ABSTRACT
Chemotherapy as a common anticancer therapeutic modality is often challenged by various obstacles such as poor stability, low solubility, and severe side effects of chemotherapeutic agents as well as multidrug resistance of cancerous cells. Nanoparticles in the role of carriers for chemotherapeutic drugs and platforms for combining different therapeutic approaches have effectively participated in overcoming such drawbacks. In particular, nanoparticles able to induce their therapeutic effect in response to specific stimuli like tumor microenvironment characteristics (e.g., hypoxia, acidic pH, high levels of glutathione, and overexpressed hydrogen peroxide) or extrinsic stimulus of laser light bring about more precise and selective treatments. Among them, nanostructures of covalent organic frameworks (COFs) have drawn great interest in biomedical fields during recent years. Possessing large surface area, high porosity, structural stability, and customizable architecture, these biocompatible porous crystalline polymers properly translate to promising platforms for drug delivery and induction of combination therapies. With the focus on stimuli-responsive characteristics of nanoscale COFs, this study aims to propose an overview of their potentiality in cancer treatment on the basis of chemotherapy alone or in combination with sonodynamic, chemodynamic, photodynamic, and photothermal therapies.
ABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder that leads to growth cysts in the kidney, ultimately resulting in loss of function. Currently, no effective drug therapy can be safely used in the clinic. So, looking for effective therapeutic drugs is urgent for treating ADPKD. Our natural product library was prepared based on the ZINC-15 database. Lipinski's rule of five, drug-likeness, and toxicity screening of the designed library were evaluated. Swiss model online server was used for modeling of GANAB target. Finally, docking-based screening against ADPKD targets was done by MOE 2019 software. The top 14 favorable druglike and non-toxic hits were selected for docking studies. Our results showed that compound-10 (ZINC 6073947) as a sesquiterpene coumarin had more negative binding interaction into the active site of PPARG, OXSR1, GANAB, AVPR2, and PC2 with docking scores of -8.22, -7.52, -6.98, -6.61 and -6.05 kcal/mol, respectively, in comparison to Curcumin, as a natural product that is now in phase 4 clinical trial in ADPKD disease, with an affinity of -8.03, -6.42, -6.82, -5.84 and -5.10 kcal/mol, respectively. Furthermore, seven sesquiterpene coumarins similar to compound 10 were generated and docked. Farnesiferol B (16), compared to compound-10, showed binding affinity of -8.16, -6.4, -7.46, -6.92, and -6.11 kcal/mol against the above targets, respectively. Molecular dynamics, which was done on the compound-10 and 16 (Farnesiferol B) in complex with PPARG, GANAB, and AVPR2, showed more negative binding free-energy than Pioglitazone, Miglitol, and Tolvaptan as FDA-approved drugs for each target, respectively.Communicated by Ramaswamy H. Sarma.
Subject(s)
Polycystic Kidney, Autosomal Dominant , Sesquiterpenes , Humans , Polycystic Kidney, Autosomal Dominant/drug therapy , Polycystic Kidney, Autosomal Dominant/genetics , PPAR gamma , Sesquiterpenes/therapeutic use , Zinc , Protein Serine-Threonine KinasesABSTRACT
BACKGROUND: Prostate cancer is the second most prevalent and the fifth deadliest cancer among men worldwide. To improve radiotherapy outcome, we investigated the effects of 7-geranyloxycoumarin, also known as auraptene (AUR), on radiation response of prostate cancer cells. METHODS AND RESULTS: PC3 cells were pretreated with 20 and 40 µM AUR for 24, 48 and 72 h, followed by X-ray exposure (2, 4 and 6 Gy). After 72 h recovery, cell viability was determined by alamar Blue assay. Flow cytometric analysis was performed to assess apoptosis induction, clonogenic assay was carried out to investigate clonogenic survival, and the expression of P53, BAX, BCL2, CCND1 and GATA6 was analyzed by quantitative polymerase chain reaction (qPCR). Cell viability assay indicated that toxic effects of radiation was enhanced by AUR, which was also confirmed by increased numbers of apoptotic cells and reduced amount of survival fraction. The qPCR results demonstrated significant induction of P53 and BAX, while the expression of BCL2, GATA6, and CCND1 was significantly downregulated. CONCLUSION: The findings of the present study indicated, for the first time, that AUR improved radio sensitivity in prostate cancer cells, and thus, has the potential to be used in future clinical trials.
Subject(s)
Prostatic Neoplasms , Tumor Suppressor Protein p53 , Male , Humans , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism , Tumor Suppressor Protein p53/genetics , Apoptosis , Radiation Tolerance/physiology , Prostatic Neoplasms/metabolism , Cell Line, TumorABSTRACT
The application of novel bacterial strains for effective biosynthesis of nanoparticles minimizes negative environmental impact and eliminates challenges of available approaches. In the present study, cell-free extract of Stenotrophomonas sp. BS95. was used for synthesis of copper oxide nanoparticles (CuONPs). Characterization of crude and calcined CuONPs was carried out by UV-vis spectroscopy, X-ray diffraction (XRD), fourier transform infrared (FTIR) spectroscopy, zeta potential, dynamic light scattering, field emission scanning electron microscopy, transmission electron microscopy, and atomic force microscopy. Afterward, biogenic CuONPs were evaluated for antibacterial, antioxidant, and cytotoxic effects using broth micro-dilution method, DPPH assay and alamarBlue assay, respectively. Finally, molecular mechanisms behind anticancer effects of CuONPs was ascertained by real time PCR. UV-vis absorbance spectra registered surface plasmon resonance peaks at 286 nm and 420 nm for crude and calcined CuONPs, respectively. FTIR spectra exhibited bands associated with organic functional groups of bacterial proteins, confirming capping and functionalization of CuONPs. The average crystallite size of crude and calcined CuONPs was determined as 18.24 and 21.3 nm by XRD, respectively. The average zeta potentials of crude and calcined CuONPs were as -28.57 ± 5.13 and -29.47 ± 4.78 mV, respectively, indicating their high stability. Electron microscopy revealed that crude and calcined CuONPs were roughly spherical particles with an average size of 35.24 ± 4.64 and 43.68 ± 2.31 nm, respectively. Biogenic CuONPs induced antibacterial effects with minimal inhibitory concentrations ranging from 62.5 to 1,000 µg/ml against Gram-negative and Gram-positive strains. The antioxidant activity of crude and calcined CuONPs was found to be 83% ± 2.64% and 78% ± 1.73%, respectively. More intriguingly, CuONPs exerted considerable cytotoxic effects on human colon and gastric adenocarcinoma cells, while induced low toxicity on normal cells. Anticancer effects of biogenic CuONPs were confirmed by significant changes induced in the expression of apoptosis-related genes, including P53, BAX, BCL2 and CCND1. Hence, biosynthesized CuONPs could be considered as potential antimicrobial, antioxidant and anticancer agents.
ABSTRACT
Gold nanorods (GNRs/AuNRs) are a group of gold nanoparticles which their simple surface chemistry allows for various surface modifications, providing the possibility of using them in the fabrication of biocompatible and functional nano-agents for cancer therapy. AuNRs, moreover, exhibit a maximum absorption of longitudinal localized surface plasmon resonance (LSPR) in the near-infrared (NIR) region which overlaps with NIR bio-tissue 'window' suggesting that they are proper tools for thermal ablation of cancer cells. AuNRs can be used for induction of mono or combination therapies by administering various therapeutic approaches such as photothermal therapy (PTT), photodynamic therapy (PDT), chemotherapy (CT), radiotherapy (RT), and gene therapy (GT). In this review, anticancer therapeutic capacities of AuNRs along with different surface modifications are summarized comprehensively. The roles of AuNRs in fabrication of various nano-constructs are also discussed.
Subject(s)
Metal Nanoparticles , Nanotubes , Neoplasms , Photochemotherapy , Gold , Metal Nanoparticles/therapeutic use , Phototherapy , Neoplasms/therapyABSTRACT
Understanding the atomic interaction mechanism between chitosan and insulin at different pH levels is essential in the design of chitosan-based drug-delivery systems. In the present study, insulin-loaded nanoparticles were prepared via ionic gelation of tripolyphosphate (TPP) and chitosan with 76 ± 5.5% encapsulation efficiency. Our results showed that the nanoparticles were spherical with a size of 254 nm. Furthermore, the in vitro release profile of insulin was evaluated for two different pH levels. The release of insulin from nanoparticles after 48 h at pH 4.0 was 92%, compared to 56% at pH 7.4. The kinetics of the release were best fitted by the Weibull equation, which described a burst release in the first five hours followed by a sustained insulin release for up to 48 h. Moreover, we designed a long single chain chitosan (128 kDa)/TPP nanoparticles in real size for the first time and studied the system behavior in acidic and neutral environments using molecular dynamic simulation for 40 nanoseconds (ns). Our results showed that chitosan chains opened more with higher root-mean-square deviation (RMSD) values at pH 4.0 than at pH 7.4. Also, RMSD plots for insulin and TPP molecules showed that insulin molecules diffused away from chitosan chains, and that TPP were randomly dispersed further away from the chitosan chain in an acidic medium than in a neutral one. The in silico studies were in agreement with our in vitro data. Thus self-assembled chitosan/TPP nanoparticles show promise as a means to release protein drugs in acidic environments.Communicated by Ramaswamy H. Sarma.
Subject(s)
Chitosan , Nanoparticles , Chitosan/chemistry , Insulin , Drug Carriers/chemistry , Molecular Dynamics Simulation , Particle Size , Nanoparticles/chemistry , Hydrogen-Ion ConcentrationABSTRACT
The N-terminal sequence of the Smac (second-mitochondria derived activator) protein is known to be involved in binding to the BIR3 (Baculovirus IAP repeat) domain of the IAPs (inhibitors of apoptosis proteins), and antagonized their function. Short peptides derived from N-terminal residues of Smac have shown to sensitize cancer cells to chemotherapeutic agents. In this regard, small library including 6-mer peptides were designed using docking to the BIR3 domain of cIAP1 in silico. Molecular dynamics simulation studies were also done on top-scored hits (SmacAQ, SmacIQ) using Desmond 2017-2 for 150 ns simulation time. These two peptides were conveniently synthesized using solid phase peptide synthesis on Fmoc-Gln (Trt)-Wang resin. Furthermore, we encapsulated DOX (doxorubicin) and synthesized peptides in PLGA: PLGA-PEG (9:1) NPs (nanoparticles) followed by MD (molecular dynamic) studies to understand the NP structure and the interactions between either DOX or peptide with polymeric nanoparticles during 100 ns simulation. Finally, the cytotoxic activity of these peptides in combination with DOX against two cancer cell lines including MCF7 and C26 were investigated. As a result, we found that DOX or peptide-loaded NPs had stable structure during the simulation. MD simulation also showed that alanine at N-terminal of Smac could be replaced with isoleucine without alternation of biological activity which was in agreement with in vitro experiments. Moreover, NPs-SmacIQ and NPs-SmacAQ significantly enhanced the cytotoxicity effect of NPs-DOX in vitro (p < 0.001).Communicated by Ramaswamy H. Sarma.