Xuan Zhu

Chemotherapeutic drug-photothermal agent co-self-assembling nanoparticles for near-infrared fluorescence and photoacoustic dual-modal imaging-guided chemo-photothermal synergistic therapy

ABSTRACT Multimodal imaging‐guided synergistic combination therapy has shown great potential for cancer treatment. However, the nanocarrier‐based theranostic systems suffer from batch‐to‐batch variation, complexity of multicomponent, poor drug loading, and carrier‐related toxicity issues. To address these issues, herein we developed a novel carrier‐free theranostic system with nanoscale characteristics for near‐infrared fluorescence (NIRF) and photoacoustic (PA) dual‐modal imaging‐guided synergistic chemo‐photothermal therapy (PTT). Indocyanine green (ICG) and epirubicin (EPI) could co‐self‐assemble into small molecular nanoparticles (NPs) in aqueous solution without any molecular precursor or excipient via collaborative interactions (electrostatic, &pgr;–&pgr; stacking, and hydrophobic interactions). The exceptionally high dual‐drug loading (˜ 92 wt%) ICG‐EPI NPs showed good physiological stability, preferable photothermal response, excellent NIRF/PA imaging properties, pH‐/photo‐responsive drug release behavior, and promoted cellular endocytosis compared with free ICG or EPI. Importantly, the ICG‐EPI NPs showed excellent tumor targeting ability with high spatial resolution and deep penetration via in vivo NIRF/PA dual‐modal imaging. Moreover, in comparison with individual chemotherapy or PTT, the combinational chemo‐PTT therapy of ICG‐EPI NPs with NIR laser irradiation synergistically induced apoptosis and death of cancer cells in vitro, and showed synergistic chemo‐PTT efficiency in vivo as evidenced by highly efficient tumor ablation. Furthermore, the ICG‐EPI NPs exhibited inappreciable toxicity. This co‐self‐assembly of both FDA‐approved agents provides a safe and “Molecular economical” strategy in the rational design of multifunctional nano‐theranostic systems for real‐time self‐monitoring intracellular drug delivery and targeting multimodal imaging‐guided synergistic combination therapy.

Pharmacokinetics, tissue distribution and excretion study of dl-praeruptorin A of Peucedanum praeruptorum in rats by liquid chromatography tandem mass spectrometry

dl-Praeruptorin A (Pd-Ia), isolated from Chinese traditional herbal medicine Peucedanum praeruptorum Dunn, has been proved to be a novel Ca²+-influx blocker and K+-channel opener, and displayed bright prospects in prevention and therapy of cardiac diseases. The aim of this study was to investigate the pharmacokinetics, tissue distribution and excretion of Pd-Ia in rats following a single intravenous (i.v.) administration. The levels of Pd-Ia in plasma, tissues, bile, urine and feces were measured by a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The results showed that Pd-Ia was rapidly distributed and then eliminated from rat plasma and manifested linear dynamics in dose range of 5-20 mg/kg. The mean elimination half-life (t(½) of Pd-Ia for 5, 10 and 20 mg/kg dose were 57.46, 60.87 and 59.01 min, respectively. The major distribution tissues of Pd-Ia in rats were spleen, heart and lung, and low polarity enabled Pd-Ia to cross the blood-brain barrier. There was no long-term accumulation of Pd-Ia in rat tissues. Total recoveries of Pd-Ia within 24 h were low (0.097% in bile, 0.120% in urine and 0.009% in feces), which might be resulted from liver first pass effect.

Light/magnetic hyperthermia triggered drug released from multi-functional thermo-sensitive magnetoliposomes for precise cancer synergetic theranostics

ABSTRACT 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. Graphical abstract Figure. No Caption available.

Self-assembly of multifunctional integrated nanoparticles loaded with a methotrexate–phospholipid complex: combining simplicity and efficacy in both targeting and anticancer effects

Recently, the global trend in the field of nanomedicine has been toward the design of highly sophisticated drug delivery systems with active targeting and therapeutic functions, as well as responsiveness to biological stimuli for improving therapeutic efficacy. But offering sophistication generally increases their complexity that might be disadvantageous in pharmaceutical development. In this paper, we hypothesize that using a clinical anticancer drug methotrexate (MTX) as both a targeting ligand and a therapeutic agent to interact with natural product phospholipid (PC) and thus self-assemble will lead to an efficient but simple and flexible, moreover, multifunctional integrated system. The methotrexate (MTX)–phospholipid (PC) complex is prepared by a co-solvent method and can be self-assembled into nanoparticles (MTX–PC NPs), which significantly increases the drug-loading ability and reduces the burst drug release compared with free MTX and MTX-loaded liposomes. The MTX–PC complex and its self-assembled MTX–PC NPs were evaluated by UV, TGA, DSC, XRD, FTIR, 1H-NMR, SEM, TEM, AFM, and in an in vitro drug release study. The MTX-PC NPs had a particle size of 152.5 ± 3.2 nm, a narrow size distribution, a high drug-loading efficiency of 20.7 ± 2.4%, and a controlled and sustained release behavior. The in vitro cellular uptake results showed that a vital advantage of this system is that MTX-PC NPs with pH-triggered drug release can exert an early-phase good active targeting efficiency (attributed to the surface-absorbed MTX) cooperating with a late-phase excellent anticancer efficiency (was attributed to the core-dispersed MTX). The concept of the self-targeted anticancer effect based on drug–lipid hybrid systems might be a promising candidate for cancer therapy compared with traditional drug delivery systems.

Dual-acting, function-responsive, and high drug payload nanospheres for combining simplicity and efficacy in both self-targeted multi-drug co-delivery and synergistic anticancer effect.

Recently, the global trend in the field of nanomedicine has been toward the design of highly sophisticated drug delivery systems with specific targeting and synergistic therapeutic functions for improving therapeutic efficacy. But offering sophistication generally increases their complexity that might be disadvantageous in pharmaceutical development. We hypothesize that using a macromolecular prodrug with a dual role will be conductive to integrating its dual function into self-targeted multidrug co-delivery and combination cancer therapy. In this paper, the on-off switching function-responsive, macromolecular methotrexate (MTX) prodrug-self-targeted, controlled-/sustained-release, and high drug-loading hydroxylcamptothecin (HCPT) drug nanospheres were prepared and characterized. The self-targeting system can co-deliver multi-drug to different action sites with distinct anticancer mechanisms to specifically target folate receptors-overexpressing cancer cells with synergistic therapeutic efficiency.

Novel Core-Interlayer-Shell DOX/ZnPc Co-loaded MSNs@ pH-Sensitive CaP@PEGylated Liposome for Enhanced Synergetic Chemo-Photodynamic Therapy

PurposeThis work was intended to develop novel doxorubicin (DOX)/zinc (II) phthalocyanine (ZnPc) co-loaded mesoporous silica (MSNs)@ calcium phosphate (CaP)@PEGylated liposome nanoparticles (NPs) that could efficiently achieve collaborative anticancer therapy by the combination of photodynamic therapy (PDT) and chemotherapy. The interlayer of CaP could be utilized to achieve pH-triggered controllable drug release, promote the cellular uptake, and induce cell apoptosis to further enhance the anticancer effects.MethodsMSNs were first synthesized as core particles in which the pores were diffusion-filled with DOX, then the cores were coated by CaP followed by the liposome encapsulation with ZnPc to form the final DOX/ZnPc co-loaded MSNs@CaP@PEGylated liposome.ResultsA core-interlayer-shell MSNs@CaP@PEGylated liposomes was developed as a multifunctional theranostic nanoplatform. In vitro experiment indicated that CaP could not only achieve pH-triggered controllable drug release, promote the cellular uptake of the NPs, but also generate high osmotic pressure in the endo/lysosomes to induce cell apoptosis. Besides, the chemotherapy using DOX and PDT effect was achieved by the photosensitizer ZnPc. Furthermore, the MSNs@CaP@PEGylated liposomes showed outstanding tumor-targeting ability by enhanced permeability and retention (EPR) effect.ConclusionsThe novel prepared MSNs@CaP@PEGylated liposomes could serve as a promising multifunctional theranostic nanoplatform in anticancer treatment by synergic chemo-PDT and superior tumor-targeting ability.

Zinc phthalocyanine-soybean phospholipid complex based drug carrier for switchable photoacoustic/fluorescence image, multiphase photothermal/photodynamic treatment and synergetic therapy

ABSTRACT For the purpose of precision theranostic of tumor, multifunctional drug delivery systems are always receiving great attentions. Here, we developed a zinc phthalocyanine‐soybean phospholipid (ZnPc‐SPC) complex based drug delivery system with doxorubicin (Dox) as loading cargo to achieve additional chemotherapy while the carrier itself could serve as multifunctional and switchable theranostic agent. In the early phase, the ZnPc‐SPC complex assembled to nanostructure displaying photothermal therapy (PTT) and photoacoustic (PA) properties while in the late phase, the prepared NPs dis‐assembled into ZnPc‐SPC complex again performing photodynamic therapy (PDT) and low‐background fluorescence (FL) image. With the decoration of folate receptors &agr; (FR&agr;) targeted MTX, Dox‐loaded, MTX‐decorated self‐assembled ZnPc‐SPC complex NPs (DZSM) was formed. In vitro and in vivo evaluations both indicated that DZSM presented high selectivity for FR&agr; over‐expressed tumor cells, excellent switchable PA/FL image, significant multiphase PTT/PDT effect, as well as great synergetic therapy potential, leading to notable inhibition of tumor growth. Graphical abstract Schematic illustration of the early phase PA image and PTT effect at assemble state and late phase FL image and PDT effect at dis‐assemble state. Figure. No caption available.

Novel theranostic zinc phthalocyanine–phospholipid complex self-assembled nanoparticles for imaging-guided targeted photodynamic treatment with controllable ROS production and shape-assisted enhanced cellular uptake

The novel drug delivery system based on self-assembly of zinc phthalocyanine-soybean phosphatidylcholine (ZnPc-SPC) complex was developed by a co-solvent method followed by a nanoprecipitaion technique. DSPE-PEG-methotrexate (DSPE-PEG-MTX) was introduced on the surface of ZnPc-SPC self-assembled nanoparticles (ZS) to endow them with folate receptor-targeting property. NMR, XRD, FTIR, and UV-vis-NIR analysis demonstrated the weak molecular interaction between ZnPc and SPC. The ZS functionalized with DSPE-PEG-MTX (ZSPM) was successfully constructed with an average particle size of ∼170nm, a narrow size distribution, and could remain physiologically stable for at least 7days. In vitro cellular uptake and cytotoxicity studies demonstrated that ZSPM exhibited stronger cellular uptake efficacy and photodynamic cytotoxicity against HeLa and MCF-7 cells than ZS functionalized with DSPE-mPEG (ZSP) and free ZnPc. More importantly, ZSPM showed the enhanced accumulation effect at the tumor region compared with ZSP by the active-plus-passive targeting via enhanced permeability and retention (EPR) effect and folate receptor-mediated endocytosis. Furthermore, in vivo antitumor effect and histological analysis demonstrated the superior tumor growth inhibition effect of ZSPM. In addition, the needle-shape ZSP (ZSPN) exhibited better in vitro cellular uptake and in vivo tumor accumulation compared with ZSP due to the shape-assisted effect. Moreover, the interesting off-on switch effect of reactive oxygen species (ROS) production of ZnPc-SPC complex-based nanoparticles was discovered to achieve photodynamic treatment in a controllable way. These findings suggested that the ZnPc-SPC complex-based self-assembled nanoparticles could serve as a promising and effective formulation to achieve tumor-targeting fluorescence imaging and enhanced photodynamic treatment.

Theranostic micelles combined with multiple strategies to effectively overcome multidrug resistance

AIM To develop precise targeting and versatile Fe3O4@SiO2-P123/PTX-ZnPc nanoparticles (FSP-PTX-ZnPc NPs) to reverse paclitaxel (PTX)-induced multidrug resistance in breast cancer. MATERIALS & METHODS PTX and zinc (II) phthalocyanine (ZnPc) co-loaded FSP-PTX-ZnPc NPs were designed. The resulting multifunctional NPs were evaluated systematically in vitro and in vivo, and the mechanism of drug-resistance reversal was investigated. RESULTS The NPs enhanced drug uptake in MCF-7/PDR cells by increasing drug solubility and impairing P-glycoprotein efflux. Additionally, magnetic targeting and enhanced permeation and retention (EPR) effect enhanced drug accumulation in tumor, facilitating the chemotherapeutic and photodynamic therapy effects. Moreover, FSP-PTX-ZnPc NPs could penetrate the blood-brain barrier, a desirable trait for brain disease therapy. CONCLUSION The multifunctional FSP-PTX-ZnPc NPs are an effective tool for overcoming drug resistance in breast cancer.

Steroidal Saponins from Vernonia amygdalina Del. and Their Biological Activity

In the present study, four new steroidal saponins, namely vernoniamyoside A–D (1–4), together with the two known steroidal saponins vernoamyoside D (5) and vernonioside B2 (6) were isolated from the ethanol extract of leaves of the African medicinal plant Vernonia amygdalina Del. (Asteraceae). Their structures were demonstrated by spectral analyses along with 1D and 2D nuclear magnetic resonance (NMR) techniques and mass spectrometry (MS). The cytotoxicity of the compounds was also tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method on the cell lines Hela, MCF-7, BT-549 and MDA-MB-231. Vernoniamyoside A, vernoniamyoside B, and vernonioside B2 showed cytotoxicity towards BT-549 cell lines. Vernoniamyoside C, vernoniamyoside D and vernoamyoside D showed different levels of cytotoxic activities.