Promising Potential In Cancer Therapy Research Articles

Amino acid‐decorated mesoporous silica nanoparticles loaded with titanocene derivatives for targeted anticancer studies

Nanostructured materials possess promising potential for cancer therapy through precise adjustment of their functionalization and physicochemical attributes. This study primarily focuses on the synthesis and characterization of mesoporous silica nanoparticles (MSN) that are functionalized with titanocene dichloride (a therapeutic agent) and one of several amino acids—cysteine, captopril, penicillamine, or methionine—utilizing 3‐aminopropyltriethoxysilane (AP) as a linker. This synthesis yielded four innovative metallodrug‐functionalized nanostructured materials (MSN‐AP‐Cys‐Ti, MSN‐AP‐Cap‐Ti, MSN‐AP‐Pen‐Ti, and MSN‐AP‐Met‐Ti), meticulously characterized using diverse analytical techniques such as X‐ray diffraction (XRD), X‐ray fluorescence (XRF), diffuse reflectance ultraviolet–visible (DR UV–Vis), Fourier transform infrared (FTIR), solid‐state nuclear magnetic resonance (NMR) spectroscopy, and transmission electron microscopy (TEM). The textural properties of the nanomaterials post‐functionalization displayed slight modifications, confirming the successful integration of the therapeutic agents. Evaluation of cytotoxicity in the breast cancer cell line MDA‐MB‐231, with the healthy cell line Hek‐293T as control via MTT assays, revealed the active nature of the functionalized silica‐based materials. The viability of both cell lines indicated a concentration‐dependent response to the materials. Among the tested systems, cysteine and captopril exhibited the highest activity concerning IC50 relative to material concentration. The enhanced biological activity of higher functionalized nanosystems suggests a favorable cell internalization facilitated by the amino acid fragment. Additionally, qualitative DNA binding studies hinted at potential DNA adsorption on the surface of the metallodrug‐functionalized nanomaterials, forming DNA adducts where a strand of DNA covalently bonds to the metallodrug moiety. This was deduced from the hypsochromic shift in absorbance of the characteristic π–π* and n–π* transitions in DNA, which occurred from 1.01 to 0.76 and 1.26–0.19 following drug (MSN‐AP‐Cap‐Ti) interaction.

Glycosidase-activated H2S donorsto enhance chemotherapy efficacy

Hydrogen sulfide (H2S) plays a critical role in cancer biology. Herein, we developed a series of glycosidase-triggered hydrogen sulfide (H2S) donors by connecting sugar moieties (including glucose, galactose and mannose) to COS donors via a self-immolative spacer. In the presence of corresponding glycosidases, H2S was gradually released from these donors in PBS buffer with releasing efficiencies from 36 to 67 %. H2S release was also detected by H2S probe WSP-1 after treatment HepG2 cells with Man1. Cytotoxicities of these glycosylated H2S donors were evaluated against HepG2 by MTT assay. Among them, Man1 and Man2 exhibited an obvious reduction of cell viability in HepG2 cells, with cell viability as 37.6 % for 80 μM of Man. Consistently, significant apoptosis was observed in HepG2 cells after treatment with Man1 and Man2. Finally, We evaluated the potential of Man1 for combination therapy with doxorubicin. A synergistic effect was observed between Man1 and Doxorubicin in HepG2 and Hela cells. All these results indicated glycosidase-activated H2S donorshave promising potential for cancer therapy.

A NIR-driven green affording-oxygen microrobot for targeted photodynamic therapy of tumors.

Photodynamic therapy (PDT) is a light-activated local treatment modality that has promising potential in cancer therapy. However, ineffective delivery of photosensitizers and hypoxia in the tumor microenvironment severely restrict the therapeutic efficacy of PDT. Herein, phototactic Chlorella (C) is utilized to carry photosensitizer-encapsulated nanoparticles to develop a near-infrared (NIR) driven green affording-oxygen microrobot system (CurNPs-C) for enhanced PDT. Photosensitizer (curcumin, Cur) loaded nanoparticles are first synthesized and then covalently attached to C through amide bonds. An in vitro study demonstrates that the developed CurNPs-C exhibits continuous oxygen generation and desirable phototaxis under NIR treatment. After intravenous injection, the initial 660 nm laser irradiation successfully induces the active migration of CurNPs-C to tumor sites for higher accumulation. Upon the second 660 nm laser treatment, CurNPs-C produces abundant oxygen, which in turn induces the natural product Cur to generate more reactive oxygen species (ROS) that significantly inhibit the growth of tumors in 4T1 tumor-bearing mice. This contribution showcases the ability of a light-driven green affording-oxygen microrobot to exhibit targeting capacity and O2 generation for enhancing photodynamic therapy.

Design, synthesis, and evaluation of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one derivatives: potent BRD4 inhibitors with anti-breast cancer activity

BRD4 inhibitors have demonstrated promising potential in cancer therapy. However, their therapeutic efficacy in breast cancer varies depending on the breast cancer subtype, particularly in the treatment of TNBC. In this study, we designed and synthesized 94 derivatives of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one to evaluate their inhibitory activities against BRD4. Notably, compound DDT26 exhibited the most potent inhibitory effect on BRD4, with an IC50 value of 0.237 ± 0.093 μM. DDT26 demonstrated significant anti-proliferative activity against both TNBC cell lines and MCF-7 cells. Intriguingly, the phthalazinone moiety of DDT26 mimicked the PAPR1 substrate, resulting in DDT26 displaying a moderate inhibitory effect on PARP1 with an IC50 value of 4.289 ± 1.807 μM. Further, DDT26 was shown to modulate the expression of c-MYC and γ-H2AX, induce DNA damage, inhibit cell migration and colony formation, and arrest the cell cycle at the G1 phase in MCF-7 cells. Our findings present potential lead compounds for the development of potent anti-breast cancer agents targeting BRD4.

In Vitro/In Vivo Preparation and Evaluation of cRGDyK Peptide-Modified Polydopamine-Bridged Paclitaxel-Loaded Nanoparticles.

Cancer remains a disease with one of the highest mortality rates worldwide. The poor water solubility and tissue selectivity of commonly used chemotherapeutic agents contribute to their poor efficacy and serious adverse effects. This study proposes an alternative to the traditional physicochemically combined modifications used to develop targeted drug delivery systems, involving a simpler surface modification strategy. cRGDyK peptide (RGD)-modified PLGA nanoparticles (NPs) loaded with paclitaxel were constructed by coating the NP surfaces with polydopamine (PD). The average particle size of the produced NPs was 137.6 ± 2.9 nm, with an encapsulation rate of over 80%. In vitro release tests showed that the NPs had pH-responsive drug release properties. Cellular uptake experiments showed that the uptake of modified NPs by tumor cells was significantly better than that of unmodified NPs. A tumor cytotoxicity assay demonstrated that the modified NPs had a lower IC50 and greater cytotoxicity than those of unmodified NPs and commercially available paclitaxel formulations. An in vitro cytotoxicity study indicated good biosafety. A tumor model in female BALB/c rats was established using murine-derived breast cancer 4T1 cells. RGD-modified NPs had the highest tumor-weight suppression rate, which was higher than that of the commercially available formulation. PTX-PD-RGD-NPs can overcome the limitations of antitumor drugs, reduce drug toxicity, and increase efficacy, showing promising potential in cancer therapy.

Bismuth Oxide (Bi2O3) Nanoparticles Cause Selective Toxicity in a Human Endothelial (HUVE) Cell Line Compared to Epithelial Cells.

A review of recent literature suggests that bismuth oxide (Bi2O3, referred to as B in this article) nanoparticles (NPs) elicit an appreciable response only after a concentration above 40-50 µg/mL in different cells all having an epithelial origin, to the best of our knowledge. Here, we report the toxicological profile of Bi2O3 NPs (or BNPs) (71 ± 20 nm) in a human endothelial cell (HUVE cell line) in which BNPs exerted much steeper cytotoxicity. In contrast to a high concentration of BNPs (40-50 µg/mL) required to stimulate an appreciable toxicity in epithelial cells, BNPs induced 50% cytotoxicity in HUVE cells at a very low concentration (6.7 µg/mL) when treated for 24 h. BNPs induced reactive oxygen species (ROS), lipid peroxidation (LPO), and depletion of the intracellular antioxidant glutathione (GSH). BNPs also induced nitric oxide (NO,) which can result in the formation of more harmful species in a fast reaction that occurs with superoxide (O2•-). Exogenously applied antioxidants revealed that NAC (intracellular GSH precursor) was more effective than Tiron (a preferential scavenger of mitochondrial O2•-) in preventing the toxicity, indicating ROS production is extra-mitochondrial. Mitochondrial membrane potential (MMP) loss mediated by BNPs was significantly less than that of exogenously applied oxidant H2O2, and MMP loss was not as intensely reduced by either of the antioxidants (NAC and Tiron), again suggesting BNP-mediated toxicity in HUVE cells is extra-mitochondrial. When we compared the inhibitory capacities of the two antioxidants on different parameters of this study, ROS, LPO, and GSH were among the strongly inhibited biomarkers, whereas MMP and NO were the least inhibited group. This study warrants further research regarding BNPs, which may have promising potential in cancer therapy, especially via angiogenesis modulation.

Comparative and Functional Analyses Reveal Conserved and Variable Regulatory Systems That Control Lasalocid Biosynthesis in Different Streptomyces Species.

Lasalocid, a representative polyether ionophore, has been successfully applied in veterinary medicine and animal husbandry and also displays promising potential for cancer therapy. Nevertheless, the regulatory system governing lasalocid biosynthesis remains obscure. Here, we identified two conserved (lodR2 and lodR3) and one variable (lodR1, found only in Streptomyces sp. strain FXJ1.172) putative regulatory genes through a comparison of the lasalocid biosynthetic gene cluster (lod) from Streptomyces sp. FXJ1.172 with those (las and lsd) from Streptomyces lasalocidi. Gene disruption experiments demonstrated that both lodR1 and lodR3 positively regulate lasalocid biosynthesis in Streptomyces sp. FXJ1.172, while lodR2 plays a negative regulatory role. To unravel the regulatory mechanism, transcriptional analysis and electrophoretic mobility shift assays (EMSAs) along with footprinting experiments were performed. The results revealed that LodR1 and LodR2 could bind to the intergenic regions of lodR1-lodAB and lodR2-lodED, respectively, thereby repressing the transcription of the lodAB and lodED operons, respectively. The repression of lodAB-lodC by LodR1 likely boosts lasalocid biosynthesis. Furthermore, LodR2 and LodE constitute a repressor-activator system that senses changes in intracellular lasalocid concentrations and coordinates its biosynthesis. LodR3 could directly activate the transcription of key structural genes. Comparative and parallel functional analyses of the homologous genes in S. lasalocidi ATCC 31180T confirmed the conserved roles of lodR2, lodE, and lodR3 in controlling lasalocid biosynthesis. Intriguingly, the variable gene locus lodR1-lodC from Streptomyces sp. FXJ1.172 seems functionally conserved when introduced into S. lasalocidi ATCC 31180T. Overall, our findings demonstrate that lasalocid biosynthesis is tightly controlled by both conserved and variable regulators, providing valuable guidance for further improving lasalocid production. IMPORTANCE Compared to its elaborated biosynthetic pathway, the regulation of lasalocid biosynthesis remains obscure. Here, we characterize the roles of regulatory genes in lasalocid biosynthetic gene clusters of two distinct Streptomyces species and identify a conserved repressor-activator system, LodR2-LodE, which could sense changes in the concentration of lasalocid and coordinate its biosynthesis with self-resistance. Furthermore, in parallel, we verify that the regulatory system identified in a new Streptomyces isolate is valid in the industrial lasalocid producer and thus applicable for the construction of high-yield strains. These findings deepen our understanding of regulatory mechanisms involved in the production of polyether ionophores and provide novel clues for the rational design of industrial strains for scaled-up production.

Trienzyme-like Co3O4@TiO2-x nanozymes for heterojunction-enhanced nanocatalytic-sonodynamic tumor therapy

Nanozymes have shown promising potential in cancer therapy owing to the advantages of low-cost, excellent stability, and high reproducibility. However, the inherent low catalytic activity of nanozymes and highly complex tumor microenvironment (TME) severely restricted the clinical applications of nanocatalytic therapy. Herein, we first reported a heterojunction (HJ)-enhanced nanocatalytic-sonodynamic therapy platform based on Co3O4@TiO2-x Z-scheme HJs by depositing Co3O4 nanoparticles (NPs) onto TiO2-x nanosheets (NSs). Co3O4@TiO2-x HJs not only exhibited excellent ultrasound (US)-triggered reactive oxygen species (ROS) generation ability, but also possessed triple enzyme-mimic activities (peroxidase-mimic, catalase-mimic, and GSH depletion activities) to realize the amplification of ROS levels and relieve tumor hypoxia. More importantly, the triple enzyme-mimic activities and sonodynamic properties of single-component Co3O4 or TiO2-x were greatly enhanced by the construction of Z-scheme HJs owing to the accelerate carrier transfer process and improved spatial separation dynamics of US-generated electron-hole pairs. The synergetic therapeutic effect of Co3O4@TiO2-x through HJ-enhanced nanocatalytic-sonodynamic therapy could achieve complete tumor eradication without recurrence. Our work will open up a promising approach to engineer semiconductor HJs with both sonodynamic and enzyme-mimic activities for enhanced nanocatalytic-sonodynamic combination therapy.

Influence of chain length on the anticancer activity of the antimicrobial peptide CAMEL with fatty acid modification

Antimicrobial peptides (AMPs) display promising potential in cancer therapy. Modification with fatty acids is a simple and effective approach to improve the activity of AMPs. In the present study, we investigated the effects of fatty acid chain lengths on the anticancer activity, self-assembly and mechanism of action of CAMEL (CM15, KWKLFKKIGAVLKVL-NH2), an amphipathic AMP with 15 amino acids. Conjugation of fatty acids could obviously improve the in vitro anticancer activity of CAMEL. Among the tested peptides, C12-CAMEL showed the highest anticancer activity, while C16-CAMEL killed cancer cells with the slowest kinetics. This may be related to the self-assembly of C12-CAMEL and C16-CAMEL, which could form spherical nanoparticles and tightened nanofibers, respectively. In addition, necrosis and necroptosis rather than apoptosis were the major mechanisms underlying the anticancer activity of CAMEL, C12-CAMEL and C16-CAMEL, implying that modification with fatty acids did not obviously alter the mechanism of action of CAMEL. Notably, C12-CAMEL, with high and rapid cell-killing activity, exhibited significantly stronger in vivo anticancer activity than CAMEL and C16-CAMEL. Overall, the present work suggests that the choice of a suitable fatty acid for structural modification is necessary for improving the anticancer activity of AMPs.

A site-oriented nanosystem for active transcellular chemo-immunotherapy to prevent tumor growth and metastasis

Immunotherapy has shown promising potential in cancer therapy; however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadvantages, a site-specific and active transcellular drug delivery system was developed herein for chemotherapy-enhanced immunotherapy. When arriving at the tumor site, the matrix metallopeptidase 2 (MMP2)-responsive shell detached from the nanosystem, releasing positively charged cores. The cationic surface of the inner cores induced adsorption-meditated transcytosis, which facilitated transendothelial transportation and transcellular drug delivery into distal tumor cells. PD-L1 antibody and chemotherapeutic drugs were loaded in the outer layer and inner cores of the nanosystem, respectively, to be precisely delivered to target sites, thereby achieving synchronized delivery and site-oriented release of different anticancer agents. PD-L1 antibody released in the tumor microenvironment effectively blocked the binding of PD-L1 to its receptors on the T cell surface. Oxaliplatin and indoximod co-delivered in the cationic cores can induce immunogenic cell death and attenuate the immunosuppressive effect throughout the tumor tissues, recruiting a large amount of T cells and further enhancing the immunotherapy. The resulting synergistic antitumor response could not only efficiently inhibit the growth of primary tumors, but also help prevent metastasis of primary tumor to distant sites. This study offers a novel nano-enabled strategy for chemo-immunotherapy in immunosuppressive tumors.

Albumin Nanostructures for Nucleic Acid Delivery in Cancer: Current Trend, Emerging Issues, and Possible Solutions.

Simple SummaryNucleic acids are showing tremendous potential in cancer therapy. However, their successful delivery to tumor sites is still a challenge. Herein, we report on the use of albumin-based nanocarriers for the delivery of nucleic acids because of their biosafety, ease of surface modification, and tumor targeting. In addition, we discuss various surface modification strategies to improve the internalization, efficacy, and specific tumor targeting of the albumin nanocarriers. Cancer is one of the major health problems worldwide, and hence, suitable therapies with enhanced efficacy and reduced side effects are desired. Gene therapy, involving plasmids, small interfering RNAs, and antisense oligonucleotides have been showing promising potential in cancer therapy. In recent years, the preparation of various carriers for nucleic acid delivery to the tumor sites is gaining attention since intracellular and extracellular barriers impart major challenges in the delivery of naked nucleic acids. Albumin is a versatile protein being used widely for developing carriers for nucleic acids. It provides biocompatibility, tumor specificity, the possibility for surface modification, and reduces toxicity. In this review, the advantages of using nucleic acids in cancer therapy and the challenges associated with their delivery are presented. The focus of this article is on the different types of albumin nanocarriers, such as nanoparticles, polyplexes, and nanoconjugates, employed to overcome the limitations of the direct use of nucleic acids in vivo. This review also highlights various approaches for the modification of the surface of albumin to enhance its transfection efficiency and targeted delivery in the tumor sites.

In vivo toxicity and antitumor activity of newly green synthesized reduced graphene oxide/silver nanocomposites

A novel biosynthesis of dual reduced graphene oxide/silver nanocomposites (rGO/AgNC) using the crude metabolite of Escherichia coli D8 (MF06257) strain and sunlight is introduced in this work. Physicochemical analysis of these rGO/AgNC revealed that they are sheet-like structures having spherically shaped silver nanoparticles (AgNPs) with an average particle size of 8 to 17 nm, and their absorption peak ranged from 350 to 450 nm. The biosynthesized rGO/AgNC were characterized by UV–vis and FT-IR spectra, X-ray diffraction, Zeta potential and transmission electron microscopy. After the injection of these nanocomposites to mice, their uptake by the kidney and liver has been proven by the ultrastructural observation and estimation of the hepatic and renal silver content. These nanocomposites caused a moderate toxicity for both organs. Changes in the liver and kidney functions and histopathological effects had been observed. The rGO/AgNC revealed a remarkable antitumor effect. They showed a dose-dependent cytotoxic effect on Ehrlich ascites carcinoma (EAC) cells in vitro. Treatment of mice bearing EAC tumors intraperitoneally with 10 mg/kg rGO/AgNC showed an antiproliferative effect on EAC cells, reduced ascites volume, and maintained mice survival. The results indicate that this green synergy of silver nanoparticles with reduced graphene oxide may have a promising potential in cancer therapy.

Developing natural killer cells producing hypoxia-inducible cytokines for effective immunotherapy against solid tumors.

Abstract Natural Killer (NK) cells are a promising means for adoptive immunotherapy for cancers. NK cell therapies against hematological cancers such as acute myeloid leukemia have demonstrated good efficacy. However, the poor effector function of tumor-infiltrating NK cells limits the potential of NK cells against solid tumors. Accumulating data suggests that hypoxia in the tumor microenvironment (TME) suppresses the effector function of NK cells. One of the immunosuppressive features of hypoxia is the generation of adenosine, a metabolite that highly suppresses NK cell cytotoxicity and proliferation. Although engineering NK cells to overexpress stimulatory cytokines before the adoptive immunotherapy has demonstrated promising potential for cancer therapy, it raises a concern that high systemic levels of cytokines may lead to cytokine-mediated pathology. Therefore, we hypothesize that driving overexpression of the potent stimulatory cytokines exclusively in the TME would circumvent systemic toxicity. An attractive strategy to achieve this goal is to take advantage of the hypoxic condition, a key characteristic of the TME. Hypoxia-inducible factor 1 alpha (HIF1-α) plays a pivotal role in expressing hypoxia-responsive genes by associating with promoters containing hypoxia response element (HRE). By mimicking the biological system, HRE-induced cytokine expression vectors were generated and tested in NK cells. The expression was inducible under hypoxic conditions and was reversible upon re-oxygenated conditions. Our results suggest that the hypoxia-inducible vector system can be beneficial to trigger TME specific cytokine expressions in NK cells and provide insight into efficient immunotherapy against solid tumors.

A Red Light‐Triggered Drug Release System Based on One‐Photon Upconversion‐Like Photolysis

Photoresponsive drug release systems can enhance drug accumulation at the sites where light is applied. Nowadays, the photocleavable groups used in the systems usually require ultraviolet or blue light irradiation, which limits tissue penetration depth and is harmful to normal cells and living bodies. A one-photon upconversion-like photolysis strategy, which can cleave green light-activatable prodrugs with red light at the presence of a red light-excitable photosensitizer in organic solvents, is developed. However, both the prodrug and photosensitizer are hydrophobic and their energy transfer process is sensitive to oxygen molecules. Here, a simple strategy to address these problems by loading the two components in biocompatible and biodegradable polymeric micelles, is presented. The developed low-irradiance red light-triggered drug release system has a size around 40nm and exhibits good stability in aqueous solutions. The micellar encapsulation protects the photolysis reaction from oxygen quenching in normoxia aqueous solutions. The therapeutic effect of the system enhanced by the redlight irradiation is demonstrated through in vitro and in vivo studies, indicating promising potential in cancer therapy. The study provides the first example and also an important reference for applying one-photon upconversion-like photolysis in biomedical applications.

PH-Responsive and Biodegradable ZnO-Capped Mesoporous Silica Composite Nanoparticles for Drug Delivery.

As a drug delivery system (DDS), traditional mesoporous silica nanoparticles (MSNs) suffer from bioaccumulation in vivo and premature drug release in systemic circulation due to low degradation rate and lack of protective gatekeeper. Herein, we developed a safe and intelligent DDS with characteristics of pH-responsive biodegradation and controlled drug release based on mesoporous silica composite nanoparticles (MSCNs) capped with ZnO quantum dots (ZnO QDs). Acidic degradable MSCNs were successfully synthesized by doping Ca2+ and PO43− into the MSNs’ framework. The in vitro doxorubicin hydrochloride (DOX) release was inhibited at neutral pH 7.4 but triggered significantly at pH 5.0 due to the dissociation of ZnO caps. The internalization behavior and cytotoxicity of 4T1 cells indicated MSCNs-ZnO could efficiently deliver DOX into the cells with significant antitumor activity. Such a DDS with pH-responsive biodegradation and controlled drug release has promising potential for cancer therapy.

Potential applications of multifunctional mesoporous carbon nanoplatform for tumor microenvironment improving by combined chemo-/phototherapy

At present, conventional drug therapy for tumor strongly stimulates tumor tissue, leading to tumor necrosis and acute inflammatory response, and tumor metastasis. How to kill tumor cells under mild conditions and prolong the survival of patients is a hot topic of tumor therapy. In this study, a multifunctional nanoplatform was designed based on mesoporous carbon nanoparticles, grafting with anti-inflammatory drug (celecoxib) and loading chemotherapy drug (doxorubicin). The constructed nanoplatform mesoporous carbon/celecoxib @doxorubicin was found to capable of, induce intravascular thrombosis, blocking nutrient supply for tumor, and over-inflammatory suppression avoiding acute tissue necrosis. Meanwhile, this study demonstrates combined chemo- and photothermal therapy and exhibits a promising potential in cancer therapy.

Host-guest fabrication of dual-responsive hyaluronic acid/mesoporous silica nanoparticle based drug delivery system for targeted cancer therapy

In this paper, a targeting hyaluronic acid (HA)/mesoporous silica nanoparticle (MSN) based drug delivery system (DDS) with dual-responsiveness was prepared for cancer therapy. To avoid the side reaction between the anti-cancer drug doxorubicin hydrochloride (DOX) and HA, host-guest interaction was applied to fabricate the DDS named DOX@MSN-SS-N=C-HA. The “nanocontainer” MSN was modified with benzene ring via both pH-sensitive benzoic imine bond and redox-sensitive disulfide linkage. When DOX was loaded in the pores of MSN, the channels were then capped by the “gatekeeper” β-CD grafted HA (HA-g-CD) through host-guest interaction between β-CD and benzene. HA endowed the drug carriers with the targeting capability in CD44 over-expressed cancer cells. After cellular uptake, the carriers could rapidly release DOX for cell apoptosis due to both the hydrolysis of benzoic imine bond at low pH and the cleavage of disulfide bond at a high concentration of glutathione (GSH) intracellular. In vitro drug release studies and in vitro cytotoxicity studies were taken to investigate the dual-responsiveness of the carriers. And the CD44-receptor mediated cancer cell targeting capability was investigated as well. In conclusion, the targeted dual-responsive complex DDS fabricated through host-guest interaction has promising potential in cancer therapy.

Glutathione Depletion in a Benign Manner by MoS2 -Based Nanoflowers for Enhanced Hypoxia-Irrelevant Free-Radical-Based Cancer Therapy.

Tumor hypoxia significantly diminishes the efficacy of reactive oxygen species (ROS)-based therapy, mainly because the generation of ROS is highly oxygen dependent. Recently reported hypoxia-irrelevant radical initiators (AIBIs) exhibit promising potential for cancer therapy under different oxygen tensions. However, overexpressed glutathione (GSH) in cancer cells would potently scavenge the free radicals produced from AIBI before their arrival to the specific site and dramatically limit the therapeutic efficacy. A synergistic antitumor platform (MoS2 @AIBI-PCM nanoflowers) is constructed by incorporating polyethylene-glycol-functionalized molybdenum disulfide (PEG-MoS2 ) nanoflowers with azo initiator and phase-change material (PCM). Under near-infrared laser (NIR) irradiation, the photothermal feature of PEG-MoS2 induces the decomposition of AIBI to produce free radicals. Furthermore, PEG-MoS2 can facilitate GSH oxidation without releasing toxic metal ions, greatly promoting tumor apoptosis and avoiding the introduction of toxic metal ions. This is the first example of the use of intelligent MoS2 -based nanoflowers as a benign GSH scavenger for enhanced cancer treatment.

Theranostic α-Lactalbumin-Polymer-Based Nanocomposite as a Drug Delivery Carrier for Cancer Therapy.

A nanotheranostic system was developed using α-lactalbumin along with Fe3O4 nanoparticles as an magnetic resonance imaging (MRI) contrast agent for medical imaging and doxorubicin as the therapeutic agent. α-lactalbumin was precipitated and cross-linked using poly(ethylene glycol) and glutaraldehyde. Besides, polyethylenimine was applied to increase the number of amine groups during cross-linking between α-lactalbumin and Fe3O4 nanoparticles. Interestingly, 90% of the initial protein used for the coaggregation process was incorporated in the prepared 130 nm nanocomposites, which facilitated the 85% doxorubicin loading. Formation of pH-sensitive imine bonds between glutaraldehyde and amine groups on α-lactalbumin and polyethylenimine resulted in higher release of doxorubicin at acidic pHs and consequently development of a pH-sensitive nanocarrier. The designed nanocomposite was less immunogenic owing to stimulating the production of less amounts of C3a, C5a, platelet factor 4, glycoprotein IIb/IIIa, platelet-derived β-thromboglobulin, interleukin-6, and interleukin-1β compared to the free doxorubicin. Furthermore, 1000 μg/mL nanocomposite led to 0.2% hemolytic activity, much less than the 5% standard limit. The void nanocarrier induced no significant level of cytotoxicity in breast cancer and normal cells following 96 h incubation. The doxorubicin-loaded nanocomposite presented higher cytotoxicity, apoptosis induction, and doxorubicin uptake in cancer cells than free doxorubicin. Conversely, lower cytotoxicity, apoptosis induction, and doxorubicin uptake were observed in normal cells treated with the doxorubicin-loaded nanocarrier compared to free doxorubicin. In line with the results of in vitro experiments, in vivo studies on tumor-bearing mice showed more suppression of tumor growth by the doxorubicin-loaded nanocomposite compared to the free drug. Moreover, the pharmacokinetic study revealed slow release of doxorubicin from the nanocomposite. Besides, in vitro and in vivo MRI studies presented a higher r2/r1 ratio and comparable contrast to the commercially available DOTAREM, respectively. Our findings suggest that this new nanocomposite is a promising nanotheranostic system with promising potential for cancer therapy and diagnosis.

Synthesis and anti-tumor activity of [1,4] dioxino [2,3-f] quinazoline derivatives as dual inhibitors of c-Met and VEGFR-2

Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.