Tailoring bismuth-based nanoparticles for enhanced radiosensitivity in cancer therapy.

Achieving a complete response to cancer treatment is a severe challenge, and has puzzled humans for a long time. Fortunately, radiotherapy (RT) gives rise to a common clinical treatment method, during which the usage of radiosensitizers is essential. Among preclinical radiosensitizers, bismuth-based nanoparticles (Bi-based NPs) are widely explored in cancer diagnosis and treatment, because they share favourable properties, such as low toxicity, strong X-ray absorption and facile preparation. However, pure Bi alone cannot achieve both efficient and safe RT outcomes, mainly due to poor targeting of tumor sites, long retention-induced systemic toxicity and immune resistance. This work provides an overview of recent advances and developments in Bi-based NPs that are tailored to enhance radiosensitivity. For the fabrication process, surface modification of Bi-based NPs is essential to achieve tumor-targeted delivery and penetration. Moreover, the incorporation of other elements, such as Fe ions, can increase diagnostic accuracy with optimal theranostic efficacy. Meanwhile, the structure-activity relationship can also be manipulated to maximize the chemotherapeutic drug loading capability of Bi-based NPs, to enhance X-ray attenuation by means of a large surface area or to achieve safer metabolic routes with rapid clearance from the human body. In addition, Bi-based NPs exhibit synergistic antitumor potential when combined with diverse therapies, such as photothermal therapy (PTT) and high-intensity focused ultrasound (HIFU). To summarize, the latest research on Bi-based NPs as radiosensitizers is described in the review, including both their advantages and disadvantages for improving treatment, thus providing a useful guide for future clinical application.

Microbes-mediated synthesis strategies of metal nanoparticles and their potential role in cancer therapeutics.

Past few years have seen a paradigm shift towards ecofriendly, green and biological fabrication of metal nanoparticles (MNPs) for diverse nanomedicinal applications especially in cancer nanotheranostics. Besides, the well-known green synthesis methods of plant materials, the potential of the microbial world (bacteria, fungi, alga, etc.) in biofabrication is equally realized. Biomolecules and enzymes in the microbial cells are capable of catalyzing the biosynthesis process. These microbial derived inorganic nanoparticles have been frequently evaluated as potential agents in cancer therapies revealing exciting results. Through, cellular and molecular pathways, these microbial derived nanoparticles are capable of killing the cancer cells. Considering the recent developments in the anticancer applications of microbial derived inorganic MNPs, a dire need was felt to bring the available information to a single document. This manuscript reviews not only the mechanistic aspects of the microbial derived MNPs but also include the diverse mechanisms that governs their anticancer potential. Besides, an updated literature review is presented that includes studies of 2019-onwards.

Extraction optimization, Total Phenolic-Flavonoids content, HPLC-DAD finger printing, antimicrobial, antioxidant and cytotoxic potentials of Chinese folklore Ephedra intermedia Schrenk & C. A. Mey

Abstract Plants from genus Ephedra are commonly used by the Chinese people as folk medicine for treatment of various diseases. The current study was designed to explore the ethno-pharmacological based pharmacological potentials of Ephedra intermedia Schrenk & C.A. Mey. (E. intermedia). Plant aerial parts were extracted using ten solvent systems with increasing order of polarity. Samples were analyzed for total phenolic and flavonoid contents, HPLC-DAD analysis, antibacterial, antifungal, HepG2 cell line cytotoxicity, hemolysis and antioxidant potentials following standard procedures. Highest percent extract recovery was observed in Eth+WT (25.55 % w/w) solvent system. Flavonoid and phenolic contents were higher in chloroform and Met+WT fractions respectively. Considerable antibacterial activity was shown by Eth+Met extract against B. subtilis and K. pneumonia (MIC of 11.1μg/mL for each). Eth extract exhibited high antifungal activity against A. fumigates (15±0.31 mm DIZ). Met+WT extract showed significant cytotoxicity against HepG2 cell lines with IC50 of 13.51+0.69 μg/mL. Substantial free radical scavenging activity (74.9%) was observed for Met+Eth extract. In the current study, several solvent systems were used for more effective extraction of fractions and can be useful in the isolation of phytochemicals. Various fractions exhibited considerable antimicrobial, antioxidant and cytotoxic potentials. Biological potentials of E. intermedia signify its potential uses in microbial, cancer and degenerative disorders and thus warrant further detailed studies.

Stimulus-Responsive Smart Nanoparticles-Based CRISPR-Cas Delivery for Therapeutic Genome Editing.

The innovative research in genome editing domains such as CRISPR-Cas technology has enabled genetic engineers to manipulate the genomes of living organisms effectively in order to develop the next generation of therapeutic tools. This technique has started the new era of "genome surgery". Despite these advances, the barriers of CRISPR-Cas9 techniques in clinical applications include efficient delivery of CRISPR/Cas9 and risk of off-target effects. Various types of viral and non-viral vectors are designed to deliver the CRISPR/Cas9 machinery into the desired cell. These methods still suffer difficulties such as immune response, lack of specificity, and efficiency. The extracellular and intracellular environments of cells and tissues differ in pH, redox species, enzyme activity, and light sensitivity. Recently, smart nanoparticles have been synthesized for CRISPR/Cas9 delivery to cells based on endogenous (pH, enzyme, redox specie, ATP) and exogenous (magnetic, ultrasound, temperature, light) stimulus signals. These methodologies can leverage genome editing through biological signals found within disease cells with less off-target effects. Here, we review the recent advances in stimulus-based smart nanoparticles to deliver the CRISPR/Cas9 machinery into the desired cell. This review article will provide extensive information to cautiously utilize smart nanoparticles for basic biomedical applications and therapeutic genome editing.

Review on Recent Progress in Magnetic Nanoparticles: Synthesis, Characterization, and Diverse Applications.

Diverse applications of nanoparticles (NPs) have revolutionized various sectors in society. In the recent decade, particularly magnetic nanoparticles (MNPs) have gained enormous interest owing to their applications in specialized areas such as medicine, cancer theranostics, biosensing, catalysis, agriculture, and the environment. Controlled surface engineering for the design of multi-functional MNPs is vital for achieving desired application. The MNPs have demonstrated great efficacy as thermoelectric materials, imaging agents, drug delivery vehicles, and biosensors. In the present review, first we have briefly discussed main synthetic methods of MNPs, followed by their characterizations and composition. Then we have discussed the potential applications of MNPs in different with representative examples. At the end, we gave an overview on the current challenges and future prospects of MNPs. This comprehensive review not only provides the mechanistic insight into the synthesis, functionalization, and application of MNPs but also outlines the limits and potential prospects.

Designing Stimuli-Responsive Upconversion Nanoparticles that Exploit the Tumor Microenvironment.

Tailoring personalized cancer nanomedicines demands detailed understanding of the tumor microenvironment. In recent years, smart upconversion nanoparticles with the ability to exploit the unique characteristics of the tumor microenvironment for precise targeting have been designed. To activate upconversion nanoparticles, various bio-physicochemical characteristics of the tumor microenvironment, namely, acidic pH, redox reactants, and hypoxia, are exploited. Stimuli-responsive upconversion nanoparticles also utilize the excessive presence of adenosine triphosphate (ATP), riboflavin, and Zn2+ in tumors. An overview of the design of stimulus-responsive upconversion nanoparticles that precisely target and respond to tumors via targeting the tumor microenvironment and intracellular signals is provided. Detailed understanding of the tumor microenvironment and the personalized design of upconversion nanoparticles will result in more effective clinical translation.

Association of Non-Hodgkin lymphoma risk with CYP1A1, GSTM1 and GSTT1 gene variants, in tobacco addicted patients of Pashtun ethnicity of Khyber Pakhtunkhwa, Pakistan.

The current study determines the possible antitumor and immunomodulatory effects of thymosin against the in vivo and in vitro growth of tumor-derived cell line in mice. Peritoneal phagocytes count, Ehrlich ascites tumor (EAT) cells, T- lymphocytes, and B- lymphocytes activities were determined. In addition, serum level of interleukin 2 (IL-2) and liver functions were measured. In animal testing, thymosin at doses of 0.50 and 1mg activated the phagocytic function of macrophages, as well as T- and B- cell function. Thymosin caused a marked shortage in the proliferation of EAT cells in the peritoneal fluid with dose 0.50g as compared with that of the corresponding control group. Furthermore, treatment with thymosin caused effectively elevate in serum level of IL-2, on the contrary reduce in serum levels of ALT, AST and total proteins. The size of solid Ehrlich tumor was significantly decreased, as measured morphologically with the doses 0.50 and 1 mg (P<0.01). These results confirmed that many biological activities attributed to thymosin and is as an adjuvant for immune enhancement.

Association of nasopharyngeal cancer risk with genetic polymorphisms of drug-metabolizing enzyme genes GSTM1, GSTT1 and CYP1A1 (rs4646903 variant), in tobacco addicted patients of Pashtun ethnicity of Khyber Pakhtunkhwa Province of Pakistan.

Associations of GSTM1, GSTT1 and CYP1A1 gene variants with risk of developing nasopharyngeal cancer were evaluated in this case-control study, in which 130 cases along with 151 population-based healthy controls of Pashtun ethnicity from Khyber Pakhtunkhwa province of Pakistan were recruited. Socio-demographic data were obtained and blood samples were collected with informed consent for analysis. Specific RT-PCR and conventional PCR methods were used to detect CYP1A1 and GSTs, respectively, and results analyzed through SPSS version 20. Study showed that CYP1A1 homozygous (C/C) had an almost 4-fold increased risk for nasopharyngeal cancer; while heterozygous (T/C) had an almost 2 times increased risk. Overall the C allele is significantly associated with nasopharyngeal cancer as compared to T allele. Null genotypes of GSTM1 were having 3-fold increased risk; whereas null genotype of GSTT1 was having 2 times increased risk. Similarly, GSTM/GSTT both null genotype was having more than 5 times increased association. Presence of all three gene variants showed strong and significant association. Findings of the study suggest that presence of GSTM1 and/or GSTT1 null genotypes along with variant alleles of CYP1A1 are significant risk factors for nasopharyngeal cancer susceptibility in Pashtun population.

Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging Associated Neurological Disorders.

Modern research has revealed that dietary consumption of flavonoids and flavonoids-rich foods significantly improve cognitive capabilities, inhibit or delay the senescence process and related neurodegenerative disorders including Alzheimer's disease (AD). The flavonoids rich foods such as green tea, cocoa, blue berry and other foods improve the various states of cognitive dysfunction, AD and dementia-like pathological alterations in different animal models. The mechanisms of flavonoids have been shown to be mediated through the inhibition of cholinesterases including acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), ß-secretase (BACE1), free radicals and modulation of signaling pathways, that are implicated in cognitive and neuroprotective functions. Flavonoids interact with various signaling protein pathways like ERK and PI3-kinase/Akt and modulate their actions, thereby leading to beneficial neuroprotective effects. Moreover, they enhance vascular blood flow and instigate neurogenesis particularly in the hippocampus. Flavonoids also hamper the progression of pathological symptoms of neurodegenerative diseases by inhibiting neuronal apoptosis induced by neurotoxic substances including free radicals and ß-amyloid proteins (Aß). All these protective mechanisms contribute to the maintenance of number, quality of neurons and their synaptic connectivity in the brain. Thus flavonoids can thwart the progression of age-related disorders and can be a potential source for the design and development of new drugs effective in cognitive disorders.

Tailoring Nanomaterials for Targeting Tumor-Associated Macrophages.

Advances in the field of nanotechnology together with an increase understanding of tumor immunology have paved the way for the development of more personalized cancer immuno-nanomedicines. Nanovehicles, due to their specific physicochemical properties, are emerging as key translational moieties in tackling tumor-promoting, M2-like tumor-associated macrophages (TAMs). Cancer immuno-nanomedicines target TAMs primarily by blocking M2-like TAM survival or affecting their signaling cascades, restricting macrophage recruitment to tumors and re-educating tumor-promoting M2-like TAMs to the tumoricidal, M1-like phenotype. Here, the TAM effector mechanisms and strategies for targeting TAMs are summarized, followed by a focus on the mechanistic considerations in the development of novel immuno-nanomedicines. Furthermore, imaging TAMs with nanoparticles so as to forecast a patient's clinical outcome, describing treatment options, and observing therapy responses is also discussed. At present, strategies that target TAMs are being investigated not only at the basic research level but also in early clinical trials. The significance of TAM-targeting biomaterials is highlighted, with the goal of facilitating future clinical translation.

Bio-guided profiling and HPLC-DAD finger printing of Atriplex lasiantha Boiss.

BACKGROUND: Plants represent an intricate and innovative source for the discovery of novel therapeutic remedies for the management of various ailments. The current study has been aimed to validate the therapeutic potential of ethnomedicinally significant plant Atriplex lasiantha Boiss. METHODS: The polarity based extraction process was carried out using fourteen solvents to figure out best extraction solvent and bioactive fractions. Total phenolic-flavonoids contents were quantified colorimetrically and polyphenolics were measured using HPLC-DAD analysis. Moreover, the test samples were tested against several diseases targets following various assays including free radicals scavenging, antibacterial, antifungal, cytotoxic and antileishmanial assay. RESULTS: Among the solvent fractions, maximum yield was obtained with methanol-water extract i.e., 11 ± 0.49%. Maximum quantity of gallic acid equivalent phenolic content and quercetin equivalent flavonoid content were quantified in methanol-ethyl acetate extract of A. lasiantha. Significant quantity of rutin i.e., 0.3 µg/mg was quantified by HPLC analysis. The methanol-ethyl acetate extract of A. lasiantha exhibited maximum total antioxidant and total reducing power with 64.8 ± 1.16 AAE/mg extract respectively, while showing 59.8 ± 1.07% free radical scavenging potential. A significant antibacterial potential was exhibited by acetone-distilled water extract of A. lasiantha with 11 ± 0.65 mm zone of inhibition against B. subtilis. Considerable antifungal activity was exhibited by ethyl acetate-n-hexane extract of aerial part of A. lasiantha with 14 ± 1.94 mm zone of inhibition against A. fumigatus. Highest percentage of α-amylase inhibition (41.8 ± 1.09%) was observed in ethyl acetate-n-hexane extract. Methanol-acetone extract of A. lasiantha demonstrated significant inhibition of hyphae formation with 11 ± 0.49 mm bald zone of inhibition. Significant in-vitro cytotoxicity against Hep G2 cell line has been exhibited by methanol-chloroforms extract of A. lasiantha. CONCLUSION: The current study reveals the prospective potential of Atriplex lasiantha Boiss. for the discovery of biologically active compounds through bioassay guided isolation against various diseases.

Extraction optimization, total phenolic, flavonoid contents, HPLC-DAD analysis and diverse pharmacological evaluations of Dysphania ambrosioides (L.) Mosyakin & Clemants.

The present study aims to evaluate phytochemical and pharmacological potentials of Dysphania ambrosioides (L.) Mosyakin & Clemants previously known as Chenopodium ambrosioides L. Extraction was carried out using 14 solvents with wide range of polarity to find out the best solvent system for each bioactivity. Total phenolic and flavonoids contents were measured colorimetrically and polyphenolics were quantified via HPLC-DAD analysis. The samples were screened for inhibitory potentials against free radicals, leishmania, cancer cell lines, protein kinase, α-Amylase enzymes and microbial strains. Among all solvents, maximum percentage of extract was recovered from methanol-water fraction of leaves. HPLC analysis exhibited the presence of rutin, myricetin and quercetin. In DPPH assay, methanolic leaf extract exhibited IC50 value of 130.7 ± 0.57 µg/mL. Considerable α-amylase inhibitory, cytotoxic, leishmanicidal and antimicrobial potentials were exhibited by plant samples. D. ambrosioides revealed significant antioxidant, cytotoxic, antimicrobial and anti-diabetic potentials and thus warrant further detailed studies to find novel drugs.

Biosynthesis of Metal Nanoparticles via Microbial Enzymes: A Mechanistic Approach.

During the last decade, metal nanoparticles (MtNPs) have gained immense popularity due to their characteristic physicochemical properties, as well as containing antimicrobial, anti-cancer, catalyzing, optical, electronic and magnetic properties. Primarily, these MtNPs have been synthesized through different physical and chemical methods. However, these conventional methods have various drawbacks, such as high energy consumption, high cost and the involvement of toxic chemical substances. Microbial flora has provided an alternative platform for the biological synthesis of MtNPs in an eco-friendly and cost effective way. In this article we have focused on various microorganisms used for the synthesis of different MtNPs. We also have elaborated on the intracellular and extracellular mechanisms of MtNP synthesis in microorganisms, and have highlighted their advantages along with their challenges. Moreover, due to several advantages over chemically synthesized nanoparticles, the microbial MtNPs, with their exclusive and dynamic characteristics, can be used in different sectors like the agriculture, medicine, cosmetics and biotechnology industries in the near future.

Efficacy of green nanoparticles against cancerous and normal cell lines: a systematic review and meta-analysis.

This study aimed to perform a systematic review and meta-analysis of papers discussing the efficacy of microbial synthesised metallic nanoparticles (MNPs) against cancerous and normal cell lines by exploiting Bayesian generalised linear (BGL) model. Data was systematically collected from published papers via Cochrane library, Web of Science, PubMed, Science Direct, ProQuest, Scopus, and Embase. Impressively, most of the studies were carried out on HeLa and A549 cancer cell lines. Specifically, a hefty 65.67% of studies employed bacteria to biofabricate MNPs. Significantly, BGL meta-analysis represented highly valuable information. Hence, based on adjusted analysis, the MNPs with the size of 25-50 nm were found to be far less cytotoxic than the MNPs with the size of ≤25 nm (OR = 0.233, P ˂ 0.05) against either cancerous or normal cell lines. Interestingly, it was found that the odds of cytotoxicity in cancerous cell lines were practically nine times more than normal cell lines, representing the substantially more cytotoxicity of MNPs in cancerous cell lines (OR = 9.004, P ˂ 0.001). Green MNPs mentioned here may be developed as novel anti-cancer agents, which could lead to a revolution in the treatment of cancer.

Multifunctional theranostic applications of biocompatible green-synthesized colloidal nanoparticles.

Phytochemicals offer immense promise for sustainable development and production of nanotechnology-enabled products. In the present study, Olax nana Wall. ex Benth. (family: Olacaceae) aqueous extract was used as an effective stabilizing agent to produce biogenic silver (ON-AgNPs) and gold nanoparticles (ON-AuNPs), which were investigated for biocompatibility and prospective biomedical applications (antibacterial, anticancer, antileishmanial, enzyme inhibition, antinociceptive, and anti-inflammatory activities). Various characterization techniques (XRD, FTIR, SEM, TEM, DLS, EDX, and SAED) revealed efficient biosynthesis of ON-AgNPs (26 nm) and ON-AuNPs (47 nm). In the toxicological assessment, ON-AgNPs and ON-AuNPs were found biocompatible towards human RBCs and macrophages (IC50 > 200 µg/mL). In a concentration range of 62.5-2000 µg/mL, a strong antibacterial effect was produced by ON-AgNPs against Staphylococcus epidermidis (MIC = 7.14 µg/mL) and Escherichia coli (8.25 µg/mL), while ON-AuNPs was only active against Staphylococcus aureus (9.14 µg/mL). At a concentration of 3.9-500 µg/mL, a dose-dependant inhibition of HepG2 cancer cells was produced by ON-AgNPs (IC50 = 14.93 µg/mL) and ON-AuNPs (2.97 µg/mL). Both ON-AgNPs and ON-AuNPs were found active against Leishmania tropica (KMH23) promastigotes (IC50 = 12.56 and 21.52 µg/mL) and amastigotes (17.44 and 42.20 µg/mL), respectively, after exposure to a concentration range of 1-200 µg/mL for 72 h. Preferential enzyme inhibition against urease and carbonic anhydrase II were noted for ON-AgNPs (39.23 and 8.89%) and ON-AuNPs (31.34 and 6.34%), respectively; however, these were found inactive against xanthine oxidase at 0.2 mg/mL. In the in vivo antinociceptive (acetic acid-induced abdominal constrictions) and anti-inflammatory (carrageenan-induced paw edema) activities, ON-AgNPs and ON-AuNPs at doses of 40 and 80 mg/kg, significantly attenuated the tonic nociception (P < 0.001) and ameliorated the carrageenan-induced inflammation (P < 0.01, P < 0.001). The results of in vitro and in vivo activities indicated that the biogenic nanoparticles can be used as valuable theranostic agents for further exploration of diverse biomedical applications.

Fabrication of poly (butadiene-block-ethylene oxide) based amphiphilic polymersomes: An approach for improved oral pharmacokinetics of Sorafenib.

Sorafenib (SFN), a hydrophobic anticancer drug, has several limitations predominantly poor aqueous solubility and hepatic first-pass effect, limiting its oral delivery that results into several other complications. Present study aims to develop Sorafenib loaded polymersomes using poly butadiene block poly ethylene oxide (PB-b-PEO), an amphiphilic co-block polymer. Prior to drug loading, critical aggregate concentration (CAC) of polymer was calculated for stable formulation synthesis. The developed SFN loaded PB-b-PEO polymersomes (SFN-PB-b-PEO, test formulation) characterized by DLS and cryo-TEM showed particle size 282 nm, polydispersity (PDI) of less than 0.29 and membrane thickness of about 20 nm. SFN-PB-b-PEO polymersomes demonstrated encapsulation efficiency of 71% and showed sustained drug release up to 144 h. Formulation remained stable for 3 months in suspension form. In vitro cytotoxicity against HepG2 cells showed 1.7 folds improved toxicity compared to SFN suspension. In addition, oral administration of SFN-PB-b-PEO polymersomes in BALB/c mice showed increased Cmax and AUC0-96 by 1.7 and 2.77-fold respectively (p < 0.05) compared to those of SFN suspension (reference formulation). Findings suggest that the SFN-PB-b-PEO polymersomes can be a potential candidate for oral delivery of SFN.

Advances in nano-delivery systems for doxorubicin: an updated insight.

Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumours, transplantable leukemias and lymphomas. Conventional DOX-induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet®) and pegylated liposomal (Doxil®) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of DOX in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimising its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumour resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on DOX nanoformulations, in this article we for the first time have given an updated insight on DOX nano delivery systems.

Biomimetic synthesis of silver nanoparticles from Streptomyces atrovirens and their potential anticancer activity against human breast cancer cells.

Silver nanoparticles (AgNPs) have been undeniable for its antimicrobial activity while its antitumour potential is still limited. Therefore, the present study focused on determining cytotoxic effects of AgNPs on Michigan cancer foundation-7 (MCF-7) breast cancer cells and its corresponding mechanism of cell death. Herein, the authors developed a bio-reduction method for AgNPs synthesis using actinomycetes isolated from marine soil sample. The isolated strain was identified by 16s ribotyping method and it was found to be Streptomyces atrovirens. Furthermore, the synthesised AgNPs were characterised by various bio-analytical techniques such as ultraviolet-visible spectrophotometer, atomic force microscopy, transmission electron microscopy, Fourier transform infra-red spectroscopy, and X-ray diffraction. Moreover, the results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay reveals 44.51 µg of AgNPs to have profound inhibition of cancer cell growth; furthermore, the inhibition of MCF-7 breast cancer cell line was found to be dose dependent on treatment with AgNPs. Acridine orange and ethidium bromide double staining methods were performed for cell morphological analysis. The present results showed that biosynthesised AgNPs might be emerging alternative biomaterials for human breast cancer therapy.