A multifunctional theranostics nanosystem featuring self-assembly of alcohol-abuse drug and photosensitizers for synergistic cancer therapy.

Conventional treatments for cancer, such as chemotherapy, surgical resection, and radiotherapy, have shown limited therapeutic efficacy, with severe side effects, lack of targeting and drug resistance for monotherapies, which limit their clinical application. Therefore, combinatorial strategies have been widely investigated in the battle against cancer. Herein, we fabricated a dual-targeted nanoscale drug delivery system based on EpCAM aptamer- and lactic acid-modified low-polyamidoamine dendrimers to co-deliver the FDA-approved agent disulfiram and photosensitizer indocyanine green, combining the imaging and therapeutic functions in a single platform. The multifunctional nanoparticles with uniform size had high drug-loading payload, sustained release, as well as excellent photothermal conversion. The integrated nanoplatform showed a superior synergistic effect in vitro and possessed precise spatial delivery to HepG2 cells with the dual-targeting nanocarrier. Intriguingly, a robust anticancer response of chemo-phototherapy was achieved; chemotherapy combined with the efficacy of phototherapy to cause cellular apoptosis of HepG2 cells (>35%) and inhibit the regrowth of damaged cells. Furthermore, the theranostic nanosystem displayed fluorescence imaging in vivo, attributed to its splendid accumulation in the tumor site, and it provided exceptional tumor inhibition rate against liver cancer cells (>76%). Overall, our research presents a promising multifunctional theranostic nanoplatform for the development of synergistic therapeutics for tumors in further applications.

Platelet membrane-cloaked selenium/ginsenoside Rb1 nanosystem as biomimetic reactor for atherosclerosis therapy.

Cardiovascular disease remains the dominant contributor to human mortality, and the main etiology of which is atherosclerosis (AS). Enhancing the targeted ability of nanosystem and improving plaque stability are critical challenges for the current management of AS. Herein, we leverage the marked role of platelets in AS to construct a biomimetic nanodrug delivery system (PM@Se/Rb1 NPs), which prepared by cloaking platelet membrane (PM) around Selenium (Se) and ginsenoside Rb1 nanoparticles (Se/Rb1 NPs) core. The core endows the delivery system antioxidant, lipid metabolism and anti-inflammatory effects for AS effective treatment. Moreover, PM-coated nanoparticles reserve platelets' inherent biological elements to deliver drugs to plaques. We further explored the potential effect of PM@Se/Rb1 NPs' combination with the clinical anticoagulant drug warfarin (War) to treat AS and elucidated the possible drug interaction mechanism. As a result, the PM@Se/Rb1 NPs are not only capable of improving inflammatory behaviors such as inhibitory adhesion ability and anti-angiogenesis therapeutic effect in vitro, but also administer efficiently localizing to atherosclerotic plaque explaining by aortic samples from established ApoE-/- mice. Therefore, this study provided a theoretical basis of biomimetic nanodrug in the treatment of AS as well as an effective reference for the combined application of nanodrug and clinical drugs.

Biomimetic polyphenol-coated nanoparticles by Co-assembly of mTOR inhibitor and photosensitizer for synergistic chemo-photothermal therapy.

Rapamycin (RAPA) functions as effectively clinical immunosuppressive agent, its significant tumor growth suppression effect via various pathways in diverse cancers, especially combined with photothermal therapy, is gaining a burgeoning attention. However, its critical defects, low solubility and poor stability, have severely hampered its further application. Herein, RAPA, indocyanine green (ICG) and epigallocatechin gallate (EGCG) serving as chemotherapeutic drug, photosensitizer and biomimetic coatings, respectively, were co-assembled into carrier-free, high biocompatible ICG-RAPA-EGCG nanoparticles (IRE NPs) for synergistic cancer therapy. Particularly, the bioinspired EGCG coatings not only improved the stability of IRE NPs under physiological conditions to avert NPs disassembly and drug release, but also maintained the photostability of ICG to achieve excellent photothermal response. The results indicated that the as-prepared IRE NPs displayed good monodispersity and enhanced stability at various stored media after introducing of EGCG. Compared with monotherapy of RAPA or ICG, IRE NPs showed higher dose-dependent toxicity in MCF-7 cells, HepG2 cells and HeLa cells, especially plus near-infrared laser irradiation. Furthermore, IRE NPs exhibited quicker uptake in cells, higher accumulation in tumor region (even in 48 h) than free ICG and effectively inhibited tumor growth without side effect in H22 tumor-bearing mice. Collectively, the carrier-free IRE NPs provided a simply alternative approach to fabricate RAPA/photosensitizer co-loaded nanoparticles for combinatorial tumor therapy.

Biomimetic nanoparticles: U937 cell membranes based core-shell nanosystems for targeted atherosclerosis therapy.

Atherosclerosis (AS), with its intricate pathogenesis, is primarily responsible for the development and progression of cardiovascular diseases. Although drug development has made some achievements in AS therapy, limited targeting ability and rapid blood clearance remain great challenges for achieving superior clinical outcomes. Herein, ginsenoside (Re)- and catalase (CAT)-coloaded porous poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs) were prepared and then surface modified with U937 cell membranes (UCMs) to yield a dual targeted model and multimechanism treatment biomimetic nanosystem (Cat/Re@PLGA@UCM). The nanoparticles consisted of a core-shell spherical morphology with a favorable size of 112.7 ± 0.4 nm. Furthermore, UCM assisted the nanosystem in escaping macrophage phagocytosis and targeting atherosclerotic plaques. Meanwhile, loading with catalase might not only exhibit favorable antioxidant effects but also enable H2O2-responsive drug release ability. The Cat/Re@PLGA@UCM NPs also exhibited outstanding ROS scavenging properties, downregulating ICAM-1, TNF-α and IL-1ß, while preventing angiogenesis to attenuate the progression of AS. Moreover, the nanodrugs displayed 2.7-fold greater efficiency in reducing the atherosclerotic area in ApoE-/- mouse models compared to free Re. Our nanoformulation also displayed excellent biosafety in response to long-term administration. Overall, our study demonstrated the superiority of UCM-coated stimuli-responsive nanodrugs for effective and safe AS therapy.

Accelerating transdermal delivery of insulin by ginsenoside nanoparticles with unique permeability.

Diabetes is a metabolic disease caused by insufficient insulin secretion, action or resistance, in which insulin plays an irreplaceable role in the its treatment. However, traditional administration of insulin requires continuous subcutaneous injections, which is accompanied by inevitable pain, local tissue necrosis and hypoglycemia. Herein, a green and safe nanoformulation with unique permeability composed of insulin and ginsenosides is developed for transdermal delivery to reduce above-mentioned side effects. The ginsenosides are self-assembled to form shells to protect insulin from hydrolysis and improve the stability of nanoparticles. The nanoparticles can temporarily permeate into cells in 5 min and promptly excrete from the cell for deeper penetration. The insulin permeation is related to the disorder of stratum corneum lipids caused by ginsenosides. The skin acting as drug depot mantains the nanoparticles released continuously, therefore the body keeps euglycemic for 48 h. Encouraged by its long-lasting and effective transdermal therapy, ginsenosides-based nano-system is expected to deliver other less permeable drugs like proteins and peptides and benefit those who are with chronic diseases that need long-term medication.

A smart dual-drug nanosystem based on co-assembly of plant and food-derived natural products for synergistic HCC immunotherapy.

Nanotechnology has emerged as an ideal approach for achieving the efficient chemo agent delivery. However, the potential toxicity and unclear internal metabolism of most nano-carriers was still a major obstacle for the clinical application. Herein, a novel "core‒shell" co-assembly carrier-free nanosystem was constructed based on natural sources of ursolic acid (UA) and polyphenol (EGCG) with the EpCAM-aptamer modification for hepatocellular carcinoma (HCC) synergistic treatment. As the nature products derived from food-plant, UA and EGCG had good anticancer activities and low toxicity. With the simple and "green" method, the nanodrugs had the advantages of good stability, pH-responsive and strong penetration of tumor tissues, which was expected to increase tumor cellular uptake, long circulation and effectively avoid the potential defects of traditional carriers. The nanocomplex exhibited the low cytotoxicity in the normal cells in vitro, good biosafety of organic tissues and efficient tumor accumulation in vivo. Importantly, UA combined with EGCG showed the immunotherapy by activating the innate immunity and acquired immunity resulting in significant synergistic therapeutic effect. The research could provide new ideas for the research and development of self-assembly delivery system in the future, and offer effective intervention strategies for clinical HCC treatment.

A study to evaluate herb-drug interaction underlying mechanisms: An investigation of ginsenosides attenuating the effect of warfarin on cardiovascular diseases.

Warfarin and ginseng have been widely used in the treatment of cardiovascular diseases. However, the clinical safety and effectiveness of herb-drug combination treatment are still controversial. Therefore, it is very essential to probe the interaction between warfarin and ginseng. In this study, in vitro and in vivo study was carried out to demonstrate that whether there is an interaction between warfarin and ginsenosides (GS), which is the main component of ginseng. In vitro study showed that the adhesion ability between endothelial cells and matrigel/platelets was enhanced due to the up-regulating expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) proteins by treatment of warfarin+GS combination compared to warfarin/GS treatment alone. Moreover, GS could weaken the anticoagulation effect of warfarin in hyperlipemia rats owning to the increased expression levels of coagulation factors and hepatic cytochrome P450 enzymes in plasma after long-term co-administration of warfarin with GS. The results of both in vitro and in vivo study demonstrated that there is a serious interaction between warfarin and ginseng, which may deteriorate atherosclerosis and thrombosis after combined use of warfarin and GS.

Carrier-free nanodrugs for in vivo NIR bioimaging and chemo-photothermal synergistic therapy.

The combination of chemotherapy and photothermal therapy displays improved anti-cancer effects and lower systematic toxicity of a free drug compared with monotherapy. In this study, we designed innovative, carrier-free nanodrugs (PTX/ICG NDs) composed of the chemotherapeutic agent paclitaxel (PTX) and the photosensitizer indocyanine green (ICG) via self-assembly. The nanodrugs not only incorporated two different modalities into one delivery system for combined chemo-photothermal therapy but also enhanced the solubility of PTX without the need for any carrier. The as-prepared PTX/ICG NDs exhibited the merits of a relatively uniform size of 140 ± 1.4 nm, surface charge of -36 ± 2.2 mV, and high drug loading content of PTX. The combination strategy exerted a synergistic effect on the cytotoxicity of cancer cells in vitro, which could be attributed to the high cellular uptake and sustained release of PTX. Furthermore, an in vivo study indicated that PTX/ICG NDs showed higher accumulation in the tumor site than free ICG and possessed strong synergistic chemo-photothermal therapy efficacy against tumors in H22 tumor-bearing mice. Taken together, our study demonstrates that PTX/ICG NDs hold promise to become an alternative chemo-photothermal therapy agent to treat cancers.

Ursolic Acid in Cancer Treatment and Metastatic Chemoprevention: From Synthesized Derivatives to Nanoformulations in Preclinical Studies.

BACKGROUND: Cancer metastasis has emerged as a major public health threat that causes majority of cancer fatalities. Traditional chemotherapeutics have been effective in the past but suffer from low therapeutic efficiency and harmful side-effects. Recently, it has been reported ursolic acid (UA), one of the naturally abundant pentacyclic triterpenes, possesses a wide range of biological activities including anti-inflammatory, anti-atherosclerotic, and anti-cancer properties. More importantly, UA has the features of low toxicity, liver protection and the potential of anti-cancer metastasis. OBJECTIVE: This article aimed at reviewing the great potential of UA used as a candidate drug in the field of cancer therapy relating to suppression of tumor initiation, progression and metastasis. METHODS: Selective searches were conducted in Pubmed, Google Scholar and Web of Science using the keywords and subheadings from database inception to December 2017. Systemic reviews are summarized here. RESULTS: UA has exhibited chemopreventive and therapeutic effects of cancer mainly through inducing apoptosis, inhibiting cell proliferation, preventing tumor angiogenesis and metastatic. UA nanoformulations could enhance the solubility and bioavailability of UA as well as exhibit better inhibitory effect on tumor growth and metastasis. CONCLUSION: The information presented in this article can provide useful references for further studies on making UA a promising anti-cancer drug, especially as a prophylactic metastatic agent for clinical applications.

Small Molecule Nanodrug Assembled of Dual-Anticancer Drug Conjugate for Synergetic Cancer Metastasis Therapy.

The nanocarrier-based delivery system has emerged as a promising candidate for cancer therapy; nevertheless, their quality problems, variation between batches, and carrier-related toxicity issues have restricted their clinical utilization. Compared with traditional carrier-based nanoparticles, carrier-free nanodrug delivery systems preferred to overcome all these drawbacks and will have a wide range of applications in biomedicine and nanotechnology. Herein, we developed a novel carrier-free nanodrug Asp-UA consisted of the classical drug aspirin and the natural plant drug UA via a green and simple approach. The Asp-UA NPs were investigated for shape, particle size, zeta potential, stability, and UV-vis spectroscopy absorption. Cellular uptake study showed that Asp-UA NPs could be easily internalized by HepG2 cells; cellular study demonstrated that Asp-UA NPs held better inhibitory efficiency on tumor metastasis with low toxicity in vitro and in vivo. Moreover, Asp-UA NPs could obviously suppress the progress of cancer metastasis by H22 cells in vivo. Overall, Asp-UA NPs possess a variety of advantages and hold promise to become an alternative to the treatment of cancer metastasis.