基于钙离子驱动的药物负载构建光响应性介孔硅纳米粒的研究

目的 提高介孔硅纳米粒(mesoporous silicon nanoparticles,MSNs)中药物负载量,并使其具备光响应性等功能。方法 本研究采用模板法制备氨基化的介孔硅纳米粒(MSN-NH₂),并通过钙离子负载的MSNs(MSN-Ca)诱导化疗药物阿霉素(Doxorubicin,Dox)及光热治疗药物Cypate、二氢卟吩e6(Ce6)的高效负载,制得光响应性载单药或多药的MSNs,并对其理化性质及释药特性进行研究。结果 钙离子可有效负载于MSNs内,并可以诱导Dox、Cypate、Ce6在MSNs孔道内的高效负载,其载药量可分别达到(28.5±1.4)%,(36.8±1.5)%,(36.6±1.7)%;MSN-Ca还可以实现Dox、Cypate、Ce6中的2种或3种药物共同负载。负载Cypate的MSNs具有良好的光热升温效果。载Dox的MSNs具有酸性pH响应性释放Dox的特点。785 nm激光照射可明显增强MSN-Ca-Dox/Cypate的Dox释放,具有光响应性释药的特点。结论 钙离子驱动的药物负载策略在多功能MSNs的构建及其抗肿瘤协同治疗研究中具有重要作用。     

Synthesis,Characterization, and In vitro Studies of PLGA–PEG Nanoparticles for Oral Insulin Delivery

Therapeutic proteins and peptides are corresponding to a major area of research in biotechnology companies and current pharmaceutical. Because of their natural instability, the enormous majority of these drugs require parentéral administration. Oral insulin delivery would be a highly attractive alternative process of administration, though it continues to be a mysterious target due to the enzymatic digestion of insulin and low levels of absorption from the gastrointestinal region. Hydrogel polymers can be considered as potential carriers for oral insulin delivery. In particular, a pH responsive hydrogel composed of PLGA–PEG has shown the ability to protect insulin from enzymes in the gastric environment and release in small intestines. However, this material has not shown similar potential for oral protein delivery of further model drugs. To date, the unique interaction between PLGA–PEG and insulin, as a potential drug for oral delivery, is not completely understood. The focus of this research is synthetization and characterization of hydrogels PLGA–PEG insulin nanoparticles and also pH sensitivity of insulin nanoparticles was investigated.     

Chitosan‐Coated Superparamagnetic Iron Oxide Nanoparticles for Doxorubicin Delivery: Synthesis and Anticancer Effect Against Human Ovarian Cancer Cells

Doxorubicin‐loaded chitosan‐coated superparamagnetic iron oxide nanoparticles (Fe₃O₄; SPIO‐NPs) were prepared by coprecipitation and emulsification cross‐linking method and uniform NPs with an average particle size of 82 nm, with high encapsulation efficiencies, were obtained. The drug‐loading efficiency of doxorubicin (3.2 mg/mg NPs) showed better results for the chitosan‐loaded SPIO‐NPs as compared to the bare ones (0.5 mg/mg; p < 0.05). The incubation of A2780 and OVCAR‐3 human ovarian cancer cells with doxorubicin‐loaded and doxorubicin‐loaded chitosan‐coated SPIO‐NPs, for 24, 48, 72, 96, and 120 h, showed significant IC₅₀ (2.0 ± 0.6 and 7.1 ± 2.7 mm doxorubicin) and IC₉₀ (4.0 ± 9.2 and 10 ± 0.5 mm doxorubicin), respectively, after 96 h of incubation. While, 95% and 98% growth inhibition was seen in A2780 and OVCAR‐3 cells after the 96‐h exposure to the doxorubicin‐chitosan‐SPIO‐NPs (p < 0.05). A 5‐day (120 h) incubation with doxorubicin‐chitosan‐SPIO‐NPs showed that A2780 and OVCAR‐3 cells were able to uptake 120 and 110 pg iron/cell, respectively, when treated with doxorubicin‐chitosan‐SPIO‐NPs for 72 h (p < 0.05).     

β‐lactoglobulin–pectin Nanoparticle‐based Oral Drug Delivery System for Potential Treatment of Colon Cancer

Colon cancer is one of the most common internal malignancies, and conventional chemotherapy is not effective in its treatment. Nanoparticles hold tremendous potential as an effective drug delivery system. The physicochemical properties of β‐lactoglobulin, the main whey protein of cow's milk, such as its stability at low pH, its resistance to gastric protease, and its ability to bind hydrophobic ligands, give it potential for transporting drugs specifically for colon cancer. In the present research, β‐lactoglobulin–pectin nanoparticles were designed to transfer a newly synthesized, anticancer platinum complex (bipyridine ethyl dithiocarbamate Pt(II) nitrate), to the colon. The effects of multiple factors on the size and the colloidal stability of the nanoparticles were studied using dynamic light scattering and scanning electron microscopy techniques. Results showed that the best particle size and highest colloidal stability were obtained in phosphate buffer, pH 4.5, with 0.5 mg/mL β‐lactoglobulin and 0.025–0.05wt% pectin. The drug release profile in simulated gastrointestinal conditions demonstrated that β‐lactoglobulin with a secondary coating is stable in acidic conditions but is able to release its cargo at pH 7. Hence, these nanoparticles have potential to serve as novel and effective vehicles for oral drug delivery preparations.     

Heat‐Shock Protein 90 (Hsp90) as Anticancer Target for Drug Discovery: An Ample Computational Perspective

There are over 100 different types of cancer, and each is classified based on the type of cell that is initially affected. If left untreated, cancer can result in serious health problems and eventually death. Recently, the paradigm of cancer chemotherapy has evolved to use a combination approach, which involves the use of multiple drugs each of which targets an individual protein. Inhibition of heat‐shock protein 90 (Hsp90) is one of the novel key cancer targets. Because of its ability to target several signaling pathways, Hsp90 inhibition emerged as a useful strategy to treat a wide variety of cancers. Molecular modeling approaches and methodologies have become ‘close counterparts’ to experiments in drug design and discovery workflows. A wide range of molecular modeling approaches have been developed, each of which has different objectives and outcomes. In this review, we provide an up‐to‐date systematic overview on the different computational models implemented toward the design of Hsp90 inhibitors as anticancer agents. Although this is the main emphasis of this review, different topics such as background and current statistics of cancer, different anticancer targets including Hsp90, and the structure and function of Hsp90 from an experimental perspective, for example, X‐ray and NMR, are also addressed in this report. To the best of our knowledge, this review is the first account, which comprehensively outlines various molecular modeling efforts directed toward identification of anticancer drugs targeting Hsp90. We believe that the information, methods, and perspectives highlighted in this report would assist researchers in the discovery of potential anticancer agents.     

The toxicity and distribution of iron oxide–zinc oxide core‐shell nanoparticles in C57BL/6 mice after repeated subcutaneous administration

Therapeutic cancer vaccines promote immune responses by delivering tumour‐specific antigens. Recently, we developed iron oxide (Fe₃O₄)–zinc oxide (ZnO) core‐shell nanoparticles (CSNPs) as carriers for antigen delivery into dendritic cells (DCs), and the CSNPs were injected subcutaneously into C57BL/6 mice to examine the systemic toxicity, tissue distribution and excretion of the CSNPs. The doses injected were 0, 4, 20 and 200 mg kg^–1 weekly for 4 weeks. No significant changes were observed after the CSNPs administration with respect to mortality, clinical observations, body weight, food intake, water consumption, urinalysis, haematology, serum biochemistry,and organ weights. A dose‐dependent increase in granulomatous inflammation was observed at the injection site of the CSNP‐treated animals, but no other histopathological lesions in other organs could be attributed to the CSNPs. The Zn concentration, which is an indicator for CSNPs, was not significantly higher in the sampled tissues, urine, or faeces after the CSNP injection. In contrast, the Zn concentration at the subcutaneous skin of the site injected with the CSNPs increased in a dose‐dependent manner, along with a macroscopic deposition of the CSNPs. The CSNP residue at the injection site resulted in a foreign body response with the appearance of macrophage infiltration, but otherwise did not show any systemic distribution or toxicity at up to 200 mg kg^–1 during this study. In conclusion, CSNPs could be used as good antigen carriers for DC‐based immunotherapy, although further study is needed to completely clear the residue of the CSNPs at the injection site. Copyright © 2015 John Wiley & Sons, Ltd.     

Discovery of New Sites for Drug Binding to the Hypertension‐Related Renin–Angiotensinogen Complex

Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ≈ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small drug‐like molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension.     

Novel reduction‐sensitive micellar nanoparticles assembled from Rituximab–doxorubicin conjugates as smart and intuitive drug delivery systems for the treatment of non‐Hodgkin's lymphoma

In this study, a novel reduction‐sensitive drug delivery system, the rituximab–doxorubicin (RTX‐DOX) micellar nanoparticle (RDMN), was specially designed for targeted delivery and release of DOX in non‐Hodgkin's lymphoma (NHL) cells. The RDMN was fabricated by self‐assembling of amphiphilic RTX‐DOX conjugates (RDCs), which were synthesized by conjugating the hydrophilic Fab fragments of RTX (an anti‐CD20 monoclonal antibody) and hydrophobic DOXs by a reduction‐responsive linker, 3‐(2‐Pyridyldithio) propionyl hydrazide (PDPH). The RDMNs were characterized via dynamic light scattering and transmission electron microscopy, both showed the sizes of approximately 94.1 ± 14.5 nm with a uniform size distribution. Polyplex dissociation, which was indicated by accelerated DOX release rate and increased particle size, was observed in the presence of 2.5 mm 1,4‐dithiothreitol due to the cleavage of disulfide bonds in PDPH linkers. In vitro transfection assays against human NHL cell line, JeKo‐1, showed significantly increased uptake for RDMNs, as compared to RDCs and free RTX/DOX. Both in and ex vivo experiments demonstrated that RDMNs showed the highest therapeutic effect among all the experimental groups. These results suggested that this RDMN could be a potential, safe and efficient drug delivery vector, which deserves further investigation in the clinic.     

Synthesis,molecular modeling,in vivo study,and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen

A new series of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen ( 7a–m ) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier‐transform infrared spectroscopy, ¹H‐nuclear magnetic resonance (NMR), ¹³C‐NMR, and high‐resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase‐2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU‐145, and LNCaP) using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU‐145 and LNCaP cancer cell lines with IC₅₀ values of 26.0, 34.5, and 48.8 μM, respectively. Compounds 7b , 7k , and 7m showed anticancer activity against cancer cell lines PC3 and DU‐145 with IC₅₀ values of 43.0, 36.5, 29.3 μM and 49.8, 49.1, 31.6 μM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC₅₀ values of 43.4 and 34.5 μM, respectively. To assess the biodistribution in mice of IRDye800, dye‐labeled compound 7a or 100 μM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.     

A new approach for 11C–C bond formation: Synthesis of 17α‐(3′‐[11C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol

A new approach for ¹¹C–C bond formation via a Sonogashira‐like cross‐coupling reaction of terminal alkynes with [¹¹C]methyl iodide was exemplified by the synthesis of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol. The LC‐purified title compound was obtained in decay‐corrected radiochemical yields of 27–47% (n=8) based on [¹¹C]methyl iodide within 21–27 min after EOB. In a typical synthesis starting from 9.6 GBq [¹¹C]methyl iodide, 1.87 GBq of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol was synthesized in radiochemical purity >99%. The specific radioactivity ranged between 10 and 19 GBq/µmol, and the labeling position was verified by ¹³C‐NMR analysis of the corresponding ¹³C‐labeled compound. Copyright © 2003 John Wiley & Sons, Ltd.