Current Topics in Medicinal Chemistry - Volume 21, Issue 14, 2021

Background: Despite advances in surgery, radiotherapy and chemotherapy, brain tumors are still a major health issue due to poor prognosis and high mortality rate. The current treatment options have limited efficiency. The main barriers to effective clinical treatment are systemic toxicity of cytotoxic compounds, the physical and functional barrier of the blood-brain barrier (BBB), and low selectivity of the therapeutic agents to tumor cells. Objective: The study aimed to review the advances in targeted drug delivery systems and strategies for brain tumors. Methods: We searched the electronic databases of PubMed, EMBASE, Web of Science, BIOSIS Previews, Cambridge Scientific Abstracts, google scholar and additional sources for published and unpublished trials using the set search terms. The date of the most recent search was 20 March 2020. The studies investigating the applications of targeted drug delivery for brain tumors were collected and the most relevant studies were selected for a comprehensive review. Results: Different anticancer agents and nucleic acid-based therapies have been developed and assessed as novel targeted drug delivery techniques for brain tumors. New vehicles include polymeric and liposomal nanoparticles (NPs), wafers, microchips, microparticle-based nanosystems and cells-based vectors. Strong evidence from preclinical and translational studies indicate the great potential of these NPs-based technologies for use in brain tumors and improving the therapeutic outcomes. Research is ongoing to develop effective new anticancer agents as well as strategies for BBB modulation and penetration. Conclusion: New targeted drug delivery systems based on stimuli-responsive NPs have shown promising outcomes in brain tumors. Advances in material design and nanochemistry lead to enhanced intracranial concentrations. Non-invasive technologies such as magnetic resonance imaging- guided ultrasound and high-intensity focused ultrasound have been utilized for BBB modulation with higher precision and improved drug delivery performance.

Background: Recent evidence has been demonstrated that Sinomenine (SIN) exerts antitumor activity in vitro. However, the clinical utility of SIN remains limited mainly because of its poor bioavailability. Exosomes are nanoscale vesicles that play crucial roles in intracellular communications through functionally active substances such as DNA and RNA. Exosomes have been utilized as nanocarriers for targeted drug delivery of different anticancer drugs. Methods: The present study aimed to evaluate the effectiveness of combined Exosomes-SIN for the treatment of hepatocellular carcinoma (HCC) in a rat model. To do so, we prepared a mixture of SIN and exosomes (Exo-SIN) to improve the bioavailability of SIN to treat liver cancer. The in vitro releasing profile of the Exo-SIN was examined. Results: We observed a continuous, slow release of SIN from Exo-SIN in simulated body fluid as well as tumor microenvironment. In the cytotoxicity test, Exo-SIN exhibited a significantly stronger inhibition in HepG2 cells compared to free SIN. The flow cytometry assessments showed that Exo-SIN could suppress HepG2 cell migration in a Transwell assay and induce cell cycle arrest and cellular apoptosis. Western blotting showed that survivin, a crucial protein for the survival of living cells, was significantly downregulated after treatment with Exo-SIN. Conclusion: In conclusion, our data suggested that Exo-SIN could serve as a potential, effective delivery platform for hepatic carcinoma therapy.

Background: Virus-like Particles (VLPs) are non-genetic multimeric nanoparticles synthesized through in vitro or in vivo self-assembly of one or more viral structural proteins. Immunogenicity and safety of VLPs make them ideal candidates for vaccine development and efficient nanocarriers for foreign antigens or adjuvants to activate the immune system. Aims: The present study aimed to design and synthesize a chimeric VLP vaccine of the phage Qbeta (Qβ) coat protein presenting the universal epitope of the coronavirus. Methods: The RNA phage Qβ coat protein was designed and synthesized, denoted as Qbeta. The CoV epitope, a universal epitope of coronavirus, was inserted into the C-terminal of Qbeta using genetic recombination, designated as Qbeta-CoV. The N-terminal of Qbeta-CoV was successively inserted into the TEV restriction site using mCherry red fluorescent label and modified affinity purified histidine label 6xHE, which was denoted as HE-Qbeta-CoV. Isopropyl β-D-1-thiogalactopyranoside (IPTG) assessment revealed the expression of Qbeta, Qbeta-CoV, and HE-Qbeta-CoV in the BL21 (DE3) cells. The fusion protein was purified by salting out using ammonium sulfate and affinity chromatography. The morphology of particles was observed using electron microscopy. The female BALB/C mice were immunized intraperitoneally with the Qbeta-CoV and HE-Qbeta-- CoV chimeric VLPs vaccines and their sera were collected for the detection of antibody level and antibody titer using ELISA. The serum is used for the neutralization test of the three viruses of MHV, PEDV, and PDCoV. Results: The results revealed that the fusion proteins Qbeta, Qbeta-CoV, and HE-Qbeta-CoV could all obtain successful expression. Particles with high purity were obtained after purification; the chimeric particles of Qbeta-CoV and HE-Qbeta-CoV were found to be similar to Qbeta particles in morphology and formed chimeric VLPs. In addition, two chimeric VLP vaccines induced specific antibody responses in mice and the antibodies showed certain neutralizing activity. Conclusion: The successful construction of the chimeric VLPs of the phage Qβ coat protein presenting the universal epitope of coronavirus provides a vaccine form with potential clinical applications for the treatment of coronavirus disease.

Background and Objective: Mesenchymal stem cells (MSCs), particularly bone MSCs (BMSCs) offer great potentials for targeted therapeutic applications owing to their migratory and differentiation capacities. Significant advances have been achieved in the differentiation of hepatocyte or hepatocyte-like cells both in vitro and in vivo. However, there is limited knowledge on the differentiation of BMSCs into bipotential hepatic progenitor cells or cholangiocyte. This study reviews the potentials and advances in using MSCs as vehicles for targeted drug delivery and proposes a new method for the induction of differentiation in rat BMSCs into hepatic progenitor cells in vitro and assesses the differential and migratory capacities. Methods: The BMSCs of Sprague Dawley (SD) rats were harvested from the femur and the tibiae of the rats. After isolation and culturing, BMSCs from Passage 1 were used for the study. The in vitro differentiation of the hepatic progenitor cells was performed using a 2-step induction approach after 5-day serum deprivation from the BMSCs and culturing in Dulbecco's modified eagle medium. Spontaneous in vitro differentiation of BMSCs was examined in the absence of growth factors for 15 days as control treatment. Hepatocytes differentiation was achieved by exposing the culture to collagen type I-coated plates. Cholangiocytes differentiation was achieved with replating the BMC-HepPCs on a layer of Matrigel. Immunofluorescence was conducted on twelve-well plates to determine cell differentiations. Real-Time Quantitative Reverse Transcription PCR (qRTPCR) was used to determine the total RNA extracted using the Trizol LS reagent. In the hepatocyte differentiation group, after periodic acid-schiff (PAS) staining for glycogen, inverted microscope was used to determine differentiations and undifferentiated BMC-HepPCs served as controls. The amount of low-density lipoprotein (LDL) uptake by the BMSCs-derived hepatocytes was assessed using fluorescence microscopy. The secretion of rat albumin was quantified using a quantitative ELISA kit. Results: Differentiation induction is indicative of the sequential supplementation of sodium butyrate and cytokines, which are involved in the embryonic development of the mammalian liver. Hepatic progenitor cells, derived from bone marrow, can be differentiated bidirectionally in vitro into both hepatocyte and cholangiocyte cell-lines. The differentiated cells, including hepatic progenitor cells, hepatocytes, and bile duct-like cells, were identified and analyzed at mRNA and protein levels. Conclusion: Our findings show that BMSCs can be utilized as novel bipotential hepatic progenitor cells and thereby for hepatobiliary disease treatment or hepatobiliary tissue-engineering.

Aims: Research on developing targeted delivery of anticancer drugs for the treatment of hepatocellular carcinoma (HCC) is ongoing. This study aimed to synthesize nanoliposomes modified by glycyrrhetinic acid (GA) and ferric tetroxide (Fe3O4) for targeted delivery of paclitaxel for selective and specific therapy of HCC. Objective: During this project, GA and Fe3O4 were used to jointly modify the active targeting and magnetic orientation of paclitaxel nanoliposomes for enhanced targeting of HCC to improve the efficacy, while reducing the systemic toxicity and side effects of the drug. Methods: In this study, liposomes were prepared utilizing a thin film dispersion method, in which the average particle size of GA/Fe3O4-PTX-LP was 148.9 ± 2.3 nm, and the average Zeta potential was -23.2 ± 3 mV. Based on TEM characterization, GA/Fe3O4-PTX-LP is a closed particle with bilayer membranes. In vitro release assessments of the drug indicated that the release of GA/Fe3O4- PTX-LP was sustained. Results: In vitro cell tests have demonstrated that GA/Fe3O 4-PTX-LP can inhibit the proliferation, affect the morphology, migration and invasion, and interfere with the cycle of HCC cells. Uptake tests have confirmed that GA/Fe3O4-PTX-LP can promote the uptake of the drug in HCC cells. Conclusion: In vivo targeting experiments have shown that GA/Fe3O4-PTX-LP has a strong ability to target tumors. In vivo antitumor assessments have proven that GA/Fe3O4-PTX-LP can inhibit tumor growth without obvious toxicity. This project provides a promising nano-targeted drug delivery system for the treatment of HCC.

Background: Epithelial Ovarian Carcinoma (EOC) is a ubiquitous gynecological malignancy with complicated pathogenesis. Genetic risk factors and pathways involved in the prognosis of this cancer are not yet understood completely. Determining genetic markers with diagnostic and prognostic values would pave the way for efficient management of cancer. Objective: This study aimed to investigate the genes and the regulatory networks involved in the occurrence and prognosis of EOC through different bioinformatics analysis tools. In addition, recent advances in using bioinformatic analysis approaches based on the genes and regulatory networks, particularly Differentially Expressed Genes (DEGs) in improving the diagnosis and prognosis of EOC, are discussed. Methods: The gene expression profiles of GSE18520, GSE54388, and GSE27651 were downloaded from the Gene Expression Omnibus (GEO) database and further analyzed with different analyses in R language. Current literature on using bioinformatics based on DEGs and associated regulatory networks to improve the diagnosis and prognosis of EOC was reviewed. Results: Analyses of the gene expression levels between the malignant tissue against normal tissue unveiled 163 DEGs. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on the target genes using cluster profile package and Cytoscape package was employed to assess the protein interaction network of these genes. The protein-protein interaction network was analyzed using the CytoHubba plug-in to identify 20 hub genes. In addition, we analyzed the prognosis of the hub genes using the Kaplan-Meier survival analysis that revealed evident differences in the prognosis of 13 genes. The malignant tissues exhibited a differential expression of 12 genes against healthy tissues as shown by Gene Expression Profiling Interactive Analysis (GEPIA) analysis. Conclusion: Findings of this study revealed 12 genes to be significantly up-regulated and the prognosis was significantly different, which could be employed to potentially target EOC in clinical practice.

Background and Objective: Chromosomal abnormalities are one of the genetic disorders caused by abnormal chromosome number or structure and can endanger multiple organs, morphology and function of the systems in the human body. This study aims to investigate the relationship between prenatal diagnosis indications and abnormal karyotypes to improve prenatal screening. Methods: The karyotype analyses were carried out on 4646 pregnant women with prenatal diagnosis indications referred to the first medical center of Chinese PLA General Hospital from 2012 to 2019. The incidence, distribution, and statistical features of chromosomal abnormality of different prenatal diagnosis indications were analyzed, and the relationships with the prenatal diagnosis indications were assessed. Results: A total of 351 fetal chromosomal abnormalities were detected in 4646 karyotypes, with an incidence of 7.6%. The chromosomal abnormality incidence in the single indication group, two indications group, and three indications group was 5.8%, 16.1%, and 70.0%, respectively, indicating a statistically significant difference (p < 0.05). Advanced maternal age (AMA), high-risk maternal serum screening (MSS), and non-invasive prenatal DNA testing (NIPT) were the important indications for predicting abnormal karyotype. The number of prenatal diagnosis indications was highly correlated with fetal chromosomal abnormalities. The overall incidence of chromosomal abnormalities showed a tendency to increase with age. The incidence of Trisomy 21 was 3.2%, accounting for 42.5% of all chromosomal abnormalities, and the incidence tended to increase with maternal age. Conclusion: Prenatal karyotype analysis of pregnant women with prenatal diagnosis indications can effectively prevent the birth of defective children. AMA, MSS and NIPT were the important indications for predicting abnormal karyotype. In addition, the number of prenatal diagnosis indications is highly correlated with chromosomal abnormalities.