Carrier-Free, Pure Nanodrug Formed by the Self-Assembly of an Anticancer Drug for Cancer Immune Therapy.

Ursolic acid (UA) is a food-plant-derived natural product which has good anticancer activities and low toxicity. However, the poor water solubility of UA limits its application in clinic. To address this issue, we developed a carrier-free nanodrug by self-assembly of UA. Here, we showed that UA nanoparticles (NPs) have a near-spherical shape with a diameter of ∼150 nm. UA NPs exhibited higher antiproliferative activity; significantly caused apoptosis; decreased the expression of COX-2/VEGFR2/VEGFA; and increased the immunostimulatory activity of TNF-α, IL-6, and IFN-ß and decreased the activity of STAT-3 in A549 cells in vitro. Furthermore, UA NPs could inhibit tumor growth and have the ability of liver protection in vivo. More importantly, UA NPs could significantly improve the activation of CD4+ T-cells, which indicated that UA NPs have the potential for immunotherapy. Overall, a carrier-free UA nanodrug may be a promising drug to further enhance their anticancer efficacy and immune function.

A self-assembly nanodrug delivery system based on amphiphilic low generations of PAMAM dendrimers-ursolic acid conjugate modified by lactobionic acid for HCC targeting therapy.

Ursolic acid (UA), a natural triterpene acid, is a promising anti-cancer drug due to its inhibitory effect on tumor growth and metastasis. However, clinical translation of UA is limited by its poor water solubility and low bioavailability. To overcome these problems, herein an amphiphilic self-assembly nanodrug composed of UA, lactobionic acid (LA) and low-polyamidoamine (low-PAMAM) dendrimers is developed. This near-spherical nanodrug with a uniform size (~180 nm) demonstrated to have an enhanced cytotoxicity against liver cancer SMMC7721 cells, and could attenuate the migration and adhesion of SMMC7721 cells at non-toxic concentrations by suppressing metastasis-related protein MMP-9 expression. Furthermore, in vivo study indicates that the nanodrug exhibited prolonged circulation time in blood as well as increased AUC, MRT and Cmax, and could effectively inhibit the tumor growth in H22 mice model. Overall, the UA-based nanodrug delivery system reported in the present work represents a novel strategy for targeted tumor therapy.

Validation and Application of an Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry Method for Yuanhuacine Determination in Rat Plasma after Pulmonary Administration: Pharmacokinetic Evaluation of a New Drug Delivery System.

Yuanhuacine was found to have significant inhibitory activity against A-549 human lung cancer cells. However, there would be serious adverse toxicity effects after systemic administration of yuanhuacine, such as by oral and intravenous ways. In order to achieve better curative effect and to alleviate the adverse toxicity effects, we tried to deliver yuanhuacine directly into the lungs. Ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was used to detect the analyte and IS. After extraction (ether:dichloromethane = 8:1), the analyte and IS were separated on a Waters BEH-C18 column (100 mm × 2.1 mm, 1.7 µm) under a 5 min gradient elution using a mixture of acetonitrile and 0.1% formic acid aqueous solution as mobile phase at a flow rate of 0.3 mL/min. ESI positive mode was chosen for detection. The method was fully validated for its selectivity, accuracy, precision, stability, matrix effect, and extraction recovery. This new method for yuanhuacine concentration determination in rat plasma was reliable and could be applied for its preclinical and clinical monitoring purpose.

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.

Co-delivery of sorafenib and siVEGF based on mesoporous silica nanoparticles for ASGPR mediated targeted HCC therapy.

Combination with chemotherapeutic drug and gene therapy has been proven highly effective in suppressing tumor progression. Hence, an asialoglycoprotein receptor (ASGPR)-targeting nanodrug delivery system based on mesoporous silica (MSN) nanocarrier for co-delivery of sorafenib (SO) and vascular endothelial growth factor (VEGF) targeted siRNA (siVEGF) to hepatocellular carcinoma (HCC) was successfully designed and synthesized. The structure of nanoparticles was characterized by IR, particle size, zeta potential and N2 adsorption-desorption. The nanoparticles were further evaluated for drug release, cellular uptake, transfection, cell cytotoxicity and cell cycle against HepG2 and Huh7 cells. In vitro testing demonstrated that MSN-LA delivery system could not only induce S cell cycle arrest, enhance the cytotoxicity and improve the tumor target of SO and siVEGF, but also enhance the siVEGF transfection efficiency in ASGPR-overexpressing Huh7 cells. Overall, the MSN-LA delivery system can be a promising drug carrier which could further enhance the anti-cancer efficacy of SO and siVEGF via the active targeting property of LA.

Carrier-free nanodrug by co-assembly of chemotherapeutic agent and photosensitizer for cancer imaging and chemo-photo combination therapy.

Nanosized drug delivery systems (NDDS) with photothermal therapy (PTT) and photodynamic therapy (PDT) have been extensively exploited to improve the therapeutic performance and bio-safety of chemotherapeutic drugs in cancer. In this work, a carrier-free nanodrug was developed by co-assembly of the anti-cancer agent ursolic acid (UA), an asialoglycoprotein receptor (ASGPR), which can recognize the target molecule lactobionic acid (LA), and the near-infrared (NIR) probe dye indocyanine green (ICG) to form UA-LA-ICG NPs by a simple and green self-assembly approach. The UA-LA-ICG NPs had suitable stability, showed controlled release profile of UA drugs, and exhibited preferable temperature response (∼59.4 °C) under laser irradiation (808 nm, 1 W/cm2). Compared with free ICG, the UA-LA-ICG NPs significantly enhanced the intracellular ICG uptake. Upon irradiation of the NIR laser, co-assembled nanodrugs demonstrated great performance as a reactive oxygen species (ROS) producer and exhibited more anti-proliferative activities on ASGPR-overexpressing HepG2 cells than ASGPR low-expressing HeLa cells. Meanwhile, in vivo NIR fluorescence imaging exhibited that the co-assembled nanodrugs were specifically targeted to the tumor by the active targeting property of LA, and its circulation time was much longer than that of free ICG. In addition, UA-LA-ICG NPs + NIR irradiation treatment displayed enhanced inhibitory effect on tumor growth in H22 tumor-bearing mice. Overall, the co-assembly of chemotherapeutic agent and photosensitizer by the self-assembly approach might open an alternative avenue and give inspiration to fabricate new carrier-free nanodrugs for cancer imaging and chemo-photo combination therapy. STATEMENT OF SIGNIFICANCE: The present study for the first time reported carrier-free nanoparticles (NPs) by co-assembly of a natural product ursolic acid (UA), an asialoglycoprotein receptor (ASGPR)-recognized sugar molecule lactobionic acid (LA), and the near-infrared dye indocyanine green (ICG) through a simple and green approach. The preparation process of nanodrugs is simple, rapid, effective, and labor-saving. The co-assembled nanodrugs were capable of stabilizing the ICG molecules and specifically targeting to the tumor, which could increase the tumor accumulation in cancer imaging and also enhance the efficacy of chemo-phototherapy.

Synergistic Chemopreventive and Therapeutic Effects of Co-drug UA-Met: Implication in Tumor Metastasis.

The anticancer properties of ursolic acid (UA) and metformin (Met) have been well demonstrated. However, whether these compounds can act synergistically to prevent and treat cancer is not known. We present in this study, the synergism between UA and Met, and that of a new codrug made of UA and Met (UA-Met) against several cancer cell lines. The combination of high concentration of UA (25, 50, 75, 100 µM) and Met (5, 10, 20, 40 mM) resulted in synergetic cytotoxicity on MDA-MB-231 and MCF-7 cells (CI < 0.8). Molecular and cellular studies showed that codrug UA-Met significantly inhibited the invasion (∼55.3 ± 2.74%) and migration (∼52.4 ± 1.57%) of TGF-ß induced breast cancer MDA-MB-231 and MCF-7 cells in vitro at low concentration of 10 µM. These effects were accompanied by down-regulation of CXCR4, uPA, vimentin, E-cadherin, N-cadherin, and MMP-2/9 proteins expression and regulation of the AMPK/m-TOR signaling pathways as expected from UA and Met. Moreover, UA-Met could reduce the progression of pulmonary metastasis by 4T1 cells (63.4 ± 3.52%) without influencing the glucose blood level in mice. Our study suggests that the codrug UA-Met is safe and effective in preventing cancer metastasis and possibly treatment of cancer.

A Small Molecule Nanodrug by Self-Assembly of Dual Anticancer Drugs and Photosensitizer for Synergistic near-Infrared Cancer Theranostics.

Phototherapy including photodynamic therapy (PDT) and photothermal therapy (PTT) has attracted great attention. However, applications of some photosensitizers remain an obstacle by their poor photostability. To enhance the treatment efficiency of photosensitizers and tumor theranostic effect, herein, we reported a novel carrier-free, theranostic nanodrug by self-assembly of small molecule dual anticancer drugs and photosensitizer for tumor targeting. The developed carrier-free small molecule nanodrug delivery system was formed by hydrophobic ursolic acid, paclitaxel, and amphipathic indocyanine green (ICG) associated with electrostatic, π-π stacking, and hydrophobic interactions exhibiting water stability. The self-assembling of ICG on the dual anticancer nanodrug significantly enhanced water solubility of hydrophobic anticancer drugs and ICG photostability contributing to long-term near-infrared (NIR) fluorescence imaging and effective chemophototherapy of tumor. The in vivo NIR fluorescence imaging showed that the theranostic nanodrug could be targeted to the tumor site via a potential enhanced permeability and retention effect proving the efficient accumulation of nanoparticles in the tumor site. Dramatically, chemophototherapy of tumor-bearing mice in vivo almost completely suppressed tumor growth and no tumor recurrence was observed. Encouraged by its carrier-free, prominent imaging and effective therapy, the small molecule nanodrug via self-assembly will provide a promising strategy for synergistic cancer theranostics.

A carrier-free dual-drug nanodelivery system functionalized with aptamer specific targeting HER2-overexpressing cancer cells.

Exploration of a green carrier to avoid potential systemic toxicity and the unclear metabolic mechanism of traditional nanocarriers is of high importance for cancer therapy. Hence, we developed a carrier-free nanosystem for co-delivery of dual anti-cancer drugs ursolic acid (UA) and doxorubicin (DOX) using a "green" and simple method. The co-assembled nanodrug was further modified with a HER2 aptamer by electrostatic interactions. The co-assembled dual nanodrug presented a spherical morphology with a uniform size (∼108.9 nm) and in a pH-triggered drug release manner. It made UA sensitize DOX to display synergistic anticancer effects at a low dose of DOX. Further, the aptamer surface decoration improved the intracellular drug retention of UA and DOX to as much as 2-fold in HER2 overexpressing cancer cells. In addition, the in vivo results further proved that the co-assembled nanodrug could significantly inhibit the tumor growth with a little side effects. In a word, this novel carrier-free dual-drug nanodelivery system could be a potential drug candidate for HER2 overexpressing cancer therapy, and UA could be used as a "green" nanocarrier for delivery of hydrophobic drugs and fluorescent dyes in cancer treatment and diagnosis.

Metapristone suppresses non-small cell lung cancer proliferation and metastasis via modulating RAS/RAF/MEK/MAPK signaling pathway.

BACKGROUND: Metastasis is the key phase of cancer progression that characterizes a more advanced stage and a poorer prognosis. The majority of cancer fatalities occur as a consequence of metastasis. OBJECTIVE: Mifepristone (RU486), a chemical abortifacient, has recently been used in clinical trials for psychotic depression and cancer chemotherapy. As the most predominant biological active metabolite of mifepristone, metapristone is being developed as a novel cancer metastasis chemopreventive agent by us. However, there is no information available to address the effects of metapristone on non-small cell lung cancer (NSCLC). The aim of our study was to investigate the inhibitory effect of metapristone on the proliferation and metastasis of NSCLC cells. METHOD: In the present study, we evaluated the efficacy of metapristone on the growth, migration and invasion in different kinds of NSCLC cells (A549, H1975 and H1299), and further investigated the underlying mechanism of metapristone by real time PCR and western blot assay. RESULTS: Metapristone could significantly inhibit the proliferation, migration and invasion of NSCLC cells through suppressing RAS/RAF/MEK/MAPK and PI3K/AKT signaling pathways. Moreover, metapristone could effectively inhibit the formation of NSCLC cells' cytoskeleton in a concentration-dependent manner, which possibly led to the inhibition of NSCLC cells' migration. CONCLUSION: Overall, it was preliminarily demonstrated that metapristone could be developed as a useful agent to show anti-metastasis activity for NSCLC.