Rashi Mathur

Toxicity of Multiwalled Carbon Nanotubes with End Defects Critically Depends on Their Functionalization Density

Carboxylated carbon nanotubes stand as the most promising nanovectors for biomedical and pharmaceutical applications due to their ease of covalent conjugation with eclectic functional molecules including therapeutic drugs, proteins, and oligonucleotides. In the present study, we attempt to investigate how the toxicity of acid-oxidized multiwalled carbon nanotubes (MWCNTs) can be tweaked by altering their degree of functionalization and correlate the toxicity trend with their biodistribution profile. In line with that rationale, mice were exposed to 10 mg/kg of pristine (p) and acid-oxidized (f) MWCNTs with varying degrees of carboxylation through a single dose of intravenous injection. Thereafter, extensive toxicity studies were carried out to comprehend the short-term (7 day) and long-term (28 day) impact of p- and various f-MWCNT preparations on the physiology of healthy mice. Pristine MWCNTs with a high aspect ratio, surface hydrophobicity, and metallic impurities were found to induce significant hepatotoxicity and oxidative damage in mice, albeit the damage was recovered after 28 days of treatment. Conversely, acid-oxidized carboxylated CNTs with shorter lengths, hydrophilic surfaces, and high aqueous dispersibility proved to be less toxic and more biocompatible than their pristine counterparts. A thorough scrutiny of various biochemical parameters, inflammation indexes, and histopathological examination of liver indicated that toxicity of MWCNTs systematically decreased with the increased functionalization density. The degree of shortening and functionalization achieved by refluxing p-MWCNTs with strong mineral acids for 4 h were sufficient to render the CNTs completely hydrophilic and biocompatible, while inducing minimal hepatic accumulation and inflammation. Quantitative biodistribution studies in mice, intravenously injected with Tc-99m labeled MWCNTs, clearly designated that clearance of CNTs from reticuloendothelial system (RES) organs such as liver, spleen, and lungs was critically functionalization density dependent. Well-individualized MWCNTs with shorter lengths (<500 nm) and higher degrees of oxidation (surface carboxyl density >3 μmol/mg) were not retained in any of the RES organs and rapidly cleared out from the systematic circulation through renal excretion route without inducing any obvious nephrotoxicity. As both p- and f-MWCNT-treated groups were devoid of any obvious nephrotoxicity, CNTs with larger dimensions and lower degrees of functionalization, which fail to clear out from the body via renal excretion route, were thought to be excreted via biliary pathway in faeces.

Sustained Ocular Drug Delivery from a Temperature and pH Triggered Novel In Situ Gel System

Various ocular diseases like glaucoma, conjunctivitis, and dry eye syndrome require frequent drug administration. Poor ocular bioavailability of drugs (< 1%) from conventional eye drops is due mainly to the precorneal loss factors that include rapid tear turnover, nonproductive absorption, transient residence time in the cul-de-sac, and the relative impermeability of the drugs to corneal epithelial membrane. These problems may be overcome by the use of in situ gel-forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac. Our present work describes the formulation and evaluation of an ocular delivery system of timolol maleate based on the concept of both temperature and pH-triggered in situ gelation. Pluronic F-127 (a thermosensitive polymer) in combination with chitosan (pH-sensitive polymer also acts as permeation enhancer) was used as gelling agent. The developed formulation was characterized for various in vitro parameters e.g., clarity, gelation temperature and pH, isotonicity, sterility, rheological behavior, drug release profile, transcorneal permeation profile, and ocular irritation. Developed formulation was clear, isotonic solution, that converted into gel at temperatures above 35°C and pH 6.9–7.0. A significant higher drug transport across corneal membrane and increased ocular retention time was observed using the developed formulation. The developed system is a viable alternative to conventional eye drops for the treatment of glaucoma and various other ocular diseases.

Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route

Intranasal drug delivery is known to overcome the blood–brain barrier (BBB) for delivery of drugs to brain. The objective of this study was to prepare risperidone (RSP)-loaded solid lipid nanoparticles (RSLNs) and explore the possibility of brain targeting by nose-to-brain delivery. RSLNs were prepared by solvent emulsification–solvent evaporation method and characterized for drug content, particle size and size distribution, zeta potential, and in vitro drug-release study. The pharmacodynamic study of RSLNs, which was performed by paw test using Perspex platform, showed higher hindlimb retraction time (HRT) values as compared with RSP solution (RS) indicating the superiority of RSLNs over the RS for brain targeting. The pharmacokinetics and biodistribution studies in mice showed that brain/blood ratio 1 h post-administration of RSLNs (i.n.) was found to be 1.36 ± 0.06 (nearly 10- and 5-fold higher) as compared with 0.17 ± 0.05 for RS (i.v.) and 0.78 ± 0.07 for RSLNs (i.v.), respectively. Gamma scintigraphy imaging of mice brain following intravenous and intranasal administration confirmed the localization of drug in brain. This finding substantiates the existence of direct nose-to-brain delivery route for nanoparticles administered to the nasal cavity.

Opsonization, Biodistribution, Cellular Uptake and Apoptosis Study of PEGylated PBCA Nanoparticle as Potential Drug Delivery Carrier

ABSTRACTPurposeFor nanocarrier-based targeted delivery systems, preventing phagocytosis for prolong circulation half life is a crucial task. PEGylated poly(n-butylcyano acrylate) (PBCA) NP has proven a promising approach for drug delivery, but an easy and reliable method of PEGylation of PBCA has faced a major bottleneck.MethodsPEGylated PBCA NPs containing docetaxel (DTX) by modified anionic polymerization reaction in aqueous acidic media containing amine functional PEG were made as an single step PEGylation method. In vitro colloidal stability studies using salt aggregation method and antiopsonization property of prepared NPs using mouse macrophage cell line RAW264 were performed. In vitro performance of anticancer activity of prepared formulations was checked on MCF7 cell line. NPs were radiolabeled with 99mTc and intravenously administered to study blood clearance and biodistribution in mice model.ResultsThese formulations very effectively prevented phagocytosis and found excellent carrier for drug delivery purpose. In vivo studies display long circulation half life of PBCA-PEG20 NP in comparison to other formulations tested.ConclusionsThe PEGylated PBCA formulation can work as a novel tool for drug delivery which can prevent RES uptake and prolong circulation half life.

Mucoadhesive chitosan microspheres of carvedilol for nasal administration

The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres of carvedilol (CRV) for nasal delivery to improve bioavailability for treatment of hypertension and angina pectoris. The microspheres were prepared by emulsification-cross-linking method and evaluated for size, shape, entrapment efficiency (EE), in vitro mucoadhesion, in vitro drug release, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The mucoadhesive properties were also evaluated by Freundlich and Langmuir adsorption isotherms. In vivo tests were carried out in rabbits. The microspheres were spherical with size of 20–50 µm, which is favorable for intranasal absorption. The EE was observed from 42% to 68% while percentage mucoadhesion was from 74% to 88%. A strong interaction between mucin and chitosan microspheres was detected explaining adsorption with electrostatic interaction. The microspheres released around 75% of drug in 8 h. DSC and XRD studies revealed that CRV was molecularly dispersed. The absorption rate was rapid and the absolute bioavailability was high, 72.29%. The gamma scintigraphy indicated that the microspheres cleared slowly from the nasal cavity. It was concluded that chitosan microspheres could be used to deliver CRV following nasal administration for improving the bioavailability.

Synthesis, pharmacoscintigraphic evaluation and antitumor efficacy of methotrexate-loaded, folate-conjugated, stealth albumin nanoparticles

UNLABELLED The present study aims to develop a multifunctional nanoformulation based on technetium-99m labeled, folate conjugated, methotrexate-loaded human serum albumin nanoparticles (HSA NPs) and explore their potential in cancer theragnostics. MATERIALS & METHODS Methotrexate-loaded HSA NPs were synthesized by a reverse microemulsion technique, followed by chemical crosslinking with glutaraldehyde. These NPs were conjugated with folic acid (FA) through a hydrophilic polyethylene glycol spacer to render them long-circulatory and augment their tumor-specific localization. The therapeutic conjugate was further radiolabeled with a γ-emitter technetium-99m for real-time monitoring of its blood clearance kinetics and biodistribution through the measurement of blood/organ-associated radioactivity and scintigraphic imaging. RESULTS & CONCLUSION In vitro cell-uptake and cytotoxicity studies corroborated that FA conjugation enabled these NPs to specifically target and kill folate-receptor overexpressing cancer cells via S phase arrest. Blood clearance kinetics and biodistribution studies clearly indicated that circulation time, as well as tumor-specific localization of methotrexate-loaded HSA nanocarriers, could be significantly augmented upon polyethylene glycolylation and conjugation of FA. Finally, we demonstrated that these targeted HSA NPs inhibited tumor growth more effectively, as compared with the nontargeted controls.

Investigation on design of stable etoposide-loaded PEG-PCL micelles: effect of molecular weight of PEG-PCL diblock copolymer on the in vitro and in vivo performance of micelles.

In the present study, six different molecular weight diblock copolymer of methoxy poly (ethylene glycol)-b-poly (ϵ-caprolactone) (MPEG-PCL) were synthesized and characterized and was used for fabrication of etoposide-loaded micelles by nanoprecipitation technique. The particle size and percentage drug entrapment of prepared micelles were found to be dependent on the molecular weight of PCL block and drug to polymer ratio. The maximum drug loading of 5.32% was found in micellar formulation MPEG5000-PCL10000, while MPEG2000-PCL2000 exhibited 2.73% of maximum drug loading. A variation in the fixed aqueous layer thickness and PEG surface density of micellar formulations was attributed to difference in MPEG molecular weight and interaction of PEG and PCL block of copolymer. The MPEG2000-PCL2000 micelles demonstrated poor in vitro stability among other micellar formulations, due to its interaction with bovine serum albumin and immediate release of drug from micelles. Furthermore, plain etoposide and MPEG2000-PCL2000 micelles exhibited greater extent of hemolysis, due to presence of surfactants and faster release of drug from micelles, respectively. The biodistribution studies carried out on Ehrlich ascites tumor-bearing Balb/C mice confirmed higher accumulation of etoposide-loaded micellar formulation at tumor site compared to plain etoposide due to enhanced permeability and retention effect.

In vivo evaluation of alginate microspheres of carvedilol for nasal delivery.

Mucoadhesive alginate microspheres of carvedilol (CRV) for nasal administration intended to avoid first pass metabolism and to improve bioavailability were prepared and evaluated. The microspheres were prepared by emulsification cross-linking method. Radiolabeling of CRV and its microspheres was performed by direct labeling with reduced technetium-99m ((99m) Tc). In vivo studies were performed on New Zealand white rabbits by administering the microspheres intranasally using monodose nasal insufflator. The radioactivity was measured in a well-type gamma scintillation counter. The noncompartmental pharmacokinetic analysis was performed. The pattern of deposition and clearance of the microspheres were evaluated using a radioactive tracer and the noninvasive technique of gamma scintigraphy. The clearance of alginate microsphere was compared with that of control lactose. The microspheres were nonaggregated, free flowing powders with spherical shape, and smooth surface. Pharmacokinetics study displayed an increase in area under the curve and hence in relative bioavailability when compared with intravenous administration of drug. The nasal bioavailability was 67.87% which indicates that nasal administration results in improved absorption of CRV. The results of gamma scintigraphy showed that the alginate microspheres had significantly reduced rates of clearance from the rabbit nasal cavity when compared with the control lactose.

Dimeric complexes of rare-earth substituted Keggin-type silicotungstates: syntheses, crystal structure and solid state properties

A series of rare-earth substituted dimeric complexes of Keggin-type silicotungstates: [{Ln(α-SiW11O39)(H2O)}2(μ-CH3COO)2]12− [Ln = EuIII (Eu-1), GdIII (Gd-2), TbIII (Tb-3), DyIII (Dy-4), HoIII (Ho-5), ErIII (Er-6) and TmIII (Tm-7)] and [Ln(α-SiW11O39)2]13− [Ln = PrIII (Pr-8), NdIII (Nd-9), SmIII (Sm-10)] were synthesized by a single step reaction of Na10[α-SiW9O34]·16H2O with Ln(NO3)3·nH2O in potassium acetate buffer at pH 4.5. All these compounds were structurally characterized by single-crystal X-ray diffraction, and other analytical techniques including FT-IR, ICP-AES, UV/vis, photoluminescence spectroscopy, thermogravimetric analysis, 13C and 1H NMR spectroscopy and vibrating sample magnetometry (VSM). The single-crystal X-ray diffraction and FT-IR studies suggest that the compounds Na4K8[{Ln(α-SiW11O39)(H2O)}2(μ-CH3COO)2]·xH2O (Ln = Eu − Tm) (Eu-1a–Tm-7a), and K6Na7[Ln(SiW11O39)2]·xH2O (Ln = Pr, Nd, Sm) (Pr-8a–Sm-10a) are isostructural. The photoluminescence properties of Eu-1a, Tb-3a, Dy-4a and Sm-10a were studied at room temperature. VSM studies of Gd-2a, Tb-3a, Dy-4a, Ho-5a, Er-6a and Tm-7a were carried out at room temperature, and they showed paramagnetic behaviour.

Intranasal delivery of cyclobenzaprine hydrochloride-loaded thiolated chitosan nanoparticles for pain relief

Abstract The purpose of present investigation was to formulate and characterize the cyclobenzaprine HCl (CBZ)-loaded thiolated chitosan nanoparticles and assessment of in-vitro cell viability, trans-mucosal permeability on RPMI2650 cell monolayer, in-vivo pharmacokinetic and pharmacodynamic study of thiolated chitosan nanoparticles on Swiss albino mice after intranasal administration. A significant high permeation of drug was observed from thiolated chitosan nanoparticles with less toxicity on nasal epithelial cells. Brain uptake of the drug after 99mTc labeling was significantly enhanced after thiolation of chitosan. CBZ-loaded thiolated chitosan NPs significantly reverse the N-Methyl-d-Aspartate (NMDA)-induced hyperalgesia by intranasal administration than the CBZ solution. The studies of present investigation revealed that thiolation of chitosan significantly reduce trans-mucosal toxicity with enhanced trans-mucosal permeability via paracellular pathway and brain uptake of a hydrophilic drug (normally impermeable across blood brain barrier) and pain alleviation activity via intranasal route.