Xi Xie

pH-sensitive micelles based on acid-labile pluronic F68–curcumin conjugates for improved tumor intracellular drug delivery

Curcumin (Cur) is a highly pleiotropic anticancer agent that inhibits cell proliferation and induces apoptosis in cancer cells. A variety of nano-systems constituted by polymer-drug conjugates have been designed to overcome its shortages on water solubility, chemical instability, and poor bioavailability. However, most of them suffer from ineffective release of Cur in cancer cells in vivo. This work developed a novel flexible acid-responsive micelle formulation by covalently conjugating Cur on the hydrophilic terminals of pluronic F68 chains via cis-aconitic anhydride linkers. The synthesized F68-Cis-Cur conjugates can readily precipitate to form homogeneous micelles with average size about 100 nm in aqueous solution. In acid environments, F68-Cis-Cur conjugates would break down and subsequently release Cur rapidly, for the reason of pH-sensitive cleavage of cis-aconitic anhydride linkers. In vitro anticancer activity tests demonstrated that F68-Cis-Cur micelles induced higher cytotoxicity against both A2780 and SMMC 7721 cells than free Cur. It provided a larger decrease of mitochondrion membrane potential and induced cellular apoptosis. F68-Cis-Cur micelles remarkably increased cellular uptake of Cur than free Cur through caveolae-mediated endocytosis in an energy-dependent manner. This study demonstrates F68-Cis-Cur conjugation as a promising tool for improving intracellular drug delivery in cancer therapy.

Niosome Encapsulation of Curcumin

Curcumin, a natural chemical compound found in Curcuma longa, has been applied in multiple medicinal areas from antibiotic to antitumor treatment. However, the chemical structure of curcumin results in poor stability, low solubility, and rapid degradation in vivo, hindering its clinical utilization. To address these issues, we have developed a novel niosome system composed of nonionic surfactants: Span 80, Tween 80, and Poloxamer 188. Curcumin was encapsulated in the niosomes with a high entrapment efficiency of 92.3±0.4%. This system provided controlled release of curcumin, thereby improving its therapeutic capability. Dynamic dialysis was conducted to evaluate the in vitro drug release of curcumin-niosomes. Curcumin-niosomes exhibited enhanced cytotoxic activity and apoptotic rate against ovarian cancer A2780 cells compared with freely dispersed curcumin. These results demonstrate that the curcumin-niosome system is a promising strategy for the delivery of curcumin and ovarian cancer therapy.

pH-sensitive polymeric nanoparticles for co-delivery of doxorubicin and curcumin to treat cancer via enhanced pro-apoptotic and anti-angiogenic activities

Co-delivery of multiple drugs with complementary anticancer mechanisms by nano-carriers offers an effective strategy to treat cancer. The combination of drugs with pro-apoptotic and anti-angiogenic activities is potentially effective in treating human hepatocellular carcinoma (HCC). Herein, we developed a co-delivery system for doxorubicin (Dox), a pro-apoptotic drug, and curcumin (Cur), a potent drug for antiangiogenesis, in pH-sensitive nanoparticles (NPs) constituted with amphiphilic poly(β-amino ester) copolymer. Dox & Cur co-loaded NPs ((D+C)/NPs) were prepared with optimized drug ratio, showing low polydispersity, high encapsulation efficiency, and enhanced release in the acidic environment of cancer cells. Furthermore, enhanced cellular internalization of cargoes delivered from (D+C)/NPs were observed in human liver cancer SMMC 7721 cells and human umbilical vein endothelial cells (HUVECs) compared to the use of free drugs. The (D+C)/NPs induced a high rate of apoptosis in SMMC 7721 cells through decreased mitochondrial membrane potential. Additionally, (D+C)/NPs exhibited stronger anti-angiogenic effects including inhibition of HUVEC proliferation, migration, invasion, and tube formation mediated VEGF pathway modulation in vitro and in vivo. Taken together, encapsulation of the pro-apoptotic drug Dox and antiangiogenic agent Cur in pH-sensitive NPs provides a promising strategy to effectively inhibit HCC progression in a synergistic manner. STATEMENT OF SIGNIFICANCE The combination of multiple drugs has been demonstrated to be more effective than single treatment. However, the different physicochemical and pharmacokinetic profiles of each drug render optimal delivery challenging. In view of the great delivery advantage of nanocarriers to unify the multiple drugs in vivo, stimulus-responsive nano-carriers are more crucial to increase efficacy and reduce toxicity from off-target exposure. Therefore, herein the pH-sensitive nanoparticles, composed by d-α-tocopheryl polyethylene glycol 1000-block-poly (β-amino ester) (TPGS-PAE) polymers, have been fabricated for doxorubicin (Dox) and curcumin (Cur) co-delivery, which exhibited diverse anticancer approaches, i.e. pro-apoptosis and antiangiogenesis. The precise intracellular target site and effective drug combination concentration result in the enhanced antitumor efficiency and the reduced systematic toxicity of Dox. The co-encapsulation of the pro-apoptotic drug and antiangiogenic agent in pH-sensitive NPs provides a promising strategy to effectively inhibit malignant neoplasm progression in a synergistic manner.

Analgesic Microneedle Patch for Neuropathic Pain Therapy

Neuropathic pain caused by nerve injury is debilitating and difficult to treat. Current systemic pharmacological therapeutics for neuropathic pain produce limited pain relief and have undesirable side effects, while current local anesthetics tend to nonspecifically block both sensory and motor functions. Calcitonin gene related peptide (CGRP), a neuropeptide released from sensory nerve endings, appears to play a significant role in chronic neuropathic pain. In this study, an analgesic microneedle (AMN) patch was developed using dissolvable microneedles to transdermally deliver selective CGRP antagonist peptide in a painless manner for the treatment of localized neuropathic pain. Local analgesic effects were evaluated in rats by testing behavioral pain sensitivity in response to thermal and mechanical stimuli using neuropathic pain models such as spared-nerve injury and diabetic neuropathy pain, as well as neurogenic inflammatory pain model induced by ultraviolet B (UVB) radiation. Unlike several conventional therapies, the AMN patches produced effective analgesia on neuropathic pain without disturbing the normal nociception and motor function of the rat, resulting from the high specificity of the delivered peptide against CGRP receptors. The AMN patches did not cause skin irritation or systemic side effects. These results demonstrate that dissolvable microneedle patches delivering CGRP antagonist peptide provide an effective, safe, and simple approach to mitigate neuropathic pain with significant advantages over current treatments.

Redox-sensitive Pluronic F127-tocopherol micelles: synthesis, characterization, and cytotoxicity evaluation

Pluronic F127 (F127), an amphiphilic triblock copolymer, has been shown to have significant potential for drug delivery, as it is able to incorporate hydrophobic drugs and self-assemble into nanosize micelles. However, it suffers from dissociation upon dilution owing to the relatively high critical micelle concentration and lack of stimuli-responsive behavior. Here, we synthesized the α-tocopherol (TOC) modified F127 polymer (F127-SS-TOC) via a redox-sensitive disulfide bond between F127 and TOC, which formed stable micelles at relatively low critical micelle concentration and was sensitive to the intracellular redox environment. The particle size and zeta potential of the F127-SS-TOC micelles were 51.87±6.39 nm and -8.43±2.27 mV, respectively, and little changes in both particle size and zeta potential were observed within 7 days at room temperature. With 10 mM dithiothreitol stimulation, the F127-SS-TOC micelles rapidly dissociated followed by a significant change in size, which demonstrated a high reduction sensitivity of the micelles. In addition, the micelles showed a high hemocompatibility even at a high micelle concentration (1,000 μg/mL). Low cytotoxicity of the F127-SS-TOC micelles at concentrations ranging from 12.5 μg/mL to 200 μg/mL was also found on both Bel 7402 and L02 cells. Overall, our results demonstrated F127-SS-TOC micelles as a stable and safe aqueous formulation with a considerable potential for drug delivery.

Cleavable Multifunctional Targeting Mixed Micelles with Sequential pH-Triggered TAT Peptide Activation for Improved Antihepatocellular Carcinoma Efficacy

Although tumor-targeting nanovehicles for hepatocellular carcinoma (HCC) chemotherapy have attracted great research and clinic interest, the poor cancer penetration, inefficient cellular uptake, and slow intracellular drug release greatly compromise their therapeutic outcomes. In this work, a multifunctional mixed micellar system, consisting of glycyrrhetinic acid (GA) for specific liver-targeting, trans-activator of transcription (TAT) peptide for potent cell penetration, and pH-sensitive poly(β-amino ester) polymers for acidic-triggered drug release, was developed to provide HCC-targeting delivery and pH-triggered release of doxorubicin (DOX). These micelles were hypothesized to efficaciously accumulate in HCC site by the guide of GA ligands, enter into cancer cells facilitated by the activated TAT peptide on the micellar surface, and finally rapidly release DOX in cytoplasm. To demonstrate this design, DOX was initially loaded in micelles modified with both GA and TAT (DOX/GA@TAT-M) with high drug loading efficiency and pH-sensitive drug release profiles. The HCC-targeting cellular uptake and synergetic anticancer efficacy were tested, indicating DOX/GA@TAT-M could be specifically and effectively internalized into HCC cells by the effect of GA targeting and TAT penetrating with enhanced cytotoxicity. In addition, the prolonged circulation time and enhanced accumulation in tumor facilitated its potent tumor growth inhibition activity in vivo. These results demonstrated that the cleavable multifunctional mixed micelles with tumor targeting, controlled TAT peptide activation, and sequential pH-sensitive drug release could be an efficient strategy for HCC treatment.

Physical activation of innate immunity by spiky particles

Microbial biochemicals have been indicated as the primary stimulators of innate immunity, the first line of the body’s defence against infections. However, the influence of topological features on a microbe’s surface on immune responses remains largely unknown. Here we demonstrate the ability of TiO2 microparticles decorated with nanospikes (spiky particles) to activate and amplify the immune response in vitro and in vivo. The nanospikes exert mechanical stress on the cells, which results in potassium efflux and inflammasome activation in macrophages and dendritic cells during phagocytosis. The spiky particles augment antigen-specific humoral and cellular immune responses in the presence of monophosphoryl lipid A and elicit protective immunity against tumour growth and influenza viral infection. The study offers insights into how surface physical cues can tune the activation of innate immunity and provides a basis for engineering particles with increased immunogenicity and adjuvanticity.Spikes on the surface of TiO2 microparticles, mimicking the nanotopological structures found on pathogens, boost the immune response in animal models and can be used to enhance the immunogenic effect of vaccines and adjuvants.

iRGD-mediated reduction-responsive DSPE–PEG/LA–PLGA–TPGS mixed micelles used in the targeted delivery and triggered release of docetaxel in cancer

Reduction-sensitive micelles with crosslinked cores were developed to load the lipophilic chemotherapeutic drug docetaxel (DTX) in order to overcome the issues of toxicity, water insolubility, and rapid metabolism of DTX. These DTX-loaded micelles (MM(DTX/Crosslink)) provide efficient incorporation and sustained release of DTX. Using independently synthesized LA–PLGA–TPGS and DSPE–PEG polymers as vehicles, MM(DTX/Crosslink) was found to be reduction-responsive, and possessed desirable drug entrapment efficiency (84.17 ± 1.15%) and drug loading efficiency (6.21 ± 0.07%). The MM(DTX/Crosslink) quickly dissociated under reduction conditions that mimicked the reductive intracellular environment, suggesting that it can rapidly release the encapsulated DTX in vitro. Furthermore, to target MM(DTX/Crosslink) to tumors for cancer therapy, iRGD was conjugated to the surface of MM(DTX/Crosslink). The iRGD-MM(DTX/Crosslink) micelles significantly increased the cellular uptake of DTX and inhibited cell proliferation, compared to the micelles without iRGD modification. Moreover, the iRGD-MM(DTX/Crosslink) micelles presented enhanced antitumor effects based on the analyses of apoptosis and cell cycle arrest. The micelles developed in this work may constitute a stable, efficient, and powerful system to deliver DTX into cancer cells.

Nanospikes-mediated Anomalous Dispersities of Hydropobic Micro-objects and their Application for Oil Emulsion Cleaning

Many fields of applications require dispersion of hydrophobic particles in water, which is traditionally achieved by using surfactants or amphiphilic molecules to modify particle surfaces. However, surfactants or amphiphilic molecules may disturb the native solution or particles’ surface hydrophobicity, limiting extended applications such as oil emulsion cleaning. Recently one example of 2 μm-size polystyrene microparticles covered with ZnO nanospikes has been shown to exhibit excellent dispersity in water in spite of surface hydrophobicity. Whether this anomalous dispersion phenomenon was applicable to other hydrophobic microparticle systems was still unclear and its application scope was limited. Here the anomalous dispersities of different hydrophobic spiky micro-objects were systematically explored. The results show that the anomalous dispersion phenomenon was universally observed on different hydrophobic spiky micro-objects including different hydrophobic coating, particle sizes, material compositions and core particle morphologies. In addition, the spiky micro-objects displayed anomalous dispersity in water without compromising surface hydrophobicity, and their applications for oil spills absorption and oil emulsion cleaning were demonstrated. This work offers unique insight on the nanospikes-mediated anomalous dispersion phenomenon of hydrophobic micro-object and potentially extends its applicability and application scopes.

Nanospikes functionalization as a universal strategy to disperse hydrophilic particles in non-polar media

Dispersion of hydrophilic particles in non-polar media has many important applications yet remains difficult. Surfactant or amphiphilic functionalization was conventionally applied to disperse particles but is highly dependent on the particle/solvent system and may induce unfavorable effects and impact particle hydrophilic nature. Recently 2 μm size polystyrene microbeads coated with ZnO nanospikes have been reported to display anomalous dispersity in phobic media without using surfactant or amphiphilic functionalization. However, due to the lack of understanding whether this phenomenon was applicable to a wider range of conditions, little application has been derived from it. Here the anomalous dispersity phenomenons of hydrophilic microparticles covered with nanospikes were systematically assessed at various conditions including different particle sizes, material compositions, particle morphologies, solvent hydrophobicities, and surface polar groups. Microparticles were functionalized with nanospikes through hydrothermal route, followed by dispersity test in hydrophobic media. The results suggest nanospikes consistently prevent particle aggregation in various particle or solvent conditions, indicating the universal applicability of the anomalous dispersion phenomenons. This work provides insight on the anomalous dispersity of hydrophilic particles in various systems and offers potential application to use this method for surfactant-free dispersions.