component on molecular interactions between paclitaxel, which is one of the best antineoplastic agents found from nature, and dipalmitoylphosphatidylcholine (DPPC) within lipid bilayer vesicles (liposomes), which could also be used as a model cell membrane. DSC analysis showed that incorporation of paclitaxel into the DPPC bilayer causes a reduction in the cooperativity of bilayer phase transition, leading to a looser and more flexible bilayer structure. Including cholesterol component in the DPPC/paclitaxel mixed bilayer can facilitate the molecular interaction between paclitaxel and lipid and make the tertiary system more stable. EPR analysis demonstrated that both of paclitaxel and cholesterol have fluidization effect on the DPPC bilayer membranes although cholesterol has more significant effect than paclitaxel does. The reduction kinetics of nitroxides by ascorbic acid showed that paclitaxel can inhibit the reaction by blocking the diffusion of either the ascorbic acid or nitroxide molecules since the reaction is tested to be a first order one. Cholesterol can remarkably increase the reduction reaction speed. This research may provide useful information for optimizing liposomal formulation of the drug as well as for understanding the pharmacology of paclitaxel.

Effects of cholesterol component on molecular interactions between paclitaxel and phospholipid within the lipid monolayer at the air-water interface.

Cholesterol is a main component of the cell membrane and could have significant effects on drug-cell membrane interactions and thus the therapeutic efficacy of the drug. It also plays an important role in liposomal formulation of drugs for controlled and targeted delivery. In this research, Langmuir film technique, atomic force microscopy (AFM) and Fourier transform infrared spectroscopy (FTIR) are employed for a systematic investigation on the effects of cholesterol component on the molecular interactions between a prototype antineoplastic drug (paclitaxel) and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC) within the cell membrane by using the lipid monolayer at the air-water interface as a model of the lipid bilayer membrane and the biological cell membrane. Analysis of the measured surface pressure (pi) versus molecular area (a) isotherms of the mixed DPPC/paclitaxel/cholesterol monolayers at various molar ratios shows that DPPC, paclitaxel and cholesterol can form a non-ideal miscible system at the air-water interface. Cholesterol enhances the intermolecular forces between paclitaxel and DPPC, produces an area-condensing effect and thus makes the mixed monolayer more stable. Investigation of paclitaxel penetration into the mixed DPPC/cholesterol monolayer shows that the existence of cholesterol in the DPPC monolayer can considerably restrict the drug penetration into the monolayer, which may have clinical significance for diseases of high cholesterol. FTIR and AFM investigation on the mixed monolayer deposited on solid surface confirmed the obtained results.