Multifunctionalized CMCht/PAMAM Dendrimer Nanoparticles Modulate the Cellular Uptake by Astrocytes and Oligodendrocytes in Primary Cultures of Glial Cells

The efficiency of the treatments involving CNS disorders is commonly diminished by the toxicity, reduced stability and lack of targeting of the administered neuroactive compounds. In this study, we have successfully multifunctionalized CMCht/PAMAM dendrimer nanoparticles by coupling the CD11b antibody and loading MP into the nanoparticles. The modification of the new antibody‐conjugated nanoparticles was confirmed by S‐TEM observation and ¹H NMR and FTIR spectroscopy. Cytotoxicity assays revealed that the conjugates did not affect the viability of both primary cultures of glial and microglial cells. Trace analyses of FITC‐labelled nanoparticles revealed that the uptake of antibody‐conjugated nanoparticles was conserved in microglial cells but significantly decreased in astrocytes and oligodendrocytes. Thus, this study demonstrates that antibody conjugation contributes to a modulation of the internalization of these nanocarriers by different cell types, which might be of relevance for specific targeting of CNS cell populations.

     

Prostate‐Cancer‐Targeted N‐(2‐Hydroxypropyl)methacrylamide Copolymer/Docetaxel Conjugates

Biodistribution, pharmacokinetics, and efficacy of prostate‐cancer‐targeted HPMA copolymer/DTX conjugates are evaluated in nude mice bearing prostate cancer C4‐2 xenografts. PSMA‐specific monoclonal antibodies 3F/11 are used as the targeting moiety. Control conjugates contain either non‐specific IgG or no IgG. The ratios of tumor accumulation to total background organs (heart, lung, kidney, liver, spleen and blood) accumulation increase substantially with time for the targeted conjugate, and the ratio at 48 h is 7‐fold higher than that at 6 h. Preliminary evaluation of the efficacy of the conjugates in vivo show tumor growth inhibition for all HPMA copolymer/DTX conjugates.

     

自建光声超声双模态成像系统的肿瘤成像分析

现有B超成像可以提供基于声阻抗差异的组织解剖结构信息,而近年来研究发现,光声成像可以提供标记组织成分的分布和功能信息。本文基于商用B超仪和脉冲激光系统建立了光声超声双模态成像系统,实现了超声组织结构成像和光声生物功能的同时成像。首先基于血红蛋白在某些波段的较强吸光性,实现了肿瘤内部组织血管灌注图像;其次用链接有靶向抗体的纳米颗粒作为靶向光声造影剂,对恶性肿瘤边缘和内部的血管以及血管附近的肿瘤组织进行了成像。最终,通过超声和光声的融合图像提供的肿瘤结构信息与光声图像提供的肿瘤功能信息,可以准确识别肿瘤组织。     

液相色谱-高分辨质谱联用技术在食品欺诈检测鉴别中的应用

针对我国现阶段较为突出的违法使用农兽药、滥用食品添加剂、非法添加非食用物质和掺杂使假等食品欺诈问题,综述了近5年来液相色谱-高分辨质谱联用技术在该领域的应用情况。重点介绍了高分辨质谱,主要是飞行时间质谱和静电场轨道阱质谱技术的定向筛查和非定向筛查功能在食品欺诈检测鉴别中的应用,以期为解决该类食品安全问题提供有益的参考。     

叶酸受体介导的肿瘤靶向光学成像技术

叶酸受体(FR)在肿瘤细胞中都有过度表达,而在正常组织中保守表达,利用叶酸受体与叶酸及其类似物高亲合力结合的特性,将叶酸偶联荧光探针输送到肿瘤组织,从而实现肿瘤组织的特异性靶向光学成像。本文阐述了叶酸荧光探针的结构及其用于标记肿瘤细胞的作用机制,介绍了近十年来叶酸受体介导的肿瘤靶向光学成像技术,例如有机荧光染料,染料掺杂纳米颗粒,量子点,磁性纳米微粒以及多功能纳米粒子等在肿瘤靶向成像中的研究及应用进展,指出了当前研究中的主要发展方向和仍需解决的问题。     

叶酸靶向乙酰普鲁兰纳米粒的制备及其靶向作用

以普鲁兰多糖为主链, 通过乙酰化反应合成了疏水性的乙酰普鲁兰(PA), 然后以N,N′-二环己基碳二亚胺(DCC)为偶联剂, 4-二甲氨基吡啶(DMAP)为催化剂, 将叶酸与PA偶联(FPA); 采用¹H NMR和X射线晶体衍射(XRD)等方法对产物结构进行了表征. 采用溶剂扩散法制备包载表阿霉素的PA和FPA纳米粒, 载药纳米粒形态为球形, 动态光散射粒径分析显示载药纳米粒粒径随载药量增加而增大. 透析法测定纳米粒中表阿霉素的体外释放表明, FPA纳米粒中药物释放速度快于PA纳米粒; 采用激光共聚焦显微镜观察PA/EPI及FPA/EPI纳米粒在KB细胞的摄取情况, 结果表明, FPA/EPI纳米粒进入细胞主要通过叶酸受体途径, 而PA/EPI纳米粒进入细胞与叶酸受体无关, 提示FPA将成为具有一定肿瘤靶向作用的新型载体.     

An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market ‘boom’, garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have been granted FDA approval, with eight of these approved since 2017 alone. Optimism for this therapeutic approach is clear, despite the COVID-19 pandemic, 2020 was a landmark year for deals and partnerships in the ADC arena, suggesting that there remains significant interest from Big Pharma. Herein we review the enthusiasm for ADCs by focusing on the features of those approved by the FDA, and offer some thoughts as to where the field is headed.     

Enhanced Anti-Tumor Effect of Folate-Targeted FA-AMA-hyd-DOX Conjugate in a Xenograft Model of Human Breast Cancer

Folate-aminocaproic acid-doxorubicin (FA-AMA-hyd-DOX) was firstly synthesized by our group. It was indicated that FA-AMA-hyd-DOX was pH-responsive, and had strong cytotoxicity on a folate receptor overexpressing cell line (KB cells) in vitro. The aim of our study was to further explore the potential use of FA-AMA-hyd-DOX as a new therapeutic drug for breast cancer. The cellular uptake and the antiproliferative activity of the FA-AMA-hyd-DOX in MDA-MB-231 cells were measured. Compared with DOX, FA-AMA-hyd-DOX exhibited higher targeting ability and cytotoxicity to FR-positive tumor cells. Subsequently, the tissue distribution of FA-AMA-hyd-DOX was studied, and the result confirmed that DOX modified by FA can effectively increase the selectivity of drugs in vivo. After determining the maximum tolerated dose (MTD) of FA-AMA-hyd-DOX in MDA-MB-231 tumor-bearing nude mice, the antitumor effects and the in vivo safety of FA-AMA-hyd-DOX were systematically evaluated. The data showed that FA-AMA-hyd-DOX could effectively increase the dose of DOX tolerated by tumor-bearing nude mice and significantly inhibit MDA-MB-231 tumor growth in vivo. Furthermore, FA-AMA-hyd-DOX treatment resulted in almost no obvious damage to the mice. All the positive data suggest that FA-targeted FA-AMA-hyd-DOX is a promising tumor-targeted compound for breast cancer therapy.     

Comparison of Experimental Strategies to Study l-Type Amino Acid Transporter 1 (LAT1) Utilization by Ligands

l-Type amino acid transporter 1 (LAT1), expressed abundantly in the brain and placenta and overexpressed in several cancer cell types, has gained a lot of interest in drug research and development, as it can be utilized for brain-targeted drug delivery, as well as inhibiting the essential amino acid supply to cancer cells. The structure of LAT1 is today very well-known and the interactions of ligands at the binding site of LAT1 can be modeled and explained. However, less is known of LAT1′s life cycle within the cells. Moreover, the functionality of LAT1 can be measured by several different methods, which may vary between the laboratories and make the comparison of the results challenging. In the present study, the usefulness of indirect cis-inhibition methods and direct cellular uptake methods and their variations to interpret the interactions of LAT1-ligands were evaluated. Moreover, this study also highlights the importance of understanding the intracellular kinetics of LAT1-ligands, and how they can affect the regular function of LAT1 in critical tissues, such as the brain. Hence, it is discussed herein how the selected methodology influences the outcome and created knowledge of LAT1-utilizing compounds.     

A Novel Method of Magnetic Nanoparticles Functionalized with Anti-Folate Receptor Antibody and Methotrexate for Antibody Mediated Targeted Drug Delivery

Therapeutic effects of anticancer medicines can be improved by targeting the specific receptors on cancer cells. Folate receptor (FR) targeting with antibody (Ab) is an effective tool to deliver anticancer drugs to the cancer cell. In this research project, a novel formulation of targeting drug delivery was designed, and its anticancer effects were analyzed. Folic acid-conjugated magnetic nanoparticles (MNPs) were used for the purification of folate receptors through a novel magnetic affinity purification method. Antibodies against the folate receptors and methotrexate (MTX) were developed and characterized with enzyme-linked immunosorbent assay and Western blot. Targeting nanomedicines (MNP-MTX-FR Ab) were synthesized by engineering the MNP with methotrexate and anti-folate receptor antibody (anti-FR Ab). The cytotoxicity of nanomedicines on HeLa cells was analyzed by calculating the % age cell viability. A fluorescent study was performed with HeLa cells and tumor tissue sections to analyze the binding efficacy and intracellular tracking of synthesized nanomedicines. MNP-MTX-FR Ab demonstrated good cytotoxicity along all the nanocomposites, which confirms that the antibody-coated medicine possesses the potential affinity to destroy cancer cells in the targeted drug delivery process. Immunohistochemical approaches and fluorescent study further confirmed their uptake by FRs on the tumor cells’ surface in antibody-mediated endocytosis. The current approach is a useful addition to targeted drug delivery for better management of cancer therapy along with immunotherapy in the future.