Preclinical Efficacy of Cabazitaxel Loaded Poly(2-alkyl cyanoacrylate) Nanoparticle Variants.

Background: Biodegradable poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs) are receiving increasing attention in anti-cancer nanomedicine development not only for targeted cancer chemotherapy, but also for modulation of the tumor microenvironment. We previously reported promising results with cabazitaxel (CBZ) loaded poly(2-ethylbutyl cyanoacrylate) NPs (PEBCA-CBZ NPs) in a patient derived xenograft (PDX) model of triple-negative breast cancer, and this was associated with a decrease in M2 macrophages. The present study aims at comparing two endotoxin-free PACA NP variants (PEBCA and poly(2-ethylhexyl cyanoacrylate); PEHCA), loaded with CBZ and test whether conjugation with folate would improve their effect. Methods: Cytotoxicity assays and cellular uptake of NPs by flow cytometry were performed in different breast cancer cells. Biodistribution and efficacy studies were performed in PDX models of breast cancer. Tumor associated immune cells were analyzed by multiparametric flow cytometry. Results: In vitro studies showed similar NP-induced cytotoxicity patterns despite difference in early NP internalization. On intravenous injection, the liver cleared the majority of NPs. Efficacy studies in the HBCx39 PDX model demonstrated an enhanced effect of drug-loaded PEBCA variants compared with free drug and PEHCA NPs. Furthermore, the folate conjugated PEBCA variant did not show any enhanced effects compared with the unconjugated counterpart which might be due to unfavorable orientation of folate on the NPs. Finally, analyses of the immune cell populations in tumors revealed that treatment with drug loaded PEBCA variants affected the myeloid cells, especially macrophages, contributing to an inflammatory, immune activated tumor microenvironment. Conclusion: We report for the first time, comparative efficacy of PEBCA and PEHCA NP variants in triple negative breast cancer models and show that CBZ-loaded PEBCA NPs exhibit a combined effect on tumor cells and on the tumor associated myeloid compartment, which may boost the anti-tumor response.

Activation of the complement system by nanoparticles and strategies for complement inhibition.

The complement system is a multicomponent and multifunctional arm of the innate immune system. Complement contributes to non-specific host defence and maintains homeostasis through multifaceted processes and pathways, including crosstalk with the adaptive immune system, the contact (coagulation) and the kinin systems, and alarmin high-mobility group box 1. Complement is also present intracellularly, orchestrating a wide range of housekeeping and physiological processes in both immune and nonimmune cells, thus showing its more sophisticated roles beyond innate immunity, but its roles are still controversial. Particulate drug carriers and nanopharmaceuticals typically present architectures and surface patterns that trigger complement system in different ways, resulting in both beneficial and adverse responses depending on the extent of complement activation and regulation as well as pathophysiological circumstances. Here we consider the role of complement system and complement regulations in host defence and evaluate the mechanisms by which nanoparticles trigger and modulate complement responses. Effective strategies for the prevention of nanoparticle-mediated complement activation are introduced and discussed.

Biochar-layered double hydroxide composites for the adsorption of tetracycline from water: synthesis, process modeling, and mechanism.

Antibiotic-contaminated water is a crucial issue worldwide. Thus, in this study, the MgFeCa-layered double hydroxides were supported in date palm-derived biochar (B) using co-precipitation, hydrothermal, and co-pyrolysis methods. It closes gaps in composite design for pharmaceutical pollutant removal, advances eco-friendly adsorbents, and advances targeted water cleanup by investigating synthesis methodologies and gaining new insights into adsorption. The prepared B-MgFeCa composites were investigated for tetracycline (TC) adsorption from an aqueous solution. The B-MgFeCa composites synthesized through co-precipitation and hydrothermal methods exhibited better crystallinity, functional groups, and well-developed LDH structure within the biochar matrix. However, the co-pyrolysis method resulted in the LDH structure breakage, leading to the low crystalline composite material. The maximum adsorption of TC onto all B-MgFeCa was obtained at an acidic pH range (4-5). The B-MgFeCa composites produced via hydrothermal and co-pyrolysis methods showed higher and faster TC adsorption than the co-precipitation method. The kinetic results can be better described by Langmuir kinetic and mixed order models at low and high TC concentrations, indicating that the rate-limiting step is mainly associated with active binding sites adsorption. The Sip and Freundlich models showed better fitting with the equilibrium data. The TC removal by B-MgFeCa composites prepared via hydrothermal, the highest estimated uptake which is around 639.76 mg.g-1 according to the Sips model at ambient conditions, and co-pyrolysis was mainly dominated by physical and chemical interactions. The composite obtained via the co-precipitation method adsorbed TC through chemical bonding between surface functional groups with anionic species of TC molecule. The B-MgFeCa composite showed excellent reusability performance for up to five cycles with only a 30% decrease in TC removal efficiency. The results demonstrated that B-MgFeCa composites could be used as promising adsorbent materials for effective wastewater treatment.

Perspectives on complement and phagocytic cell responses to nanoparticles: From fundamentals to adverse reactions.

The complement system, professional phagocytes and other cells such as Natural killer cells and mast cells are among the important components of the innate arm of the immune system. These constituents provide an orchestrated array of defences and responses against tissue injury and foreign particles, including nanopharmaceuticals. While interception of nanopharmaceuticals by the immune system is beneficial for immunomodulation and treatment of phagocytic cell disorders, it is imperative to understand the multifaceted mechanisms by which nanopharmaceuticals interacts with the immune system and evaluate the subsequent balance of beneficial versus adverse reactions. An example of the latter is adverse infusion reactions to regulatory-approved nanopharmaceuticals seen in human subjects. Here, we discuss collective opinions and findings from our laboratories in mapping nanoparticle-mediated complement and leucocyte/macrophage responses.

Nanometer- and angstrom-scale characteristics that modulate complement responses to nanoparticles.

The contribution of the complement system to non-specific host defence and maintenance of homeostasis is well appreciated. Many particulate systems trigger complement activation but the underlying mechanisms are still poorly understood. Activation of the complement cascade could lead to particle opsonisation by the cleavage products of the third complement protein and might promote inflammatory reactions. Antibody binding in a controlled manner and/or sensing of particles by the complement pattern-recognition molecules such as C1q and mannose-binding lectin can trigger complement activation. Particle curvature and spacing arrangement/periodicity of surface functional groups/ligands are two important parameters that modulate complement responses through multivalent engagement with and conformational regulation of surface-bound antibodies and complement pattern-recognition molecules. Thus, a better fundamental understanding of nanometer- and angstrom-scale parameters that modulate particle interaction with antibodies and complement proteins could portend new possibilities for engineering of particulate drug carriers and biomedical platforms with tuneable complement responses and is discussed here.

Lignocellulosic Based Biochar Adsorbents for the Removal of Fluoride and Arsenic from Aqueous Solution: Isotherm and Kinetic Modeling.

Eucalyptus wood is made up of lignocellulosic material; this lignocellulosic material contains two types of biopolymers, i.e., carbohydrate and aromatic polymers. In this study, this lignocellulosic material was used to prepare biochar. Three biochar, i.e., laboratory-based (B1), barrel-based (B2), and brick kiln-biochar (B3), were used for fluoride and arsenic removal from aqueous solution. Barrel-based biochar was prepared by using the two-barrel method's alteration. The highest fluoride removal (99%) was attained at pH 2 in the presence of B1, while in the presence of B2 and B3, maximum fluoride removal was 90% and 45.7%, respectively. At pH 10, the maximum arsenic removal in the presence of B1, B2, and B3 was 96%, 94%, and 93%, respectively. The surface characteristics obtained by Fourier-transform infrared spectroscopy (FTIR) showed the presence of carbonyl group (C-O), and alkene (C=C) functional groups on all the three studied biochars. Isotherm studies showed that the adsorption was monolayered (all the adsorbed molecules were in contact with the surface layer of the adsorbent) as the Langmuir isotherm model best fits the obtained data. Adsorption kinetics was also performed. The R2 value supports the pseudo-second-order kinetics, which means that chemisorption was involved in adsorbing fluoride and arsenic. It is concluded that B1 gives maximum removal for both fluoride (99%) and arsenic (96%). The study shows that lignocellulose-based biochar can be used for arsenic and fluoride removal from water.

Thiolated Chitosan-Centella asiatica Nanocomposite: A Potential Brain Targeting Strategy Through Nasal Route.

The major challenge associated with the treatment of neurological disorders is the inefficiency of drugs to enter the Central Nervous System (CNS). Polymer-drug conjugates are now being tailored to overcome this hindrance associated with conventional drugs. The study aimed at developing polymer hybrid nasal nanocomposite for enhanced delivery of Centella to the CNS. Thiolated chitosan was complexed with Centella to form a composite using EDAC hydrochloride. The composite was characterized by FTIR, XRD, NMR, and MS. Further, this composite was converted into a nanoformulation by the ionic-gelation method, characterized, and subjected to ex vivo permeation studies. Additionally, MTT assay was performed using Human Uumbilical cord Vein Endothelial Cells (HUVECs) mimicking Blood-Brain Barrier (BBB) to establish the safety of nanocomposite. The targeting efficacy was predicted by molecular docking studies against receptors associated with BBB. The FTIR, XRD, NMR, and MS studies confirmed the chemical conjugation of thiolated chitosan with Centella. Nanocomposite characterization through SEM, AFM, and DLS confirmed the size and stability of the developed nanocomposite having a zeta potential of - 14.5 mV and PDI of 0.260. The nanocomposite showed no signs of nasal ciliotoxicity and good permeation of 89.44 ± 1.75% (mean ± SD, n = 3) at 8 h across the nasal mucosa. MTT assay showed that the nanocomposite had lesser toxicity compared to the free drug (IC50 of Centella-269.1 µg/mL and IC50 of CTC nanocomposite-485.375 µg/mL). The affinity of polymer to the BBB receptors as proved by docking studies suggests the ability of polymer-based nanocomposite to concentrate in the brain post nasal administration.

Tamarindus indica. Linn leaves ameliorates experimental induced heart failure in Wistar rats.

OBJECTIVES: Cardiovascular diseases (CVDs) are highly prevalent in various countries, and heart failure accounts for the majority of deaths. The present study focuses on determining the protective effect of ethanol extract of leaves of Tamarindus indica (TIEE) by in vitro and in vivo methods. METHODS: In vitro cardiotonic activity was determined using Langendorff's heart perfusion assembly. In vivo studies were performed using Doxorubicin (1.5 mg/kg, i.p for seven days) induced cardiotoxicity in rats. These animals were simultaneously treated with the TIEE at a low dose (200 mg/kg, p.o), high dose (400 mg/kg, p.o) and standard drug Digoxin (100 µg/kg, p.o) for seven days. At the end of the study, various parameters like electrocardiogram (ECG) recording, serum levels of serum glutamic pyruvic transaminase (SGPT), lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), and presence of cardiac troponin (cTnI) were determined. Isolated hearts were subjected to histopathological studies. RESULTS: The TIEE at a concentration of 60 µg/mL showed a significant cardiotonic effect in vitro that was evident by increased force of contraction, heart rate, and cardiac output. In vivo studies revealed that the TIEE decreased the prolongation of QT and RR interval of ECG, lowered the serum enzyme levels like LDH, CPK indicating cardiac protection, and the same was established by the absence of cTnI in blood. Histopathological examinations of heart tissue sections showed improved architecture in the treatment groups when compared with diseased groups. CONCLUSIONS: The study revealed the cardioprotective activity of T. indica leaf extract by both in vitro and in vivo methods.

Repression of Polyol Pathway Activity by Hemidesmus indicus var. pubescens R.Br. Linn Root Extract, an Aldose Reductase Inhibitor: An In Silico and Ex Vivo Study.

Development of diabetic cataract is mainly associated with the accumulation of sorbitol via the polyol pathway through the action of Aldose reductase (AR). Hence, AR inhibitors are considered as potential agents in the management of diabetic cataract. This study explored the AR inhibition potential of Hemidesmus indicus var. pubescens root extract by in silico and ex vivo methods. Molecular docking studies (Auto Dock tool) between ß-sitosterol, hemidesminine, hemidesmin-1, hemidesmin-2, and AR showed that ß-sitosterol (- 10.2 kcal/mol) and hemidesmin-2 (- 8.07 kcal/mol) had the strongest affinity to AR enzyme. Ex vivo studies were performed by incubating isolated goat lenses in artificial aqueous humor using galactose (55 mM) as cataract inducing agent at room temperature (pH 7.8) for 72 h. After treatment with Vitamin E acetate - 100 µg/mL (standard) and test extract (500 and 1000 µg/mL) separately, the estimation of biochemical markers showed inhibition of lens AR activity and decreased sorbitol levels. Additionally, extract also normalized the levels of antioxidant markers like SOD, CAT, GSH. Our results showed evidence that H. indicus var. pubescens root was able to prevent cataract by prevention of opacification and formation of polyols that underlines its potential as a possible therapeutic agent against diabetic complications.

Phosphoric Acid Activated Carbon from Melia azedarach Waste Sawdust for Adsorptive Removal of Reactive Orange 16: Equilibrium Modelling and Thermodynamic Analysis.

Waste wood biomass as precursor for manufacturing activated carbon (AC) can provide a solution to ever increasing global water quality concerns. In our current work, Melia azedarach derived phosphoric acid-treated AC (MA-AC400) was manufactured at a laboratory scale. This novel MA-AC400 was tested for RO16 dye removal performance as a function of contact time, adsorbent dosage, pH, temperature and initial dye concentration in a batch scale arrangement. MA-AC400 was characterized via scanning electron microscopy, energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, dynamic light scattering (DLS) and fluorescence spectroscopy. MA-AC400 is characterized as mesoporous with BET surface area of 293.13 m2 g-1 and average pore width of 20.33 Å. pHPZC and Boehm titration confirm the acidic surface charges with dominance of phenolic functional groups. The average DLS particle size of MA-AC400 was found in the narrow range of 0.12 to 0.30 µm and this polydispersity was confirmed with multiple excitation fluorescence wavelengths. MA-AC400 showed equilibrium adsorption efficiency of 97.8% for RO16 dye at its initial concentration of 30 mg L-1 and adsorbent dose of 1 g L-1. Thermodynamic study endorsed the spontaneous, favorable, irreversible and exothermic process for RO16 adsorption onto MA-AC400. Equilibrium adsorption data was better explained by Langmuir with high goodness of fit (R2, 0.9964) and this fitness was endorsed with lower error functions. The kinetics data was found well fitted to pseudo-second order (PSO), and intra-particle diffusion kinetic models. Increasing diffusion constant values confirm the intraparticle diffusion at higher RO16 initial concentration and reverse was true for PSO chemisorption kinetics. MA-AC400 exhibited low desorption with studied eluents and its cost was calculated to be $8.36/kg.

Antihyperglycemic and neuroprotective effects of Wattakaka volubilis (L. f. ) Stapf root against streptozotocin induced diabetes

ABSTRACT Murva is an important drug in Ayurveda. Wattakaka volubilis is used as one of the botanical sources of Murva. The aim of this study is to evaluate the effect of the alcohol extract of W. volubilis root in streptoztocin (STZ) induced diabetes and diabetic neuropathy. Diabetes mellitus (DM) was induced by the administration of STZ (45 mg/kg, i.p). DM was induced within 72 h. Diabetic animals were treated with glimepiride (0.5 mg/kg) and ethyl alcohol extract 100 and 200 mg/kg for 21 d. After determining the changes in fasting serum glucose and lipid profile, animals were further treated for a period of 15 d to determine the protective effect of extract against diabetic neuropathy. All the alcohol extract treated animals, showed a significant decrease in serum glucose level (P<0.001), and overall decrease in the severity of diabetic neuropathy. Alcohol extract of W. volubilis root showed antihyperglycemic activity and beneficial protection against diabetic neuropathy and hence can be a promising agent for treatment and prevention of diabetic neuropathy.

Waste biomass adsorbents for copper removal from industrial wastewater--a review.

Copper (Cu(2+)) containing wastewaters are extensively released from different industries and its excessive entry into food chains results in serious health impairments, carcinogenicity and mutagenesis in various living systems. An array of technologies is in use to remediate Cu(2+) from wastewaters. Adsorption is the most attractive option due to the availability of cost effective, sustainable and eco-friendly bioadsorbents. The current review is dedicated to presenting state of the art knowledge on various bioadsorbents and physico-chemical conditions used to remediate Cu(2+) from waste streams. The advantages and constraints of various adsorbents were also discussed. The literature revealed the maximum Cu adsorption capacities of various bioadsorbents in the order of algae>agricultural and forest>fungal>bacterial>activated carbon>yeast. However, based on the average Cu adsorption capacity, the arrangement can be: activated carbon>algal>bacterial>agriculture and forest-derived>fungal>yeast biomass. The data of Cu removal using these bioadsorbents were found best fit both Freundlich and Langmuir models. Agriculture and forest derived bioadsorbents have greater potential for Cu removal because of higher uptake, cheaper nature, bulk availability and mono to multilayer adsorption behavior. Higher costs at the biomass transformation stage and decreasing efficiency with desorption cycles are the major constraints to implement this technology.