Platinum (IV) drugs with cannabidiol inducing mitochondrial dysfunction and synergistically enhancing anti-tumor effects.

Chemotherapy resistance is an insurmountable problem in clinical anticancer therapy. Although Oxaliplatin is an effective chemotherapeutic agent for the treatment of colorectal cancer (CRC), it still suffers from serious toxicities as well as drug resistance. In this work, three Oxaliplatin tetravalent platinum prodrugs(O1-O3) and three novel mixed ammine/amine analogs(C1-C3) were constructed, introducing cannabidiol with anti-tumor activity in their axial position. All Pt(IV) prodrugs exhibited potent antitumor effects in a variety of tumor cell lines, especially in HCT-116 cells, where complex O3 showed strong inhibitory effects with the half maximal inhibitory concentrations (IC50) value of 6.02 ± 0.69 µM and about 2.6 times higher than that of Oxaliplatin. Further studies revealed that complex O3 decreased cellular mitochondrial membrane potential in a concentration-dependent manner and enhanced reactive oxygen species (ROS) accumulation by decreasing the expression of catalase, superoxide dismutase 2 (SOD2) and superoxide dismutase 3 (SOD3). Complex O3 induces mitochondrial dysfunction and upregulates the pro-apoptotic protein Noxa, ultimately leading to severe DNA damage. The upregulation of Phosphorylated histone protein H2AX (γ-H2AX) expression is clear evidence. In addition, O3 inhibits the expression of RAD51 protein and prevents DNA damage repair, thus overcoming drug resistance. This strategy of combining bioactive molecules cannabidiol with platinum drugs to improve therapeutic efficacy and overcome drug resistance has been proven to be very effective and deserves further investigation.

A Series of Planar Phosphorescent Cyclometalated Platinum(II) Complexes as New Anticancer Theranostic Agents That Induce Oncosis.

Herein, four planar cyclometalated platinum(II) complexes with a main ligand of enlarged aromatic rings have been assessed as effective anticancer theranostic agents for the first time. With an increased number of aromatic rings in the N∧N ligand, 1a-1d exhibit increased lipophilicity and cytotoxicity selectivity. The intensity of the Pt-Pt interaction of each complex can be indicated by an enhanced near-infrared (NIR) emission in phosphate-buffered saline (PBS), their binding activity with biomolecules of bovine serum albumin (BSA) is accompanied by a vivid turn-on green emission, and the intensity gradually decreased from 1a to 1d, which is consistent with the docking of two complexes with BSA. Both "turn-on" NIR and green emission of 1d can be mainly observed in nuclei of living cell within 24 h, while two phosphorescence traces of 1b were recorded in lysosomes by confocal imaging. Moreover, 1d shows the highest efficiency in inducing oncosis of Hela cells, and the relative process was investigated.

Supramolecular fluorescent probe based on acyclic cucurbituril for detection of cancer Labels in human urine.

Spermine (Spm) and spermidine (Spmd) are considered as potential biomarker for early diagnosis of human cancer. Herein, a novel acyclic cucurbituril derivative (UL-ACB) was firstly designed and synthesized, which fluoresces at 460 nm after excitation at 365 nm. UL-ACB is rich in oxygen atoms which are capable of forming coordinate bonds with copper (Cu2+) that cause quenching of UL-ACB fluorescence. Moreover, the addition of biological endogenous substances Spm and Spmd can turn on fluorescence of UL-ACB. Interestingly, the probe showed a remarkable detection efficiency for Spm and Spmd in human urine (the detection limits of Spm and Spmd were 0.156 µM and 0.762 µM, and the linear ranges are 0.156 âˆ¼ 43.06 µM and 0.762 âˆ¼ 29.10 µM), which completely covered the early diagnosis of urinary Spm (1 âˆ¼ 10 µM) and urine Spmd (1 âˆ¼ 20 µM) required concentration range in cancer patients. The probe for Spm and Spmd is simple, time-saving and selective, which may provide a new promising strategy for early cancer diagnosis.

Anion-selective "Turn-on" two color phosphorescent probes based on "Pd-Pd" interaction of a series of cyclometallated Palladium (II) complexes induced by a self-assembly in aqueous solution.

Herein, three pairs of cationic cyclometallated palladium (II) complexes with different types of C^N ligands, which is non-phosphorescent in aqueous solution, interestingly, they can be utilized as turn-on blue phosphorescent probes selectively for ClO-, HSO3- and CO32-, and turn-on green phosphorescent probe for HSO3- in aqueous solution. These different phosphorescent turn-on responses of Pd(II) complexes could be attributed to the degree of coordination and electrostatic interaction between them with specific anion. It suggests that the selectivity towards specific anion of these cyclometallated Pd(II) complexes can be further improved by rationally tuning the structure and enhancing aromaticity of C^N ligand. Our study reveals that these specific species of anions can effectively induce self-assembly of Pd(II) compounds with different C^N ligand based on PdPd interaction, the aggregation and morphology of palladium complex with anion in aqueous media was also investigated by various means of 1H NMR, UV/Vis, fluorescence spectra, and dynamic light scattering (DLS) analysis. Moreover, transmission electron microscopy (TEM) reveals that nanowires with increased length of diameters of Pd complexes can form in aqueous solution in presence of anions with different high concentration. Furthermore, the cellular uptake and location of Pd2a was also investigated by confocal imaging for the first time. DFT calculation of monomer and dimer of Pd2a was also performed, which is helpful to explain the turn on phosphorescent effect during self-assembly process.

Functional supramolecular micelles driven by the amphiphilic complex of biotin-acyclic cucurbituril and cannabidiol for cell-targeted drug delivery.

Precise delivery of hydrophobic drugs has always been a great challenge for drug delivery systems. To overcome this problem, we designed and synthesized a novel supramolecular host biotin-acyclic cucurbituril (ACBB) at the first time, and we have developed a host-guest amphiphilic complex based on ACBB and amantadine-conjugated cannabinoids (AD-CBD) that self-assembles to form functionalized supramolecular micelles (FSMs) for cell-targeted drug delivery. The 1:1 stoichiometric ratio of the amphiphilic complex and its possible host-guest inclusion behaviors are obtained by fluorescence titration, nuclear magnetic resonance (NMR), Fourier transform-infrared spectroscopy (FT-IR) and thermal analysis (TGA and DSC). Using transmission electron microscope (TEM) and dynamic light scattering (DLS), we have observed that the shape of FSMs was spherical and size was 137-192 nm. In addition, MTT test results show that FSMs have good antitumor activity, taking MCF-7 as an example, the in vitro half-maximal inhibitory concentration (IC50) values of FSMs were 1.53 µM and 5.02 µM, which were better than 30.83 µM of cisplatin. Confocal laser scanning microscopy (CLSM) results showed that FSMs loaded with Rhodamine B can specifically aggregate on the surface of tumor cells and the targeting ability has been directly verified. Flow cytometry results showed that FSMs could promote tumor cell apoptosis. All results indicated that FSMs had high bioavailability, stability, accurate targeting and excellent delivery efficiency, which had great application potential in the field of drug delivery.

Self-Assembly System Based on Cyclodextrin for Targeted Delivery of Cannabidiol.

Cannabidiol (CBD) is one specific kind of the cannabinoid in Cannabis sativa L with a wide range of pharmacological activities. However, the poor water solubility and specificity of CBD limits its application in pharmaceutical field. For solving these problems, in this work, we successfully prepared a targeted carrier by grafting biotin (BIO) onto ethylenediamine-ß-Cyclodextrin (EN-CD) in a single step to generate a functionalized supramolecule, named BIO-CD. Subsequently, an amantadine-conjugated cannabinoids (AD-CBD) was prepared and self-assembled with the BIO-CD. A series of methods were used to characterize the inclusion behavior and physicochemical properties of AD-CBD and BIO-CD. The results showed that AD-CBD entered the cavity of BIO-CD and formed a 1:1 host-guest inclusion complex. MTT assay and confocal laser scanning microscopy (CLSM) revealed that the targeting effect and anticancer activity of AD-CBD/BIO-CD inclusion complex against three human cancer cell lines were higher than BIO-CD, AD-CBD and free CBD. Moreover, the inclusion complex could release drugs under weakly acidic conditions. These results demonstrated that AD-CBD/BIO-CD inclusion complex possess excellent targeted and anticancer activity, which is hopeful to be applied in clinic as a new therapeutic approach.

Codelivery of satraplatin and aminopyrrolic receptor with Pluronic F127-based polyaniline nanoparticles with NIR induced release for combined chemotherapy.

The acquired drug resistance of the platinum-based drug is a main obstacle in cancer therapy. Herein, an aminopyrrolic receptor 1 was synthesized to sensitize satraplatin for overcoming the drug resistance as well as improving tumor targeted ability. Thus, Pluronic F127-based polyaniline nanoparticles were designed to co-deliver satraplatin and aminopyrrolic receptor 1, which could control the drug release with the Near Infrared laser irradiation (808 nm) due to the polyaniline mediated photothermal conversion. Biological evaluation shows prepared nanoparticles (Pt-ARNPs) exhibited more effective cytotoxicity (IC50 = 2.7µM) against the tested cancer cell lines under laser irradiation, compared with free satraplatin or treatment without Near-infrared radiation. Moreover, Pt-ARNPs showed comparable cytotoxicity against A549 and A549/cis cells, implying that the combination of satraplatin and aminopyrrolic receptor 1 with nano carrier might be a promising strategy to reduce platinum resistance and improve therapeutic effect in cancer therapy.

Reversing the cytotoxicity of uric acid by supramolecular encapsulation with acyclic cucurbit[n]uril.

Supramolecular encapsulation, which removes harmful substances from organisms, has evolved into a new strategy. In this paper, three supramolecular complexes of acyclic cucurbit[n]urils (ACBs) with uric acid (UA) were prepared, and the inclusion behavior of ACBs and UA was studied by fluorescence spectroscopy, UV-vis spectroscopy and nuclear magnetic resonance. Furthermore, the effect of the complexes of UA with ACBs on the expression of inflammatory biomarkers in human hepatoma HepG2 cell lines was characterized through C-reactive protein (CRP) western blot. The results showed UA molecules can be recognized by three ACBs with different binding constants, and ACBs successfully blocked the inflammatory stimulation of UA on HepG2 cell lines and inhibited the expression of the major inflammatory factor CRP by the formation of complexes between UA and ACBs. This article proves that ACBs can efficiently reverse the cytotoxicity of UA, which provides a new method for treating hyperuricemia disease.

Targeting drug delivery system for platinum(â £)-Based antitumor complexes.

Classical platinum(II) anticancer agents are widely-used chemotherapeutic drugs in the clinic against a range of cancers. However, severe systemic toxicity and drug resistance have become the main obstacles which limit their application and effectiveness. Because divalent cisplatin analogues are easily destroyed in vivo, their bioavailability is low and no selective to tumor tissues. The platinum(IV) prodrugs are attractive compounds for cancer treatment because they have great advantages, e.g., higher stability in biological media, aqueous solubility and no cross-resistance with cisplatin, which may become the next generation of platinum anticancer drugs. In addition, platinum(IV) drugs could be taken orally, which could be more acceptable to cancer patients, breaking the current situation that platinum(II) drugs can only be given by injection. The coupling of platinum(IV) complexes with tumor targeting groups avoids the disadvantages such as instability in blood, irreversible binding to plasma proteins, rapid renal clearance, and non-specific distribution in normal tissues. Because of the above advantages, the combination of platinum complexes and tumor targeting groups has become the hottest field in the research and development of new platinum drugs. These approaches can be roughly categorized into two groups: active and passive targeted strategies. This review concentrates on various targeting and delivery strategies for platinum(IV) complexes to improve the efficacy and reduce the side effects of platinum-based anticancer drugs. We have made a summary of the related articles on platinum(IV) targeted delivery in recent years. We believe the results of the studies described in this review will provide new ideas and strategies for the development of platinum drugs.

Inclusion complexes between chrysin and amino-appended ß-cyclodextrins (ACDs): Binding behavior, water solubility, in vitro antioxidant activity and cytotoxicity.

Solid inclusion complexes between chrysin and four amino-appended ß-cyclodextrins (ACDs) were prepared by suspension method and characterized in solid and solution states by kinds of analytical methods. The scanning electron microscopy (SEM) showed distinct micro-morphologies of them. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis revealed their unique thermal properties, such as decomposition temperatures and endothermic points. Powder X-ray diffractometry (XRD) analysis disclosed their unique crystal patterns. Their nuclear magnetic resonance (NMR) analyses provided the variations of chemical shifts before and after the formation of inclusion complexes. Their binding stability constants (Ks) were 574, 842, 704, and 474 L·mol-1, respectively, as determined by spectral titration. A 1:1 inclusion mode with self-assembly of their amino side chains inside the ACD cavity was proposed based on Job plot and 2D-ROESY experiments. Water solubility of chrysin was promoted up to 4411.98 µg·mL-1 after formation of inclusion complexes with ACDs, better than that of ß-CD and its derivatives, i.e., HP- and SBE-ß-CD. In vitro antioxidant activity of chrysin was also improved after inclusion complexation by the DPPH scavenging assay. Furthermore, in vitro cytotoxicity of solid inclusion complexes towards three human cancer cell lines, A549, HT-29 and HCT116 were enhanced significantly.

Cyclodextrin-based delivery systems for cancer treatment.

Cyclodextrins, one of safe excipients, are able to form host-guest complexes with fitted molecules given the unique nature imparted by their structure in result of a number of pharmaceutical applications. On the other hand, targeted or responsive materials are appealing therapeutic platforms for the development of next-generation precision medications. Meanwhile, cyclodextrin-based polymers or assemblies can condense DNA and RNA in result to be used as genetic therapeutic agents. Armed with a better understanding of various pharmaceutical mechanisms, especially for cancer treatment, researchers have made lots of works about cyclodextrin-based drug delivery systems in materials chemistry and pharmaceutical science. This Review highlights recent advances in cyclodextrin-based delivery systems for cancer treatment capable of targeting or responding to the physiological environment. Key design principles, challenges and future directions, including clinical translation, of cyclodextrin-based delivery systems are also discussed.

Acid-controlled release complexes of podophyllotoxin and etoposide with acyclic cucurbit[n]urils for low cytotoxicity.

The targeted or responsive systems are appealing therapeutic platforms for the development of next-generation precision medications. So, we design and prepare acid-controlled release complexes of podophyllotoxin (POD) and etoposide (VP-16) with pH-labile acyclic cucurbit[n]urils, and their characteristics and inclusion complexation behaviors were investigated via fluorescence spectroscopy, nuclear magnetic resonance and X-ray power diffraction. Cells incubated with complexes have been analyzed by high-content analysis (HCA), and cytotoxicity tests have been completed by MTT assay. The results showed that complexes with different binding constants can release the drug substance in the physiological pH environment of cancer cells, maintain good anticancer activity, and have low cytotoxicity. This provides a strategy about targeted and responsive systems of POD and VP-16 for clinical application.

Preparation and characterization of a novel host-guest complex based on folate-modified ß-cyclodextrin and artesunate.

The purpose of this study was to develop a novel folate-modified host-guest complex to enhance antitumor activity of the artesunate and improve the solubility and stability by encapsulated in ß-cyclodextrin and linked with folate. In this work, we designed and prepared the inclusion complex of adamantanamine conjugated artesunate (AD-ATS) with folic acid-ethylenediamine-ß-cyclodextrin (FA-EN-ß-CD). This material was characterized by 1D and 2D NMR, XRD, TG and SEM. The results suggested that AD-ATS was encapsulated within the FA-EN-ß-CD cavity to form host-guest inclusion complex, and the water solubility of AD-ATS was improved in the form of inclusion complex with FA-EN-ß-CD. The assessment of antitumor activity showed that cytotoxicity of AD-ATS/FA-EN-ß-CD complex was significantly enhanced in comparison to free AD-ATS, ATS/ß-CD inclusion complex and ATS/FA-EN-ß-CD inclusion complex.

Research progress in modern structure of platinum complexes.

Since the antitumor activity of cisplatin was discovered in 1967 by Rosenberg, platinum-based anticancer drugs have played an important role in chemotherapy in clinic. Nevertheless, platinum anticancer drugs also have caused severe side effects and cross drug resistance which limited their applications. Therefore, a significant amount of efforts have been devoted to developing new platinum-based anticancer agents with equal or higher antitumor activity but lower toxicity. Until now, a large number of platinum-based complexes have been prepared and extensively investigated in vitro and in vivo. Among them, some platinum-based complexes revealing excellent anticancer activity showed the potential to be developed as novel type of anticancer agents. In this account, we present such platinum-based anticancer complexes which owning various types of ligands, such as, amine carrier ligands, leaving groups, reactive molecule, steric hindrance groups, non-covalently binding platinum (II) complexes, Platinum(IV) complexes and polynuclear platinum complexes. Overall, platinum-based anticancer complexes reported recently years upon modern structure are emphasized.

Total Synthesis of (-)-Vindorosine.

Outlined herein is a novel and scalable synthesis of (-)-vindorosine based on two key transformations. A highly diastereoselective vinylogous Mannich addition of dioxinone-derived lithium dienolates with indolyl N-tert-butanesulfinyl imines has been developed. In addition, an intramolecular Heathcock/aza-Prins cyclization was introduced to construct both the C, and the highly substituted E rings for the synthesis of (-)-vindorosine and related alkaloids.

Highly Oxygenated Grayanane Diterpenoids from Flowers of Pieris japonica and Structure-Activity Relationships of Antifeedant Activity against Pieris brassicae.

Six new highly oxygenated grayanane diterpenoids, neopierisoids G-L, 1-6, together with 10 known related compounds, 7-16, were identified from the flowers of the poisonous plant Pieris japonica. The structures were elucidated on the basis of comprehensive NMR spectroscopy and mass analysis. The relative configurations of 1-6 were elucidated by analysis of ROESY spectra and comparison of NMR data with the analogues. The absolute configurations of 1-6 were established by the X-ray diffraction analysis of 1 and comparison of the CD spectra of 1-6. Compared with the skeleton of the normal grayanane diterpenoids, compounds 1-6 shared an unusual seco A ring moiety. The antifeedant activities of compounds 1-16 against Pieris brassicae were evaluated by using a dual-choice bioassay, and compounds 1-10 with a normal grayanane skeleton showed potent antifeedant activity against P. brassicae. The structure-activity relationships of antifeedant activities of 1-16 against P. brassicae are discussed.

Modified-epsilon-polylysine-grafted-PEI-ß-cyclodextrin supramolecular carrier for gene delivery.

Cyclodextrin-based supermolecular systems have become one of significant nonviral gene delivery carriers. In this study, epsilon-polylysine-grafted-succinic acid-grafted-ß-cyclodextrin-LMW PEI (PPC) and adamantane-functionalized poly-(ethylene glycol) derivative (PEG-AD) were synthesized, and PEG-AD was encapsulated into PPC to form the complexes. These complexes were used to condense pDNA to make polyplexes, which biophysical properties, cytotoxicity and transfection efficiencies were studied. The results showed that the polyplexes were less cytotoxic than branched PEI without degrading the transfection efficiency. These findings suggest that the complexes with high stability could be an effective and low-toxicity carrier for delivering nucleic acid to target cells.

Host-guest inclusion system of rhein with polyamine-modified ß-cyclodextrins: characterization and cytotoxicity.

We report the preparation of inclusion complexes between rhein and four polyamine-modified ß-cyclodextrins, namely amino-ß-cyclodextrins (NH2-ßCD), ethylenediamine-ß-cyclodextrins (EN-ßCD), diethylenetriamine-ß-cyclodextrins (DETA-ßCD) and triethylenetetramine-ß-cyclodextrins (TETA-ßCD) using suspension method. The solution and solid state forms of the inclusion complexes of rhein with polyamine-ß-cyclodextrins were characterized by multiple techniques. Additionally, saturated solution and MTT methods were implemented to assess the water solubilization and in vitro cytotoxicity of the inclusion complexes, respectively. The results suggested that rhein was encapsulated within the CD cavity to form a 1:1 host-guest inclusion complex. Notably, a significant enhancement of the water solubility and in vitro cytotoxicity of rhein was found in the form of inclusion complex with polyamine-ß-cyclodextrin.

Scutellarin-graft cationic ß-cyclodextrin-polyrotaxane: Synthesis, characterization and DNA condensation.

As a prerequisite of gene delivery in living cells, DNA condensation has attracted more and more attention. In order to improve the efficiencies of polyamine-ß-cyclodextrin-based cationic polyrotaxanes (PR-EDA and PR-DETA) as DNA condensation materials, we have designed and prepared two novel scutellarin-grafted cationic polyrotaxanes (PR-EDA-SCU and PR-DETA-SCU), in which scutellarins (SCU), the planar molecules, were conjugated on the cyclodextrin molecules of PR-EDA and PR-DETA. These materials were characterized by 1D and 2D NMR, XRD, TG and DSC. The electrophoresis assays showed that pDNA condensation efficiencies of PR-EDA and PR-DETA were better than that of PR-EDA and PR-DETA. The complexes of PR-EDA, PR-DETA, PR-EDA-SCU and PR-DETA-SCU with pDNA were further investigated by zeta potential and atomic force microscopy analysis. The results indicated that the planar structure of SCU played an important role in improvement of pDNA condensation efficiencies of PR-EDA-SCU and PR-DETA-SCU. The satisfactory pDNA condensation abilities of PR-EDA-SCU and PR-DETA-SCU could be helpful in designing non-viral gene delivery vectors to control gene expression and delivery.

Solid inclusion complexes of oleanolic acid with amino-appended ß-cyclodextrins (ACDs): Preparation, characterization, water solubility and anticancer activity.

Oleanolic acid (OA) is a pentacyclic triterpenoid acid of natural abundance in plants which possesses important biological activities. However, its medicinal applications were severely impeded by the poor water solubility and resultant low bioavailability and potency. In this work, studies on solid inclusion complexes of OA with a series of amino-appended ß-cyclodextrins (ACDs) were conducted in order to address this issue. These complexes were prepared by suspension method and were well characterized by NMR, SEM, XRD, TG, DSC and Zeta potential measurement. The 2:1 inclusion mode of ACDs/OA complexes was elucidated by elaborate 2D NMR (ROESY). Besides, water solubility of OA was dramatically promoted by inclusion complexation with ACDs. Moreover, in vitro anticancer activities of OA against human cancer cell lines HepG2, HT29 and HCT116 were significantly enhanced after formation of inclusion complexes, while the apoptotic response results indicated their induction of apoptosis of cancer cells. This could provide a novel approach to development of novel pharmaceutical formulations of OA.