Boosting Reactive Oxygen Species Generation with a Dual-Catalytic Nanomedicine for Enhanced Tumor Nanocatalytic Therapy.

Generating lethal reactive oxygen species (ROS) within tumors by nanocatalytic medicines is an advanced strategy for tumor-specific therapy in recent years. Nevertheless, the low yield of ROS restrains its therapeutic efficiency. Herein, a dual-catalytic nanomedicine based on tumor microenvironment (TME)-responsive liposomal nanosystem co-delivering CuO2 and dihydroartemisinin (DHA) (LIPSe@CuO2&DHA) is developed to boost ROS generation against tumor. The liposomal nanosystem can degrade in the ROS-overexpressed TME and liberate CuO2 and DHA to initiate Cu-based dual-catalytic ROS generation. Serving as generators of H2O2 and Cu2+, CuO2 can self-produce plenty of toxic hydroxyl radicals via Fenton-like reaction in the acidic TME. Meanwhile, the released Cu2+ can catalyze DHA to generate cytotoxic C-centered radicals. Together, the self-supplied H2O2 and Cu-based dual-catalytic reaction greatly increase the intratumoral level of lethal ROS. Importantly, Cu2+ can decrease the GSH-mediated scavenging effect on the produced ROS via a redox reaction and undergo a Cu2+-to-Cu+ conversion to enhance the Fenton-like reaction, further guaranteeing the high efficiency of ROS generation. Resultantly, LIPSe@CuO2&DHA induces remarkable cancer cell death and tumor growth inhibition, which may present a promising nanocatalytic medicine for cancer therapy.

The obesogenic side of Genistein.

Genistein (GN) has been highly recommended for its medicinal properties like anticancer, antidiabetic, antihyperlipidemic, antiviral, and antioxidant activities among others. Recently, scientists realized that Genistein is an endocrine disruptor. It is an obesogen that interferes with the endocrine system causing obesity through many mechanisms like inducing adipocyte differentiation, lipid accumulation, and transformation of some stem cells into adipocytes (bone marrow mesenchymal stem cells for example) in vitro. Animal studies show that GN upregulates genes associated with adipogenesis like CCAAT/enhancer binding protein alpha (Cebpα), CCAAT/enhancer binding protein beta (Cebpß), and PPARγ. In silico studies reveal a strong binding affinity for estrogen receptors. All these findings were contingent on concentration and tissues. It is beyond dispute that obesity is one of the most frustrating medical conditions under the sun. The pathophysiology of this disease was first attributed to a high-calorie diet and lack of physical activity. However, studies proved that these two factors are not enough to account for obesity in both children and adults. This mini review highlights how Genistein interaction with the peroxisome proliferator-activated receptor gamma protein can cause obesity.

A tetrasulfide bond-bridged mesoporous organosilica-based nanoplatform for triple-enhanced chemodynamic therapy combined with chemotherapy and H2S therapy.

The high glutathione (GSH) concentration and insufficient H2O2 content in tumor cells strongly constrict the efficacy of Fenton reaction-based chemodynamic therapy (CDT). Despite numerous efforts, it still remains a formidable challenge for achieving satisfactory efficacy using CDT alone. Herein, an intelligent tetrasulfide bond-bridged mesoporous organosilica-based nanoplatform that integrates GSH-depletion, H2S generation, self-supplied H2O2, co-delivery of doxorubicin (DOX) and Fenton reagent Fe2+ is presented for synergistic triple-enhanced CDT/chemotherapy/H2S therapy. Because the tetrasulfide bond is sensitive to GSH, the nanoplatform can effectively consume GSH, leading to ROS accumulation and H2S generation in the GSH-overexpressed tumor microenvironment. Meanwhile, tetrasulfide bond-induced GSH-depletion triggers the degradation of nanoparticles and the release of DOX and Fe2+. Immediately, Fe2+ catalyzes endogenous H2O2 to highly toxic hydroxyl radicals (˙OH) for CDT, and H2S induces mitochondria injury and causes energy deficiency. Of note, H2S can also decrease the decomposition of H2O2 to augment CDT by downregulating catalase. DOX elicits chemotherapy and promotes H2O2 production to provide a sufficient substrate for enhanced CDT. Importantly, the GSH depletion significantly weakens the scavenging effect on the produced ˙OH, guaranteeing the enhanced and highly efficient CDT. Based on the synergistic effect of triple-augmented CDT, H2S therapy and DOX-mediated chemotherapy, the treatment with this nanoplatform gives rise to a superior antitumor outcome.

Cryopreservation of bioflavonoid-rich plant sources and bioflavonoid-microcapsules: emerging technologies for preserving bioactivity and enhancing nutraceutical applications.

Bioflavonoids are natural polyphenolic secondary metabolites that are medicinal. These compounds possess antitumor, cardioprotective, anti-inflammatory, antimicrobial, antiviral, and anti-psoriasis properties to mention a few. Plant species that contain bioflavonoids should be preserved as such. Also, the bioactivity of the bioflavonoids as neutraceutical compounds is compromised following extraction due to their sensitivity to environmental factors like light, pH, and temperature. In other words, the bioflavonoids' shelf-life is affected. Scientists noticed that bioflavonoids have low solubility properties, poor absorption, and low bioavailability following consumption. Researchers came up with methods to encapsulate bioflavonoids in order to circumvent the challenges above and also to mask the unpleasant order these chemicals may have. Besides, scientists cryopreserve plant species that contain bioflavonoids. In this review, we discuss cryopreservation and bioflavonoid microencapsulation focusing mainly on vitrification, slow freezing, and freeze-drying microencapsulation techniques. In addition, we highlight bioflavonoid extraction techniques, medicinal properties, challenges, and future perspectives of cryopreservation and microencapsulation of bioflavonoids. Regardless of the uniqueness of cryopreservation and microencapsulation as methods to preserve bioflavonoid sources and bioflavonoids' bioactivity, there are challenges reported. Freeze-drying technology is costly. Cryoprotectants damage the integrity of plant cells, to say the least. Researchers are working very hard to overcome these challenges. Encapsulating bioflavonoids via coaxial electrospray and then cryopreserving the micro/nanocapsules produced can be very interesting.

Smart design of a therapeutic nanoplatform for mitochondria-targeted copper-depletion therapy combined with chemotherapy.

Mitochondria-targeted copper-depletion is emerging as an attractive strategy to combat cancer. However, existing copper molecular chelators are non-specific, toxic and ineffective. Here, it is reported that multifunctional nanoparticles (MSN-TPP/BNA-DPA) can not only target mitochondria to deprive copper ions to trigger copper-depletion therapy, but also serve as nanocarriers to deliver anticancer drugs for chemotherapy, which are engineered by conjugating a fluorophore 4-bromo-1,8-naphthalicanhydride (BNA), a copper-depriving moiety dimethylpyridinamine (DPA) and a mitochondrial targeting ligand triphenylphosphonium (TPP) on the surface of mesoporous silica nanoparticles (MSN). BNA and the internal charge transfer of compound BNA-DPA endow MSN-TPP/BNA-DPA with green fluorescence emission upon UV excitation, which can be used to monitor the cellular uptake of nanoparticles. When copper ions bind to DPA, green fluorescence is quenched, providing visualization feedback of copper-depletion. Therapeutically, mitochondria-targeted copper-depletion effectively causes mitochondria damage, elevated oxidative stress and reduced ATP production to induce intensive cancer cell death. Moreover, the mesoporous structure enables MSN-TPP/BNA-DPA to deliver doxorubicin to mitochondria for chemotherapy and enhances copper-depletion therapy through H2O2 production. Together, the synergistic therapeutic effect of enhanced copper-depletion therapy and doxorubicin-mediated chemotherapy achieves a remarkable cancer cell-killing effect and significant tumor growth inhibition in 4T1 tumor-bearing mice. This work provides an efficacious strategy for copper-depletion based synergistic cancer therapy.

Enzyme-Triggered Size-Switchable Nanosystem for Deep Tumor Penetration and Hydrogen Therapy.

The poor penetration of nanocarriers within tumor dense extracellular matrices (ECM) greatly restricts the access of anticancer drugs to the deep tumor cells, resulting in low therapeutic efficacy. Moreover, the high toxicity of the traditional chemotherapeutics inevitably causes undesirable side effects. Herein, taking the advantages of biosafe H2 and small-sized nanoparticles in diffusion within tumor ECM, we develop a matrix metalloprotease 2 (MMP-2) responsive size-switchable nanoparticle (UAMSN@Gel-PEG) that is composed of ultrasmall amino-modified mesoporous silica nanoparticles (UAMSN) wrapped within a PEG-conjugated gelatin to deliver H2 to the deep part of tumors for effective gas therapy. Ammonia borane (AB) is chosen as the H2 prodrug that can be effectively loaded into UAMSN by hydrogen-bonding adsorption. Gelatin is used as the substrate of MMP-2 to trigger size change and block AB inside UAMSN during blood circulation. PEG is introduced to further increase the particle size and endow the nanoparticle with long blood circulation to achieve effective tumor accumulation via the EPR effect. After accumulation into the tumor site, MMP-2 promptly digests gelatin to expose UAMSN loading AB for deep tumor penetration. Upon stimulation by the acidic tumor microenvironment, AB decomposes into H2 for further intratumor diffusion to achieve effective hydrogen therapy. Consequently, such a simultaneous deep tumor penetration of nanocarriers and H2 results in an evident suppression on tumor growth in a 4T1 tumor-bearing model without any obvious toxicity on normal tissues. Our synthetic nanosystem provides a promising strategy for the development of nanomedicines with enhanced tumor permeability and good biosafety for efficient tumor treatment.

Mesoporous peroxidase nanozyme for synergistic chemodynamic therapy and chemotherapy.

Peroxidase nanozyme, enabling decomposition of hydrogen peroxide (H2O2) into highly toxic hydroxyl radical (•OH), is an emerging technology for tumor treatment. However, limited by the low H2O2 level in the tumor microenvironment, the standalone peroxidase nanozyme-mediated therapy usually fails to achieve desirable therapeutic outcomes. Herein, we presented a mesoporous nanozyme that not only had peroxidase-like activity but also could deliver anticancer drug for synergistic tumor therapy. The nanozyme, that was, iron-doped mesoporous silica nanoparticle (FeMSN), was prepared by a sol-gel method and then a calcination treatment. The introduction of iron endowed FeMSN with peroxidase-like activity that could decompose H2O2 into •OH under acidic condition for chemodynamic therapy of tumors. Meanwhile, the mesoporous structure enabled FeMSN to deliver anticancer drug doxorubicin (DOX) for chemotherapy and enhanced chemodynamic therapy through H2O2 production, ultimately achieving synergistic effect to improve the efficacy of tumor treatment. The in-vitro and in-vivo results demonstrated that DOX-loaded FeMSN exhibited significant cancer cell-killing effect and potently inhibited tumor growth. Collectively, this study represented a paradigm for achieving efficient tumor therapy through design of peroxidase-like nanozyme with drug delivery capability, which might advance the development of nanozyme in tumor chemodynamic therapy.

Multichannel Ca2+ Generator for Synergistic Tumor Therapy via Intracellular Ca2+ Overload and Chemotherapy.

Ca2+ overload has attracted an increasing attention due to its benefit of precise cancer therapy, but its efficacy is limited by the strong Ca2+ excretion of cancer cells. Moreover, monotherapy of Ca2+ overload usually fails to treat tumors satisfactorily. Herein, we develop a multifunctional nanosystem that could induce Ca2+ overload by multipathway and simultaneously produce chemotherapy for synergistic tumor therapy. The nanosystem (CaMSN@CUR) is prepared by synthesizing a Ca-doped mesoporous silica nanoparticle (CaMSN) followed by loading the anticancer drug curcumin (CUR). CaMSN serves as the basis Ca2+ generator to induce Ca2+ overload directly in the intracellular environment by acid-triggered Ca2+ release, while CUR could not only exhibit chemotherapy but also facilitate Ca2+ release from the endoplasmic reticulum to the cytoplasm and inhibit Ca2+ efflux out of cells to further enhance Ca2+ overload. The in vitro and in vivo results show that CaMSN@CUR could exhibit a remarkable cytotoxicity against 4T1 cells and significantly inhibit tumor growth in 4T1 tumor-bearing mice via the synergy of Ca2+ overload and CUR-mediated chemotherapy. It is expected that the designed CaMSN@CUR has a great potential for effective tumor therapy.

Autocatalytic oncotherapy nanosystem with glucose depletion for the cascade amplification of hypoxia-activated chemotherapy and H2O2-dependent chemodynamic therapy.

Employing hypoxia-activated prodrugs is an appealing oncotherapy strategy, but limited by insufficient tumor hypoxia. Moreover, a standalone prodrug fails to treat tumors satisfactorily due to tumor complexity. Herein, a nanosystem (TPZ@FeMSN-GOX) was established for triple synergetic cancer starvation therapy, hypoxia-activated chemotherapy and chemodynamic therapy (CDT). TPZ@FeMSN-GOX was prepared by synthesizing iron-doped mesoporous silica nanoparticles (FeMSNs) followed by surface conjugation with glucose oxidase (GOX), and then loading with hypoxia-activated prodrug tirapazamine (TPZ). When TPZ@FeMSN-GOX entered the tumor cells, GOX could not only exhaust glucose to starve cancer cells and concomitantly produce H2O2, but also consume O2 to aggravate the hypoxia environment and amplify TPZ-mediated chemotherapy. Meanwhile, the released Fe3+ was reduced to reactive Fe2+ by endogenous glutathione, which ultimately decomposed the produced H2O2 and endogenous H2O2 into highly toxic ˙OH, guaranteeing highly efficient CDT. Together, TPZ@FeMSN-GOX could effectively kill cancer cells and significantly inhibit tumor growth, providing a good paradigm for effective tumor treatment.

Intelligent Nanoplatform with Multi Therapeutic Modalities for Synergistic Cancer Therapy.

Chemodynamic therapy (CDT) has attracted increasing attention in tumor treatment but is limited by insufficient endogenous H2O2. Moreover, it is challenging for monotherapy to achieve a satisfactory outcome due to tumor complexity. Herein, we developed an intelligent nanoplatform that could respond to a tumor microenvironment to induce efficient CDT without complete dependence on H2O2 and concomitantly generate chemotherapy and oncosis therapy (OT). The nanoplatform was constructed by a calcium- and iron-doped mesoporous silica nanoparticle (CFMSN) loaded with dihydroartemisinin (DHA). After entering into cancer cells, the nanoplatform could directly convert the intracellular H2O2 into toxic •OH due to the Fenton-like activity of CFMSN. Meanwhile, the acidic microenvironment and endogenous chelating molecules triggered Ca2+ and Fe3+ release from the nanoplatform, causing particle collapse with accompanying DHA release for chemotherapy. Simultaneously, the released Ca2+ induced intracellular Ca2+-overloading for OT, which was further enhanced by DHA, while the released Fe3+ was reduced to reactive Fe2+ by intracellular glutathione, guaranteeing efficient Fenton reaction-mediated CDT. Moreover, Fe2+ cleaved the peroxy bonds of DHA to generate C-centered radicals to further amplify CDT. Both in vitro and in vivo results confirmed that the nanoplatform exhibited excellent anticancer efficacy via the synergistic effect of multi therapeutic modalities, which is extremely promising for high-efficient cancer therapy.

pH-Responsive size-shrinkable mesoporous silica-based nanocarriers for improving tumor penetration and therapeutic efficacy.

Poor tumor penetration is a major obstacle to nanomedicine for achieving effective anticancer therapy. Tumor microenvironment-induced nanomedicine size shrinkage is a promising strategy to overcome the drug penetration barrier across the dense tumor matrix. Herein, we design a size-shrinkable nanocarrier that uses acid as a means of triggering a change in particle size for co-achievement of efficient tumor accumulation followed by deep tumor penetration and rapid clearance from the body. This nanocarrier is constructed from a pH-sensitive lipid layer shell and an ultrasmall amino-functionalized mesoporous silica nanoparticle core capable of loading drugs. After intravenous injection into mice bearing the 4T1 tumor, the nanocarrier with an initial hydrodynamic size of about 33 nm could effectively accumulate at the tumor site through the enhanced permeability and retention effect. Subsequently, in the acidic tumor microenvironment, the lipid layer comprising 9 alkyl-spiropyran (SP-C9) undergoes a volume shrinkage due to the conversion of hydrophobic SP-C9 to amphiphilic 9 alkyl-merocyanine (MC-C9), thus leading to a significant decrease in the entire particle size (hydrodynamic size ∼17 nm) for enhanced intratumoral penetration. Moreover, we find that this size-shrinkable nanocarrier could be rapidly excreted out of the body based on the ICP analysis, significantly reducing biosafety issues. Benefiting from the effective tumor accumulation and penetration of the nanocarrier, the released doxorubicin shows potent antitumor efficacy. This demonstrates the high potential of the designed nanocarrier in solid tumor treatment.

A pH-responsive dissociable mesoporous silica-based nanoplatform enabling efficient dual-drug co-delivery and rapid clearance for cancer therapy.

The balance between tumor accumulation and renal clearance has severely limited the efficacy of mesoporous silica-based drug nanocarriers in cancer therapy. Herein, a pH-responsive dissociable mesoporous silica-based nanoplatform with efficient dual-drug co-delivery, tumor accumulation and rapid clearance for cancer therapy is achieved by adjusting the wetting of the mesoporous silica surface. At pH 7.4, the synthesized spiropyran- and fluorinated silane-modified ultrasmall mesoporous silica nanoparticles (SP-FS-USMSN) self-assemble to form larger nanoclusters (denoted as SP-FS-USMSN cluster) via hydrophobic interactions, which can effectively co-deliver anticancer drugs, doxorubicin hydrochloride (Dox) and curcumin (Cur), based on the mesopores within SP-FS-USMSN and the voids among the stacked SP-FS-USMSN. At pH 4.5-5.5, the conformational conversion of spiropyran from a "closed" state to an "open" state causes the wetting of the SP-FS-USMSN surface, leading to the dissociation of the SP-FS-USMSN cluster for drug release and renal clearance. The in vitro and in vivo studies demonstrate that the Cur and Dox co-loaded SP-FS-USMSN cluster (Cur-Dox/SP-FS-USMSN cluster) possesses great combined cytotoxicity, and can accumulate into tumor tissue by its large size-favored EPR effect and potently suppress tumor growth in HepG2-xenografted mice. This research demonstrates that the SP-FS-USMSN cluster may be a promising drug delivery system for cancer therapy and lays the foundation for practical mesoporous silica-based nanomedicine designs in the future.

Synthesis of mesoporous silica-calcium phosphate hybrid nanoparticles and their potential as efficient adsorbent for cadmium ions removal from aqueous solution.

Since adsorption and nanomaterials had been respectively found to be the most promising technique and the preferred adsorbents for heavy metal ions removal, in this study, novel mesoporous silica-calcium phosphate (MS-CP) hybrid nanoparticles were synthesized by a facile one-pot method, and subsequently assessed as adsorbent for Cd2+ removal from aqueous solution. MS-CP were characterized by scanning and transmission electron microscopies, etc. The influences of initial Cd2+ concentration, contact time, solution temperature and solution pH on removal efficiency of Cd2+ were investigated in detail. The results revealed that MS-CP were nanospheres of ∼20 nm and presented a bimodal pore distribution (3.82 nm and 12.40 nm), a high surface area (314.56 m2/g) and a large pore volume (1.21 cm3/g). The Cd2+ removal experiments demonstrated that MS-CP had a high adsorption capacity due to electrostatic interaction between Cd2+ and silanol groups on MS-CP surface, as well as ion-exchange between Cd2+ and calcium in MS-CP. Additionally, removal efficiency of Cd2+ increased with increasing contact time and solution temperature, while decreased as initial Cd2+ concentration increased. The maximum adsorption capacity of Cd2+ by MS-CP was above 153 mg/L. These results suggested that the as-synthesized MS-CP could be promising adsorbent for Cd2+ removal from aqueous solution.

Amino-functionalized mesoporous silica nanoparticles as efficient carriers for anticancer drug delivery.

Amino-functionalized mesoporous silica nanoparticles (MSN-NH2) were synthesized by a post-grafting method and further studied as carriers for doxorubicin hydrochloride (DOX) delivery. The morphology, structure, and property of MSN-NH2 and DOX-loaded MSN-NH2 (DOX@MSN-NH2) were studied using various techniques, such as transmission electron microscopy, Fourier transformed infrared spectroscopy, N2 adsorption-desorption isotherms, and zeta potentials. The drug loading and release profile as well as the in vitro cell cytotoxicity were detaily investigated. The results indicated that the loading content of DOX increased with the decrease of MSN-NH2/DOX mass ratio and/or the increase of amino density. DOX@MSN-NH2 exhibited a pH-dependent drug release, drug release increased as the pH value decreased. Compared with MSN-NH2, which were neglectable cytotoxicity against non-small-cell lung cancer (A549) cells, DOX@MSN-NH2 displayed remarkable cytotoxicity toward A549 cells in dose- and time-dependent manners. It was concluded that the as-synthesized MSN-NH2 could be used as promising drug carriers for cancer therapy.

Mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel.

In this study, paclitaxel (PTX), a typical chemotherapeutic agent with poor water-solubility, was selected as the model drug to evaluate the feasibility of mesoporous silica nanoparticles (MSN) to load a hydrophobic drug in different solvents. A sol-gel method was used to synthesize MSN. Drug loading was carried out in three different solvents: dichloromethane, ethanol and dimethyl sulfoxide (DMSO) via a solvent evaporation method, and their effects on drug loading were examined. We further studied the effects of drug loading period and mass ratio of drug to carrier on drug loading capacity of MSN, as well as the in vitro drug release was analyzed. Moreover, the cytotoxic effect of PTX loaded MSN on liver carcinoma (HepG2) cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The related materials were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), dynamic light scattering (DLS), fourier transform infrared spectrometer (FTIR), small-angle x-ray scattering (SAXS), wide-angle x-ray diffraction (XRD) and N2 adsorption-desorption analyses. The results demonstrated a highly improved solubility of PTX by using MSN as drug carriers compared to free PTX. In addition, drug loading content increased as the solvent polarity parameter decreased or the drug/carrier mass ratio increased. Compared with the blank MSN, the PTX loaded MSN could produce a significant cytotoxicity on HepG2 cells. Our results indicated that MSN could be very potential drug delivery carriers for poorly water soluble drugs.

Co-delivery of erlotinib and doxorubicin by pH-sensitive charge conversion nanocarrier for synergistic therapy.

Pretreatment of lung cancer cells with epidermal growth factor receptor (EGFR) inhibitor erlotinib has been recently reported that could dramatically synergize their apoptotic response to DNA damage agent doxorubicin (DOX). To translate this synergistic therapy into in vivo anticancer therapy and clinical practice, we designed a novel pH-sensitive charge conversion nanocarrier (M-HHG2C18-L) that contained erlotinib/DOX combination and produced a sequential staggered drug release for synergistic lung cancer therapy. In this study, a synthetic zwitterionic oligopeptide lipid (1,5-dioctadecyl-l-glutamyl2-histidyl-hexahydrobenzoic acid, HHG2C18) was used to construct a pH-sensitive lipid bilayer (HHG2C18-L), which was subsequently applied to coat amino-functionalized mesoporous silica nanoparticles (MSN-NH2). Erlotinib and DOX were separately incorporated into HHG2C18-L and MSN-NH2 respectively to obtain pH-sensitive charge conversion erlotinib/DOX co-delivery nanoparticles (M-HHG2C18-L(E+D)). We confirmed that M-HHG2C18-L(E+D) were able to reverse surface zeta potential from negative to positive at tumor extracellular pH, thus facilitating the targeted cancer cell internalization. Furthermore, as erlotinib was sequestered in the exterior lipid bilayer and the controlled release ability of MSN-NH2, erlotinib released faster than DOX during the cellular transport. Additionally, HHG2C18-L became more positive at tumor intracellular pH and enhanced Coulombic repulsion with MSN-NH2, leading to increased sequential staggered release of erlotinib and DOX. Due to the pretreatment and time-staggered inhibition of EGFR with erlotinib and the enhanced intracellular release of DOX to the nucleus, the maximized synergistic cell killing effect was achieved. Compared to non-sensitive erlotinib/DOX co-delivery nanoparticles (M-SPC-L(E+D)) and simultaneous DRUG coadministration. M-HHG2C18-L(E+D) with sequential staggered drug release and pH-sensitive charge conversional properties showed great synergistic effects in antiproliferation and apoptosis of A549 human cancer cells in vitro. The in vivo study demonstrated that M-HHG2C18-L(E+D) exhibited considerable tumor accumulation and potent suppression of tumor growth in Lewis lung carcinoma tumor bearing mice. It was also demonstrated that M-HHG2C18-L(E+D) showed no systemic toxicity and possessed distinguished effect on extending survival period. These results suggested that M-HHG2C18-L(E+D) had great potential application in cancer treatment.