Synthesis and biological evaluation of 99mTc tricarbonyl complex of O,O′‐diethylethylenediamine‐N,N′‐di‐3‐propanoate as potential tumour diagnostic agent

The extensive development of radiopharmaceuticals towards early tumour detection and treatment has increased the demand for new ligands with higher tumour selectivity. Research has been done on the potential of the novel O,O′‐diethylethylenediamine‐N,N′‐di‐3‐propanoate ( L ) ligand as a radionuclide vehicle for tumour targeting. Under alkaline conditions, L hydrolyses and produces half ester ligand ( L' ) and diacid ligand ( L'' ), with characteristic donor atom array N,N,O. Ligand L was successfully labelled with ^99mTc at pH = 9 by coordination with the octahedral fac‐[^99mTc(CO)₃(H₂O)₃]⁺ intermediate, forming the main radioproduct fac‐[^99mTcL′(CO)₃] (Tc1). The ^99mTc complex showed a low lipophilic character (log P = 0.48) and low binding affinity to human serum albumin (2.51 ± 0.48%). In vitro stability studies in saline and human plasma, as well as challenge studies with cysteine and histidine, revealed high stability of the complex during 24 h. Biodistribution studies of Tc1 in female C57BL/6 mice bearing B16/F1 melanoma metastases showed significant tumour uptake: 9.81 ± 1.19%ID g^?1 in the liver, 5.87 ± 0.54%ID g^?1 in the lungs and 3.17 ± 0.33%ID g^?1 in the ovary at 30 min post‐injection. Favourable physicochemical properties, satisfactory in vitro/in vivo stability and biodistribution profile in the experimental metastatic melanoma model indicate the possible application of the radiolabelled ligand in tumour diagnosis. Copyright © 2015 John Wiley & Sons, Ltd.     

Targeted Chemo‐Photothermal Therapy: A Nanomedicine Approximation to Selective Melanoma Treatment

Melanoma is one of the most severe public health issues worldwide, not only because of the high number of cases but also for its poor prognosis in late stages. Therefore, early diagnosis and efficient treatment are key toward a future solution. However, melanoma is highly resistant to cytotoxicity in its metastatic form. In this context, a therapeutic strategy based on a targeted chemo‐photothermal nanotransporter for cytotoxic compounds is proposed. This approach comprises the use of core–multishell gold nanorods, coated with mesoporous silica and further covered with a thermosensitive polymer, which is vectorized for selective internalization in melanoma cells. The proposed nanoformulation is capable of releasing the transported cytotoxic compounds on demand, in response to near‐IR irradiation, with high selectivity and efficacy against malignant cells, even at low concentrations, thereby providing a new tool against melanoma disease.     

Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the major pungent ingredient of red pepper, has been reported to possess anti-carcinogenic and anti-mutagenic activities. In this study, the anti-migration activity of capsaicin on highly metastatic B16-F10 melanoma cells was investigated. Capsaicin significantly inhibited the migration of melanoma cells without showing obvious cellular cytotoxicity at low doses. This effect correlated with the down-regulation of phosphatidylinositol 3-kinase (PI3-K) and its downstream target, Akt. Although B16-F10 cell migration was increased by the PI3-K activator through the activation of Akt, these PI3-K activator-induced phenomena were attenuated by capsaicin. Moreover, capsaicin was found to significantly inhibit Rac1 activity in a pull-down assay. These results demonstrate that capsaicin inhibits the migration of B16-F10 cells through the inhibition of the PI3-K/Akt/Rac1 signal pathway. The present investigation suggests that capsaicin targets PI3-K/Akt/ Rac1-mediated cellular events in B16-F10 melanoma cells. Consequently, capsaicin administration should be considered an effective approach for the suppression of invasion and metastasis in malignant melanoma chemotherapy.     

溶剂诱导黑色素瘤抗原基因-2特定表位多肽异构的LC/MS研究

 研究乙醇、甲醇两种常用溶剂系统对固相合成的黑色素瘤抗原基因 2 (MAGE 2 )的特定表位多肽 (171 179)异构的影响。分别运用乙醇、甲醇溶剂体系以及极性溶剂二甲基亚砜 (DMSO)作对照预处理固相合成的黑色素瘤抗原特异性MAGE 2表位多肽 (171～ 179) ,然后用反相高效液相色谱 /质谱联用技术 (RP HPLC/MS)对合成的表位多肽的m/z进行Q1正离子监测扫描分析 ,观察其在不同溶剂系统预处理下的异构情况 ,以选择合理的预处理条件。结果发现采用乙醇及甲醇溶样时MAGE 2表位多肽有异构体产生 ,极性溶剂DMSO溶样的表位多肽未有异构现象发生。     

Synthetic Peptide ΔM4-Induced Cell Death Associated with Cytoplasmic Membrane Disruption,Mitochondrial Dysfunction and Cell Cycle Arrest in Human Melanoma Cells

Melanoma is the most dangerous and lethal form of skin cancer, due to its ability to spread to different organs if it is not treated at an early stage. Conventional chemotherapeutics are failing as a result of drug resistance and weak tumor selectivity. Therefore, efforts to evaluate novel molecules for the treatment of skin cancer are necessary. Antimicrobial peptides have become attractive anticancer agents because they execute their biological activity with features such as a high potency of action, a wide range of targets, and high target specificity and selectivity. In the present study, the antiproliferative activity of the synthetic peptide ΔM4 on A375 human melanoma cells and spontaneously immortalized HaCaT human keratinocytes was investigated. The cytotoxic effect of ΔM4 treatment was evaluated through propidium iodide uptake by flow cytometry. The results indicated selective toxicity in A375 cells and, in order to further investigate the mode of action, assays were carried out to evaluate morphological changes, mitochondrial function, and cell cycle progression. The findings indicated that ΔM4 exerts its antitumoral effects by multitarget action, causing cell membrane disruption, a change in the mitochondrial transmembrane potential, an increase of reactive oxygen species, and cell cycle accumulation in S-phase. Further exploration of the peptide may be helpful in the design of novel anticancer peptides.     

Organotin(IV)‐Loaded Mesoporous Silica as a Biocompatible Strategy in Cancer Treatment

The strong therapeutic potential of an organotin(IV) compound loaded in nanostructured silica (SBA‐15pSn) is demonstrated: B16 melanoma tumor growth in syngeneic C57BL/6 mice is almost completely abolished. In contrast to apoptosis as the basic mechanism of the anticancer action of numerous chemotherapeutics, the important advantage of this SBA‐15pSn mesoporous material is the induction of cell differentiation, an effect unknown for metal‐based drugs and nanomaterials alone. This non‐aggressive mode of drug action is highly efficient against cancer cells but is in the concentration range used nontoxic for normal tissue. JNK (Jun‐amino‐terminal kinase)‐independent apoptosis accompanied by the development of the melanocyte‐like nonproliferative phenotype of survived cells indicates the extraordinary potential of SBA‐15pSn to suppress tumor growth without undesirable compensatory proliferation of malignant cells in response to neighboring cell death.     

Ag@TiO2 Nanoprisms with Highly Efficient Near‐Infrared Photothermal Conversion for Melanoma Therapy

Melanoma is a primary reason of death from skin cancer and associated with high lethality. Photothermal therapy (PTT) has been developed into a powerful cancer treatment technique in recent years. Here, we created a low‐cost and high‐performance PTT agent, Ag@TiO₂ NPs, which possesses a high photothermal conversion efficiency of ≈65 % and strong near‐infrared (NIR) absorption about 808 nm. Ag NPs were synthesized using a two‐step method and coated with TiO₂ to obtain Ag@TiO₂ NPs by a facile sol‐gel method. Because of the oxide, Ag@TiO₂ NPs exhibit remarkable high photothermal conversion efficiencies and biocompatibility in vivo and in vitro. Cytotoxicity and therapeutic efficiency of photothermal cytotoxicity of Ag@TiO₂ NPs were tested in B16‐F10 cells and C57BL/6J mice. Under light irradiation, the elevated temperature causes cell death in Ag NPs‐treated (100 μg mL^?1) cells in vitro (both p<0.01). In the case of subcutaneous melanoma tumor model, Ag@TiO₂ NPs (100 μg mL^?1) were injected into the tumor and irradiated with a 808 nm laser of 2 W cm^?2 for 1 minute. As a consequence, the tumor volume gradually decreased by NIR laser irradiation with only a single treatment. The results demonstrate that Ag@TiO₂ NPs are biocompatible and an attractive photothermal agent for cutaneous melanoma by local delivery.     

The role of cobalt,copper, nickel,and zinc in the DNA replication inhibitory activity of p‐aminophenyl triphenylporphyrin

Cationic porphyrins have been widely used as tumor localizers in cancer therapies. When cationic porphyrins are flat they intercalate with double‐stranded DNA, duplexes of RNA or RNA–DNA. The antitumor activity of some cationic porphyrins depends on their interaction with human telomeric quadruplexes. Here, we report that noncationic meso‐(4‐aminophenyl)triphenylporphyrin (H₂TPPNH₂) ( 3 ) and its cobalt, copper, nickel, and zinc metallo derivatives ( 4 – 7 ) have DNA replication inhibitory activity in B16 mouse melanoma line cells. By means of quantification of ³HdTT radio‐labeled DNA, we observed that the nonplanar porphyrin [CoTPPNH₂] has the highest activity against carcinogenic DNA replication. Copyright © 2004 John Wiley & Sons, Ltd.     

A Self-Assembled ATP Probe for Melanoma Cell Imaging

In this investigation, a new terpyridine metal complex was developed as a probe for selective detection of ATP and imaging of melanoma cells. The probe takes advantage of the ability of the metal complex to be transformed to its imaging competent turn-on state through assembly with ATP.     

A Self‐Delivery Chimeric Peptide for Photodynamic Therapy Amplified Immunotherapy

In this paper, a self‐delivery chimeric peptide PpIX‐PEG₈‐KVPRNQDWL is designed for photodynamic therapy (PDT) amplified immunotherapy against malignant melanoma. After self‐assembly into nanoparticles (designated as PPMA), this self‐delivery system shows high drug loading rate, good dispersion, and stability as well as an excellent capability in producing reactive oxygen species (ROS). After cellular uptake, the ROS generated under light irradiation could induce the apoptosis and/or necrosis of tumor cells, which would subsequently stimulate the anti‐tumor immune response. On the other hand, the melanoma specific antigen (KVPRNQDWL) peptide could also activate the specific cytotoxic T cells for anti‐tumor immunity. Compared to immunotherapy alone, the combined photodynamic immunotherapy exhibits significantly enhanced inhibition of melanoma growth. Both in vitro and in vivo investigations confirm that PDT of PPMA has a positive effect on anti‐tumor immune response. This self‐delivery system demonstrates a great potential of this PDT amplified immunotherapy strategy for advanced or metastatic tumor treatment.