Anticancer Drug Camptothecin Research Articles

Loading studies of the anticancer drug camptothecin into dual stimuli-sensitive nanoparticles. Stability scrutiny

In recent years, the preparation of valuable drug delivery systems (DDS) from self-assembled amphiphilic copolymers has attracted much attention since these nanomaterials provide new opportunities to solve problems such as the lack of solubility in water of lipophilic drugs, improve their bioavailability, prolong their circulation time and decrease the side effects associated with their administration. In the current study two types of biocompatible pH-responsive nanoparticles derived from poly(2-hydroxyethyl methacrylate) (pHEMA) have been used as drug nano-carriers, being one of them core cross-linked to circumvent their instability upon dilution in human fluids. The present paper deals with the optimization of the loading process of the labile, hydrophobic and highly active anticancer drug, Camptothecin (CPT) into the nanoparticles with regard to four independent variables: CPT/polymer ratio, sonication, temperature and loading time. Forty experiments were carried out and a Box–Behnken experimental design was used to evaluate the significance of the independent variables related to encapsulation efficiency and drug retention capacity. The enhanced drug loading and encapsulation efficiency values (58% and >92%, respectively) of CPT were achieved by the core cross-linked NPs in 2 h at 32 °C at CPT/polymer ratio 1.5:1 w/w and 14 min of sonication. The optimized CPT-loaded NPs were studied by dynamic light scattering and scanning electron microscopy, and an increase in size of the loaded-NP compared to the unloaded counterparts was found. Other twenty experiments were conducted to study the enability to retain CPT into the conjugates at different ionic strength values and times. The stability studies demonstrated that the core cross-linked nanocarriers displayed an excellent drug retention capacity (>90%) at 25 °C for 15 days in every ionic-strength environments whereas the non-cross-linked ones were more stable at physiological ionic strength. The optimized systems proved to be a major step forward to encapsulate and retain CPT in the NP nuclei, what makes them ideal devices to control the delivery of CPT upon the triggered acidic conditions of solid tumors.

Cancer-specific chemotherapeutic strategy based on the vitamin K3 mediated ROS regenerative feedback and visualized drug release in vivo

A promising theranostic nanosystem VK3-CPT@Ru-CD is designed and fabricated by the host-guest driven self-assembly between the fluorescent adamantine-functionalized Ru(II) complexes and the ROS-labile-cyclodextrin modified thioketal linkers, in which anticancer drug camptothecin (CPT) and vitamin K3 (VK3) are effectively co-encapsulated. On account of the generative feedback between the intracellular redox cycling of VK3 and the high degree of ROS-triggered collapse of nanoparticles, VK3-CPT@Ru-CD can facilitate cancer-specific ROS amplification and drug release selectively in cancer cells, thus realizing the selective killing of tumor with minimal side-effects both in vitro and in vivo, the therapeutic effect of which is more prominent than the free anti-cancer drugs. More interestingly, the menadione structure of encapsulated VK3 can effectively quench the inherent fluorescence of Ru-CD, and a fluorescence lightening up phenomenon is observed accompanied with the ROS-triggered drug release, which can be utilized for real-time tracking of drug release in vitro and in vivo.

Titanium based mixed ligand complexes: Synthesis, spectroscopic and in vitro antiproliferative studies

Titanium complexes with composition TiCl2(L)(L1) and TiCl2(L)(L2) [where, L = benzoylacetone (bzac) and L1 = 1,2-diaminocyclohexane (dach), 1,10-phenanthroline (phen) L2 = 1-adamantylamine (ada)] have been synthesized by reacting titanium tetrachloride with benzoylacetone and nitrogen containing ligands in predetermined molar ratio. The structure of complexes was confirmed by different spectroscopic techniques i.e. FT-IR, UV-visible, 1H NMR and mass spectrometory. The unit cell parameters of complexes were calculated by using powder XRD software. Cytotoxic studies were done on HeLa (cervical), C6 (glioma), and CHO (Chinese hamster ovarian) cell lines. The complex 3 proved to be most effective than other complexes against human cervical HeLa cancer cell line with IC50 value of 5.6 µM which is even better than known anticancer drug Camptothecin having IC50 value of 6.2 µM. The flow cytometric study showed that complexes inhibited cell proliferation by arresting cell cycle in the G0 phase.

Near Infrared Light Triggered Cucurbit[7]uril-Stabilized Gold Nanostars as a Supramolecular Nanoplatform for Combination Treatment of Cancer.

Developing a spatiotemporal-controlled platform with feasible synthesis and multifunctionality is highly desirable in the field of nanomedicine. Here, we present a near-infrared (NIR)-light-triggered approach to control the supramolecular assembly system for drug release and achieve synergistic chemo-photothermal therapy for cancer. A cucurbit[7]uril (CB[7]) stabilized gold nanostar (GNS) platform is designed to encapsulate the anticancer drug camptothecin (CPT) via host-guest chemistry. Importantly, CB[7] behaves not only as a surfactant to improve the stability of GNS in the aqueous solution but also as the cage for intermolecular assembly of CPT molecules. Moreover, without the competitive complexation, the drug release could be stimulated under NIR light irradiation. Synergistic treatment of cancer can be achieved by combining chemotherapy with the photothermal effect of GNS. This work develops a NIR-light-triggered cucurbituril-based drug-release approach that opens the door for remote control of drug release in the supramolecular assembly system.

Methotrexate-based amphiphilic prodrug nanoaggregates for co-administration of multiple therapeutics and synergistic cancer therapy

The goal of nanomedicine is to seek strategies that are more efficient to address various limitations and challenges faced by conventional medicines, including lack of target specificity, poor bioavailability, premature degradability, and undesired side effects. Self-assembling drug amphiphiles represent a prospective nanomedicine for cancer therapy owing to their favorable route of administration and therapeutic efficiency compared with pristine drug counterparts. In this work, we report a class of self-deliverable prodrug amphiphiles consisting of the hydrophilic drug methotrexate (MTX) and the hydrophobic anticancer drugs camptothecin (CPT) and doxorubicin (DOX) for targeted and combinational chemotherapy. The disulfide bond and hydrazone bond, which are subject to stimuli-triggered bond cleavage, were introduced to link these therapeutic agents and form two prodrug amphiphiles, named as MTX-CPT and MTX-DOX, respectively, which could self-assemble into stable prodrug nanoaggregates (NAs) in aqueous media. MTX molecules in the prodrug NAs facilitated NA uptake into tumor cells with high expression of folic acid receptors (FRs). This systemic study provided clear evidence of the synergistic therapeutic effect by co-administrating dual prodrug NAs on various tumor cells in vitro and a xenograft tumor model in vivo. The obtained prodrug amphiphiles provide an efficient strategy for the design of multifunctional drug delivery systems and elaborate therapeutic nanoplatforms for cancer chemotherapy. Statement of SignificanceThis work presents two kinds of prodrug amphiphiles that are carrier free and integrate targeted drug delivery, stimuli-triggered drug release, synergistic therapy, and theranostic function into a single system. Reduction/acid active prodrug amphiphiles can self-assemble into micellar nanoaggregates (NAs) at a very low critical aggregation concentration. These NAs exhibit superior stability in physiological environment and disassemble in the presence of tumor cells expressing folic acid receptors or the high glutathione or in low pH tumoral endosomal environment. The induced disassembly of prodrug NAs can “switch on” the inherent fluorescence of the internalized camptothecin or doxorubicin for the detection of tumor cells. Compared to a single type of prodrug NA, co-administration of dual prodrug combination can produce an evident synergistic therapeutic effect against various tumor cells in vitro and inhibit xenograft tumor growth in vivo. The methotrexate-based prodrug amphiphiles may provide a potential strategy for developing multifunctional nanoplatforms and delivery of multiple therapeutics in chemotherapy.

PO-508 Detection and role of novel fusion oncogenes in paediatric cancers

IntroductionPaediatric cancers (PC) represent the 1 st cause of death by disease in children as 20% of patients still die from a recurrence of the malignancy. PC differ from adult cancers regarding their aetiology, cellular origin or mutational rate. Improving the knowledge on the biology of the relapsed tumours and identifying new targets are needed to provide new treatments. Fusion genes are responsible for ~20% of cancers and are the consequence of the juxtaposition of two previously separate genes which can activate proto-oncogenes or inactivate tumour suppressor genes. They are of great interest in clinics as they can be used as therapeutic targets or biomarkers. Our aim is to explore new fusion genes in relapsing/resistant paediatric patients through bioinformatics analysis of the NGS data from the molecular profiling program MOSCATO-01, and to study their function and oncogenic potential.Material and methodsWe developed an approach to optimise the detection of fusion transcripts in RNA-seq data. A biological validation of selected candidates was performed by RT-qPCR in patients’ tumour samples and available cell lines. A fusion never previously described found in a Ewing’s sarcoma (EWS) patient retained our attention, therefore we established 2 cellular models in order to assess the effect of this transcript on proliferation, migration, sensitivity to anticancer agents, gene expression in vitro and tumorigenicity in mice.Results and discussionsOur in-house pipeline ChimComp allowed the detection of 118 new potentially oncogenic fusions. Following the validation by RT-qPCR, we showed that ChimComp could be reliable at ~90%. A new fusion, LMO3-BORCS5, was found in a patient with EWS and in 12 cell lines from different origins suggesting that it is not an isolated event. Then, we explored the function and oncogenic potential of LMO3-BORCS5. Until now, we show that the stable transfection of this fusion into A673 Ewing’s sarcoma and NIH3T3 murine fibroblasts cell lines, leads to an increase of cell proliferation and an increase or an induction of tumorigenicity after injection in mice, as well as a decrease of sensitivity to anticancer drugs vincristine and camptothecin in A673 cells.ConclusionThese results suggest that LMO3-BORCS5 could play a key role in tumorigenesis and in response to treatment and could be used as a therapeutic target for patients where LMO3-BORCS5 is detected. More broadly, this study emphasises the key role of fusion genes in disease progression and their clinical interest in personalised medicine.

DOWN REGULATION OF u-PA BY A NUTRIENT MIXTURE IN HEMANGIOMA (EOMA) CELLS BY INDUCING CASPASE-DEPENDENT APOPTOSIS

To examine, whether the antitumor effects of a specific nutrient mixture are due to induction of apoptosis by inhibition of u-PA. A nutrient mixture containing lysine, proline, ascorbic acid, and green tea extract which has showed anticancer activity against a number of cancer cell lines was used as an experimental composition. EOMA cells were grown in appropriate media with antibiotics in 24-well tissue culture plates. At near confluence, the cells were treated with nutrition mixture at 10, 100, 1000µg/ml in triplicate. Analysis of u-PA activity was carried out by fibrin zymography. Morphological changes and caspase activation associated with apoptosis induction was checked by H&E staining and Live Green caspase assay, respectively. Apoptosis inducing anticancer drug camptothecin (10µM) was used as positive control. The nutrition mixture exhibited dose response toxicity with maximum toxicity 55% (p < 0.001) at 1000µg/ml. EOMA cells expressed u-PA, which was inhibited by nutrition mixture in a dose-dependent manner. The caspase analysis revealed a dose dependent increase in apoptosis of EOMA hemangioma cells, with an increasing apoptosis observed at 100μg/ml, and maximum at 1000μg/ml. Cells treated with nutrition mixture showed significantly more apoptotic changes than the control or camptothecin-treated cells. These results suggest that NM may induce apoptosis of hemangioma cells in vitro thus warranting further investigation.

Preparation of functionalized protein materials assisted by mechanochemistry

Herein, we investigate the suitability of hen egg-white lysozyme (HEWL) as a protein matrix for dispersal of various hydrophobic dyes. Moreover, we investigate the use of a mixer mill for grinding operation as an alternative to hand grinding by mortar and pestle. HEWL and various dyes are mixed by mechanochemistry, and the resulting composite material is dissolved in aqueous acid. The samples are then exposed to conditions promoting self-assembly of HEWL into protein nanofibrils (PNFs). The effect of PNF formation on dye photophysics is investigated by spectroscopic examination by absorption and luminescence spectroscopy, and product morphology is examined by scanning electron microscopy. The self-assembly process results in protein nanofibrils functionalized with luminescent dyes. Such structures may find future applications in various devices for light emission. In addition, we demonstrate that the anticancer drug camptothecin can be incorporated into protein nanofibrils giving materials that can find application as drug delivery agents.

Folate-molecular encapsulator-tethered biocompatible polymer grafted with magnetic nanoparticles for augmented drug delivery

Magnetic ferrite nanoparticles (MNPs) coated with biocompatible polymers capable of drug loading and release are fascinating nanostructures for delivering anti-cancer drugs. Herein, we report the synthesis and characterization of a novel β-cyclodextrin-folate-tethered dextran polymer. Nickel–zinc ferrite nanoparticles are prepared and coated with the polymer to form a biocompatible hybrid magnetic nanocarrier. To establish the significance of folate unit of the polymer in anticancer activity, a similar derivatized polymer, i.e. β-cyclodextrin-dextran conjugate without folate tether is used for comparison. The size of the hybrid MNPs is ∼20 nm, which is a size suitable for cancer drug targeting. The polymer-coated magnetic nanocarriers are soft ferromagnets as suggested by their narrow magnetic hysteresis loops. The anticancer drug camptothecin (CPT) is loaded on the magnetic nanocarriers. The drug loading efficiency is observed to be above 92%. The nanocarriers show sustained in vitro drug release for above 45 h. The in vitro cytotoxicity studies reveal that the loaded CPT retains its potency in the nanocarrier and the folate-tethered nanocarrier shows better anticancer activity than the one which does not carry a folate unit. The magnetic nanocarrier is suitable for magnetic field-guided drug transport, enhanced drug loading and release and folate receptor-mediated endocytotic uptake of drugs by cancer cells.

Natural polymer functionalized graphene oxide for co-delivery of anticancer drugs: In-vitro and in-vivo

The present study focuses on the development of a chitosan functionalized nanobiocomposite for the co-delivery of two anti-cancer drugs camptothecin (CPT) and 3,3′‑Diindolylmethane (DIM). The difference in the mechanism of action of the two drugs makes them a promising candidate to produce a synergistic effect against breast cancer. Herein a nanobiocomposite was developed by functionalizing a natural polymer chitosan to graphene oxide nanoparticles and decorated with folic acid. The nanobiocomposite thus synthesized was loaded with camptothecin and 3,3′‑Diindolylmethane and characterized by X-ray diffractometer (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV–visible spectroscopy (UV) and atomic force microscopy (AFM).Biocompatibility was assayed by hemolysis and anti-inflammatory assay. The cellular toxicity was measured by 3‑(4,5‑Dimethylthiazol‑2‑yl)‑2,5‑Diphenyltetrazolium Bromide (MTT), Sulforhodamine B (SRB) and cell death assay against MCF-7 cell lines. Further in vivo studies were carried out to analyze the biodistribution of the drug, blood biochemical analysis and bioavailability of the drug. The data revealed a significant increase in anticancer activity after co-loading of CPT and DIM to the nanocarrier. Also in-vivo studies revealed that DIM successfully masked the toxic effects produced by CPT.

Real-time analysis of cleavage and religation activity of human topoisomerase 1 based on ternary fluorescence resonance energy transfer DNA substrate

Human topoisomerase 1B is a ubiquitous and essential enzyme involved in relaxing the topological state of supercoiled DNA to allow the progression of fundamental DNA metabolism. Its enzymatic catalytic cycle consists of cleavage and religation reaction. A ternary fluorescence resonance energy transfer biosensor based on a suicide DNA substrate conjugated with three fluorophores has been developed to monitor both cleavage and religation Topoisomerase I catalytic function. The presence of fluorophores does not alter the specificity of the enzyme catalysis on the DNA substrate. The enzyme-mediated reaction can be tracked in real-time by simple fluorescence measurement, avoiding the use of risky radioactive substrate labeling and time-consuming denaturing gel electrophoresis. The method is applied to monitor the perturbation brought by single mutation on the cleavage or religation reaction and to screen the effect of the camptothecin anticancer drug monitoring the energy transfer decrease during religation reaction. Pathological mutations usually affect only the cleavage or the religation reaction and the proposed approach represent a fast protocol for assessing chemotherapeutic drug efficacy and analyzing mutant's properties.

Folate receptor-targeted theranostic IrSx nanoparticles for multimodal imaging-guided combined chemo-photothermal therapy.

Nano-drug delivery systems with multi-modality imaging capacities are worth pursuing because they integrate diagnostic and therapeutic functions. Herein, we report the design, synthesis and evaluation of modified iridium sulfide (IrSx) nanoparticles (NPs) for cancer therapy in vitro and in vivo. This nanosystem was prepared by modifying IrSx with polyethylene glycol (PEG) conjugated to the targeting ligand folate (FA) for multimodal imaging-guided combined chemo-photothermal therapy. Upon PEG modification, the small IrSx NPs (about 4 nm) self-assembled into much larger (about 120 nm) IrSx-PEG-FA NPs, which exhibited high photostability, ideal photothermal effect, high drug loading and pH-/photothermal-responsive drug release properties. By using the model anticancer drug camptothecin (CPT), we demonstrated that CPT@IrSx-PEG-FA can effectively target FA-receptor-positive cancer cells in vitro and show efficient tumor accumulation in vivo. The combination of CPT@IrSx-PEG-FA treatment and irradiation with an 808 nm laser resulted in complete tumor elimination. Moreover, photothermal/photoacoustic (PA)/computed tomography (CT) imaging provided an effective means to monitor the therapeutic effects. Interestingly, the nanoparticles can be cleared, resulting in low systematic toxicity of CPT@IrSx-PEG-FA. Our work demonstrates that the as-prepared IrSx-PEG-FA NPs present a promising platform for the construction of multifunctional theranostic agents for cancer therapy.

Self-assembled hyaluronic acid-testosterone nanocarriers for delivery of anticancer drugs

The present research aims at controlled delivery of anticancer drugs camptothecin and doxorubicin through encapsulation in self-assembled hyaluronic acid (HA)-testosterone conjugates. The conjugates were obtained by functionalization of either natural sodium hyaluronate or hydrazide-modified HA derivatives with testosterone hemisuccinate. From 2.0 to 7.7% of HA disaccharide units were linked to testosterone via two types of linkers of different length. Fourier transform infrared and proton nuclear magnetic resonance spectroscopies confirmed modification of HA. Conjugation of hydrophobic testosterone to hydrophilic backbone of HA resulted in the self-assembly of amphiphilic HA-testosterone conjugates in aqueous medium and the formation of stable and negatively charged nanoparticles with hydrodynamic diameter ranging from 172 to 380 nm and ζ-potential ranging from −37 to −26 mV, as evidenced from dynamic light scattering measurements. Examination of the dried conjugates by transmission electron microscopy revealed almost spherical particles of 50–100 nm size. Entrapment of camptothecin and doxorubicin in the hydrophobic core of HA-testosterone nanoparticles was performed with the drugs content of ca. 2.8 wt% and 3.5 wt% respectively. The sustained release of the anticancer drugs over 96 h was observed in phosphate buffered saline at pH 7.4. Cytotoxicity of camptothecin- and doxorubicin-loaded HA-testosterone nanoparticles against MCF-7 cancer cell line was found to be similar to the cytotoxicity of the free anticancer drugs. Based on the results of the in vitro studies, we can conclude that the developed HA-testosterone nanoparticles are promising candidates in chemotherapy treatments of cancers.

De novo transcriptome analyses reveals putative pathway genes involved in biosynthesis and regulation of camptothecin in Nothapodytes nimmoniana (Graham) Mabb.

Comprehensive transcriptome analysis of leaf and root tissues of Nothapodytes nimmoniana unravels several putative pathway genes, transcription factors and CYPs related to camptothecin (CPT) biosynthesis. Additionally, post-transcriptional suppression by artificial microRNA (aMIR) of NnCYP76B6 (geraniol 10-hydroxylase) suggests its role in CPT biosynthesis. Tissue-specific LC-MS/MS analysis revealed the presence of secologanin as the central intermediate of MIA pathway in N. nimmoniana. Nothapodytes nimmoniana is a rich source of potent anticancer drug camptothecin (CPT) whose biosynthetic pathway is unresolved due to the lack of genomic and transcriptomic information. Present investigation entails deep transcriptome analysis of N. nimmoniana which led to identification of putative pathway genes and regulatory components involved in CPT biosynthesis. Using Illumina HiSeq 2500 sequencing platform a total of 31,172,889 (6.23Gb) and 31,218,626 (6.24Gb) raw reads were generated from leaf and root wood, respectively. These were assembled de novo into 138,183 unique contigs. Additionally, 16 cytochrome P450 transcripts related to secondary metabolism were also identified. Further, transcriptome data pool presented 1683 putative transcription factors of which transcripts corresponding to WRKY TFs were the most abundant (14.14%). A total of 2741 transcripts were differentially expressed out of which 478 contigs showed downregulation in root wood and 2263 contigs were up-regulated. Further, comparative analyses of 17 genes involved in CPT biosynthetic pathway were validated by qRT-PCR. On basis of intermediates, two distinct seco-iridoid pathways are involved in the biosynthesis of monoterpene indole alkaloids either through multiple isomers of strictosidinic acid or strictosidine. Tissue-specific LC-MS/MS analysis revealed the presence of secologanin as the central intermediate of MIA pathway in N. nimmoniana. Geraniol-10 hydroxylase (NnCYP76B6) an important enzyme in CPT biosynthesis which specifically shunts geraniol into the secologanin pathway was also cloned from the trancriptome resource. In planta transient expression of NnCYP76B6 showed a significant enhancement in mRNA transcript levels coincident with enhanced CPT accumulation. Further, artificial microRNA (aMIR) mediated downregulation of NnCYP76B6 resulted in reduction of mRNA transcript levels as well as CPT content in comparison to control. These empirical results suggest a plausible regulatory role for NnCYP76B6 in CPT biosynthesis and also establish a valuable repository for deciphering various structural, rate limiting and regulatory genes of CPT biosynthetic pathway.

Camptothecin loaded graphene oxide nanoparticle functionalized with polyethylene glycol and folic acid for anticancer drug delivery

Graphene oxide nanomaterials are widely used to achieve effective cancer treatment. In this study, a novel graphene oxide mediated drug delivery system was synthesized by combining anticancer drug camptothecin (CPT) to the large surface area of graphene oxide by π-π stacking. Initially graphene oxide was synthesized by hummer's method and to obtain a more precise drug delivery, the system was loaded onto polyethylene glycol (PEG) decorated with folic acid. The resultant conjugate was characterized by Fourier Transform Infrared spectroscopy (FTIR), X-Ray Diffraction (XRD) analysis, UV-visible Spectrophotometery, Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). The graphene-oxide -polyethylene glycol-folic acid - camptothecin (GO-PEG-FA -CPT) drug delivery system showed a pH dependent drug release as observed by UV analysis. The anticancer activity of the synthesized drug delivery system was studied by MTT assay using MCF-7 breast cancer cell lines. The conjugate showed enhanced anticancer activity and thus could be used as a potential candidate for drug delivery.

Rational Design of a New Self-Codelivery System from Redox-Sensitive Camptothecin-Cytarabine Conjugate Assembly for Effectively Synergistic Anticancer Therapy.

Herein, two careful selected anticancer drugs camptothecin (CPT) and cytarabine (Ara-C) with different biological action mechanisms and different water solubility are conjugated together through a glutathione (GSH) cleavable disulfide bond to construct a redox-sensitive drug-drug conjugate, which can self-assemble into nanoparticles, thus notably improving the water solubility of CPT and the cell membrane permeability of Ara-C. Compared with free drugs, the self-assembled CPT-ss-Ara nanoparticles can concentrate in tumor tissues through the enhanced permeability and retention (EPR) effect, then they can be rapidly internalized by tumor cells and degrade into free drugs for killing the tumor cells when exposed to the reductive environment (GSH) of tumor cells, thereby reducing the injury to normal cells. Meanwhile, the CPT-ss-Ara nanoparticles can effectively protect CPT and Ara-C molecules from biological inactivation before their arrival in tumor microenvironment since free CPT and Ara-C are easy to partly lose their therapy efficacy due to their structure degradation in blood circulation. The in vitro and in vivo anticancer experimental results indicate that simultaneous release of free CPT and Ara-C can realize synergistic chemotherapy effects, thus markedly improve their anticancer activity. Therefore, our designed carrier-free, redox-sensitive CPT-ss-Ara nanoparticles might have promising clinical application to combat cancers.

Natural and synthetic polymer for graphene oxide mediated anticancer drug delivery—A comparative study

Two dimensional graphene and its derivatives have been a focus of scientific study due to its unique features which makes it suitable for biomedical applications. Herein a comparative study was carried out between chitosan polymerized graphene oxide and polyvinylpyrrolidone polymerized graphene oxide nanoparticles. The polymerized nanocarriers were further decorated with folic acid and anticancer drug camptothecin was loaded. The nanocarriers thus synthesized were characterized by x-ray diffractometer (XRD), fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), transmission electron microscope (TEM), atomic force microscopy (AFM), thermogravimetric analysis (TGA), UV–vis spectroscopy (UV), zeta potential and fluorescence spectroscopy. The biocompatibility of the two nanocarriers was compared via hemolysis and anti-inflammatory studies and the cellular toxicity was assayed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and Sulforhodamine B (SRB) assay against MCF-7 cell lines. The study indicates that chitosan polymerized graphene oxide nanocarrier was more suitable for biomedical applications in comparison to polyvinylpyrrolidone. The percentage hemolysis caused by chitosan polymerized graphene oxide was almost equivalent to diclofenac salt which served as standard. Also it has, increased drug loading capacity and greater percentage inhibition of MCF-7 cell lines as per MTT and SRB assay.

Redox-responsive polymer prodrug/AgNPs hybrid nanoparticles for drug delivery

A drug carrier system of the hybrid nanoparticles based on the redox-responsive P[(2-((2-((camptothecin)-oxy)ethyl)disulfanyl)ethylmethacrylate)-co-(2-(d-galactose)methylmethacryl-ate)] (P(MACPTS-co-MAGP)) and AgNPs is developed to deliver the anti-cancer drug camptothecin (CPT) and monitor the drug release by the recovery of the fluorescence of CPT. CPT is linked to the polymer side-chains via a redox-responsive disulfide bond, attaching on the surface of AgNPs and leading to the quenching of CPT fluorescence (“off” state) due to the nanoparticle surface energy transfer (NSET) effect. Upon the exposure to glutathione (GSH), the disulfide bond is cleaved to release CPT, resulting in the recovery of the fluorescence of CPT (“on” state). The system offers a platform to track the CPT delivery and releasing in real time

Cyclometalated Iridium(III)-Complex-Based Micelles for Glutathione-Responsive Targeted Chemotherapy and Photodynamic Therapy

The integration of chemotherapy and photodynamic therapy (PDT) in a single delivery system is highly desirable for enhancing anticancer therapeutic efficacy. Herein, two cyclometalated Ir(III) complex-constructed micelles FIr-1 and FIr-2 were demonstrated for glutathione (GSH) activated targeted chemotherapy and PDT. The cyclometalated Ir(III) complexes were prepared by conjugating phosphorescent Ir(III) compounds with chemotherapeutic drug camptothecin (CPT) through GSH responsive disulfide bond linkages, and the Ir(III) complexes were then assembled with amphiphilic surfactant pluronic F127 via noncovalent encapsulation to afford micelles. The surfaces of the micelles were further decorated with folic acid as a targeting group. The micelles showed intense fluorescence that renders them with excellent real-time imaging capability. The release of free anticancer drug CPT from the micelles was realized through GSH-activated disulfide bond cleavage in tumor cells. In addition, the micelles were capable of generating singlet oxygen used for PDT upon visible light irradiation. On account of having folic acid targeting ligand, the micelles displayed greater cellular accumulation in folate receptor (FR) overexpressed HeLa cells than FR low-expressed MCF-7 cells, leading to selective cancer cell killing effect. As compared with solo therapeutic systems, the micelles with targeted combinational chemotherapy and PDT presented superior potency and efficacy in killing tumor cells at a low dosage. On the basis of these findings, the multifunctional micelles could serve as a versatile theranostic nanoplatform for cancer cell targeted imaging and combinational therapy.

A self-immolative prodrug nanosystem capable of releasing a drug and a NIR reporter for invivo imaging and therapy.

Invivo monitoring of the biodistribution and activation of prodrugs is highly attractive, and the self-immolative dendritic architecture is deemed as a promising approach for constructing theranostic prodrug in which the release/activation of different payloads is needed. Herein, A GSH-triggered and self-immolative dendritic platform comprising an anticancer drug camptothecin (CPT), a cleavable linker and a two-photon NIR fluorophore (dicyanomethylene-4H-pyran, DCM) has been developed for in situ tracking of drug release and antitumour therapy. Invitro experiments demonstrate that, the presence of glutathione (GSH) induces the cleavage of the self-immolative linker, resulting in comitant release of the drug and the dye. Upon cell internalization and under one- or two-photon excitation, prominent intracellular fluorescence can be observed, indicating the release of the payloads in live cells. Upon loaded in phospholipid vesicles, the prodrug has also been successfully utilized for invivo and in situ tracking of drug release and cancer therapy in a mouse model. Several hours post injection, the prodrug generates strong fluorescence on tumour sites, demonstrating the prodrug's capability of monitoring the on-site drug release. Moreover, the prodrug shows considerable high activity and exerts obvious inhibition towards tumour growth. This work suggests that the prodrug with self-immolative dendritic structure can work well invivo and this strategy may provide an alternative approach for designing theranostic drug delivery systems.