Synthesis and evaluation of curcumin reduced and capped gold nanoparticles as a green diagnostic probe with therapeutic potential.

Curcumin, a compound in turmeric, shows promise for its anti-cancer properties. In this study, we successfully synthesised curcumin-reduced and capped gold nanoparticles. Most evaluations have been limited to in-vitro studies for these nanoparticles; our study takes a step further by highlighting the in-vivo assessment of these curcumin-reduced and capped gold nanoparticles (GNPCs) using non-invasive imaging (SPECT and optical) and possible therapeutic potential. The GNPCs showed an average hydrodynamic diameter of 58 nm and a PDI of 0.336. The synthesised and fully characterised GNPCs showed ex-vivo hemolysis value of ≤ 1.74 % and serum stability of ≥ 95 % over 24 h. Using in-vivo non-invasive (SPECT and optical Imaging), prolonged circulation and enhanced bioavailability of GNPCs were seen. The biodistribution studies after radiolabelling GNPCs with 99 mTc complemented the optical imaging. The SPECT images showed higher uptake of the GNPCs at the tumour site, viz the contralateral muscle and the native Curcumin, resulting in a high target-to-non-target ratio that differentiated the tumour sufficiently and enhanced the diagnostics. Other organs also accumulate radiolabeled GNPCs in systemic circulation; bio dosimetry is performed. It was found that the dose received by the different organs was safe for use, and the in-vivo toxicity studies in rats indicated negligible toxicity over 30 days. The tumour growth was also reduced in mice models treated with GNPCs compared to the control. These significant findings demonstrate that GNPC shows synergistic activity in vivo, indicating its ability as a green diagnostic probe that has the potential for therapy.

Laminin mimetic angiogenic and collagen peptide hydrogel for enhance dermal wound healing.

Laminins are essential in basement membrane architecture and critical in re-epithelialization and angiogenesis. These processes and collagen deposition are vital in skin wound healing. The role of angiogenic peptides in accelerating the wound-healing process has been known. The bioactive peptides could be a potential approach due to their similar effects as growth factors and inherent biocompatible and biodegradable nature with lower cost. They can also recognize ligand-receptor interaction and mimic the extracellular matrix. Here, we report novel angiogenic DYVRLAI, CDYVRLAI, angiogenic-collagen PGPIKVAV, and Ac-PGPIKVAV peptides conjugated sodium carboxymethyl cellulose hydrogel, which was designed from laminin. The designed peptide exhibits a better binding with the α3ß1, αvß3, and α5ß1 integrins and CXCR2 receptor, indicating their angiogenic and collagen binding efficiency. The peptides were evaluated to stimulate wound healing in full-thickness excision wounds in normal and diabetic mice (type II). They demonstrated their efficacy in terms of angiogenesis (CD31), re-epithelialization through regeneration of the epidermis (H&E), and collagen deposition (MT). The synthesized peptide hydrogel (DYVRLAI and CDYVRLAI) showed enhanced wound contraction up to 10.1 % and 12.3 % on day 7th compared to standard becaplermin gel (49 %) in a normal wound model. The encouraging results were also observed with the diabetic model, where these peptides showed a significant decrease of 5.20 and 5.17 % in wound size on day 10th compared to the commercial gel (9.27 %). These outcomes signify that the modified angiogenic peptide is a cost effective, novel peptide motif to promote dermal wound healing in both models.

Tranexamic acid (class I drug) reduced and capped gold nanoparticles as a potential hemostatic agent with enhanced performance.

External hemostatic agents play a crucial role in stabilizing an impaired process during pathological conditions. The idea is to stabilize thein vivosystem as soon as possible. This study uses a class I hemostatic drug tranexamic acid as a reducing and capping agent for synthesizing the gold nanoparticles (Tr-AuNPs). Being the synthetic analogue of lysine and a biologically inspired alkylamine molecule, the chemistry can be fine-tuned for stable material that can simultaneously target the intrinsic and extrinsic hemostatic pathway, making it promising for hemostatic applications. The Tr-AuNPs of hydrodynamic diameter ∼46 nm were synthesized and evaluated physio-chemically using various analytical techniques wherein they showed hemocompatibility and increased thrombus weight compared to the native drug. The decrease in prothrombin time (PT) and international normalized ratio supported by the dynamic thromboelastography (TEG) study indicates the prepared nano-conjugate's potential in reducing time for attaining hemostasis as compared to the native tranexamic acid drug. At a 9µg ml-1concentration, Tr-AuNPs had a procoagulant effect, shown by decreased reaction time (R) and coagulation time (K) with improvedαangle and MA. There was a significant increase in the rate of coagulationin vivoby Tr-AuNPs, i.e. (52 s) compared to the native tranexamic acid (360 s). Radiolabelling studies ascertained thein vivobiocompatibility (non-invasive distribution, residence, clearance, and stability) of the Tr-AuNPs. The short-term toxicity studies were conducted to establish a proof of concept for the biomedical application of the material. The results highlighted the use of biologically alkyl amine molecules as capping and reducing agents for the synthesis of nanoparticles, which have shown a synergistic effect on the coagulation cascade while holding the potential for also acting as potential theranostic agents.

Multifunctional, Adhesive, and PDA-Coated Bioactive Glass Reinforced Composite Hydrogel for Regenerative Wound Healing.

Effective wound management imposes several challenges in clinical outcomes due to the complexity of the wound microenvironment, bacterial infections, impaired angiogenesis, aggravated inflammation, and enduring pain. In addition, adhesion on wet biological tissue is another extremely challenging task. Addressing all the issues is necessary for an effective wound healing process. Herein, we developed a unique multifunctional, adhesive composite hydrogel composed of gelatin, chitosan, polydopamine-coated bioactive glass (BG), and curcumin-capped silver nanoparticles (Cur-AgNPs) to target the multifaceted complexity of the wound. The PDA-coated BG serves multiple purposes: (1) adhesivity: catechol groups of PDA and Ca ion released from BG chelate the group present in the hydrogel network and surrounding tissues, (2) angiogenesis: promotes vascularization due to the release of Si from BG, and (3) BG also serves as the "reservoir" for the pain-relieving diclofenac sodium drug with a sustained-release behavior. Cur-AgNPs provide excellent bactericidal and anti-inflammatory properties to the composite hydrogel. In situ application of the composite hydrogel could serve the purpose of a "skin biomimetic" and work as a barrier along with bactericidal properties to inhibit the microbial growth. The multifunctional composite hydrogel (MCH) targeted multiple aspects of wound repair including pain alleviation, elimination of microbes (up to 99%), reduced inflammation, high adhesivity, and increased angiogenesis for effective skin regeneration. The MCH showed excellent wound healing potential as significant wound closure was observed at day 7 and also significantly upregulated the expression of crucial genes involved in the skin regeneration process along with increasing vascularization in the wound area.

Development of a pH-sensitive functionalized metal organic framework: in vitro study for simultaneous delivery of doxorubicin and cyclophosphamide in breast cancer.

Exploration of an efficient dual-drug based nanocarrier with high drug loading capacity, specific targeting properties, and long-term stability is highly desirable in cancer therapy. Metal-organic frameworks (MOFs) have proven to be a promising class of drug carriers due to their high porosity, crystalline properties with defined structure information, and their potential for further functionalization. To enhance the drug efficacy as well as to overcome the burst effect of drugs, here we synthesized a pH responsive folic acid (FA) and graphene oxide (GO) decorated zeolitical imidazolate frameworks-8 (GO-FA/ZIF-8), for targeted delivery of doxorubicin (DOX) and cyclophosphamide (CP), simultaneously. In this system, DOX molecules were encapsulated in the pores of ZIF-8 during in situ synthesis of ZIF-8 and CP molecules have been captured by the GO surface via hydrogen bonding and π-π interactions as well. Furthermore, the resulting pH-responsive nanocarrier (DOX@ZIF-8/GO-FA/CP) showed in vitro sustained release characteristics (76% of DOX and 80% of CP) by cleavage of chemical bonding and disruption of the MOFs structure under acidic condition (at pH 5.6). Moreover, DOX@ZIF-8/GO-FA/CP has synergistic cytotoxic effects as compared to the combination of both the drugs without ZIF-8/GO-FA when treating MCF-7 and MDA-MB-231 breast cancer cell lines (with a combination index of 0.29 and 0.75 for MCF-7 and MDA-MB-231 cell-lines, respectively). Hence this system can be applied as an effective platform for smart dual drug delivery in breast cancer treatment through its remarkable manageable multidrug release.

99mTc-Methionine Gold Nanoparticles as a Promising Biomaterial for Enhanced Tumor Imaging.

Methionine-gold nanoparticles (MGNs) was synthesized by conjugating methionine via dithiocarbamate linkage to gold nanoparticles (GNPs), prepared simultaneously by one pot modified Burst method. Formation of MGNs was confirmed by UV-visible spectroscopy and appearance of new IR bands in the range of 934 cm-1 to 1086 cm-1 and shifting of N-C,S-S and S-C-S stretching, confirms the involvement of '-S-C-S-' group of methionine dithiocarbamate with GNPs. The presence of Au in MGNs was confirmed by EDXA spectrum, whereas TEM, SAED and XRD revealed that MGNs are nanocrystalline (~13 nm) and have face-centered cubic structure. MGNs was labeled with 99mTc (TMGNs) with radiolabeling efficiency greater than 99% using 300 µg of stannous chloride, pH 7 and 90.6 MBq of 99mTcO4. The stability data showed that the conjugate will remain infrangible in systemic circulation and in acidic microenvironment of tumor. The blood kinetic profile of TMGN in rabbits and biodistribution studies in EAT tumor bearing balb/c mice showed longer in vivo circulation and slow clearance compared to radiolabeled methionine (TM). TMGN demonstrated nearly three-fold higher tumor accumulation (3.9 ± 0.35% ID/g), 2-fold lower tumor saturation dose (1.0 µg/kg) and higher tumor retention compared with TM. Data showed that the TMGN tumor: blood ratio (1.05) is nearly 2.5-fold higher than TM (0.44), whereas TMGN tumor: muscle ratio (97.5) is nearly 8-fold higher than TM (11.6). In conclusion, TMGN showed excellent tumor targeting and has promising prospects as a SPECT-radiopharmaceutical for imaging tumors.

Synthesis and biological evaluation of modified laminin peptide (N2S2-KDP) with enhanced affinity for neuronal growth and targeted molecular imaging (SPECT).

An analog of γ1 laminin (RDIAEIIKDI) decapeptide has been used to augment neuronal survival and regeneration after injuries, during aging and other CNS disorder. As a prime synthetic peptide, KDI, is responsible for the neurite outgrowth of human embryonic neurons. In this study, we have designed, modified a KDI derivative and synthesized by replacing isoleucine (I) with Pro (P) amino acid at C-terminal to enhance its potency towards neurite growth. -Cys-Gly-Cys (-CGC) N2S2 motif was also incorporated in the present design for peptide radiolabeling. The modified peptide showed a better binding with the desired 3T1M receptor for neurite growth. The peptide was synthesized using solid phase peptide synthesis and Fmoc-strategy with more than 80% yield. The receptor binding studies of 99mTc-N2S2-KDP in Neuro2A cell lines showed Kd value in 31 nM range and the complex showed appreciable brain uptake in mice. The results on human SH-SY5Y indicate that the unlabeled N2S2-KDP may perhaps be useful for neurite growth in neurodegenerative disorder.

Tryptophan conjugated magnetic nanoparticles for targeting tumors overexpressing indoleamine 2,3 dioxygenase (IDO) and L-type amino acid transporter.

Tryptophan is an amino acid required by all life forms for protein synthesis and other important metabolic functions. It is metabolized in the body using the kynurenine pathway which involves the enzyme indoleamine 2,3 dioxygenase (IDO) and its transport is regulated through the L-type amino acid transporters (LAT 1). IDO and LAT 1 are found to be overexpressed in many cancers i.e., ovarian, lung colorectal etc. In this study we have used this specific interaction as the basis for designing diagnostic agent based on iron oxide nanoparticles which can specifically target the IDO/LAT 1 over expressing tumors. We have conjugated tryptophan to the surface of super-paramagnetic nanoparticles chemically using 3-aminopropyltrimethoxysilane as a linker. The synthesized tryptophan conjugated magnetic nano-conjugate has been characterized using FTIR, UV-Vis, TEM for its shape size, charge and NMR and Mass for conjugation. The magnetization studies show decrease in the magnetic behavior after conjugation however the desired super-paramagnetic property is still retained as shown by the signature sigmoidal B-H curve. The nano-conjugate shows minimal cytotoxicity over 24 h as shown by the SRB assay in two cell lines A-549, MCF-7. Using 99mTc labeling the biodistribution and the blood kinetics of the magnetic nano-conjugate was evaluated. The study highlights the suitability of the designed magnetic Nano bioconjugate as a potential bimodal diagnostic agent.

Correction to: Radiolabeled PLGA Nanoparticles for Effective Targeting of Bendamustine in Tumor Bearing Mice.

The typesetter did not use the Fig. 6 provided by the author with his proof corrections, and instead duplicated Fig. 7 by the Fig. 6 caption. The original article has been corrected.

Radiolabeled PLGA Nanoparticles for Effective Targeting of Bendamustine in Tumor Bearing Mice.

PURPOSE: Bendamustine is an important drug for the treatment of chronic lymphatic leukaemia (CLL), non-Hodgkin lymphoma (NHL). However, its delivery is challenging due to its instability. Current approach reports the development and characterization of bendamustine encapsulated PLGA nanoparticles for the effective targeting to leukemic cells. METHODS: The prepared, bendamustine loaded PLGA nanoparticles (BLPNP) were developed and characterized for particle size, zeta potential and polydispersity index. The formed nanoparticles were further characterized with the help of electron microscopy for surface morphology. The formed nanoparticles were evaluated for cytotoxicity, cell uptake, ROS and cell apoptosis against THP-1 leukemic cells as a part of in vitro evaluation. In vivo organ bio-distribution and tumor regression studies were performed to track in vivo behaviour of BLPNP. RESULTS: The average particle size was 138.52 ± 3.25 nm, with 0.192 ± 0.036 PDI and - 25.4 ± 1.38 mV zeta potential. TEM images revealed the homogeneous particle size distribution with uniform shape. In vitro release exhibited a sustained drug-release behaviour up to 24 h. Cytotoxicity against THP-1 cells through MTT assay observed IC50 value of 27.8 ± 2.1 µM for BLPNP compared to pure drug, which was 50.42 ± 3.4 µM. Moreover, in vitro studies like cell-uptake and cell apoptosis studies further confirmed the higher accumulation of BLPNP in comparison to the pure drug. Organ distribution and tumor regression studies were performed to track in vivo behaviour of bendamustine loaded nanoparticles. CONCLUSION: The overall study described a promising approach in terms of safety, least erythrocytic toxicity, better IC50 value with enhance tumor targeting and regression.

Nanoencapsulation of DMSA monoester for better therapeutic efficacy of the chelating agent against arsenic toxicity.

AIMS: Exposure to toxic metals remains a widespread occupational and environmental problem in world. Chelation therapy is a mainstream treatment used to treat heavy metal poisoning. This paper describes the synthesis, characterization and therapeutic evaluation of monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA)-encapsulated polymeric nanoparticles as a detoxifying agent for arsenic poisoning. MATERIALS & METHODS: Polymeric nanoparticles entrapping the DMSA monoester, which can evade the reticulo-endothelial system and have a long circulation time in the blood, were prepared. Particle characterization was carried out by transmission electron microscopy and dynamic light scattering. An in vivo study was conducted to investigate the therapeutic efficacy of MiADMSA-encapsulated polymeric nanoparticles (nano- MiADMSA; 50 mg/kg orally for 5 days) and comparison drawn with bulk MiADMSA. Swiss albino mice exposed to sodium arsenite for 4 weeks were treated for 5 days to evaluate alterations in blood, brain, kidney and liver oxidative stress variables. The study also evaluated the histopathological changes in tissues and the chelating potential of the nanoformulation. RESULTS: Our results show that nano-MiADMSA have a narrow size distribution in the 50-nm range. We observed an enhanced chelating potential of nano-MiADMSA compared with bulk MiADMSA as evident in the reversal of biochemical changes indicative of oxidative stress and efficient removal of arsenic from the blood and tissues. Histopathological changes and urinary 8-OHdG levels also prove better therapeutic efficacy of the novel formulation for arsenic toxicity. CONCLUSION: The results from our study show better therapeutic efficacy of nano-MiADMSA in removing arsenic burden from the brain and liver.

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

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 (99m)Tc labeling was significantly enhanced after thiolation of chitosan. CBZ-loaded thiolated chitosan NPs significantly reverse the N-Methyl-.-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.

Evaluation of folate conjugated superparamagnetic iron oxide nanoparticles for scintigraphic/magnetic resonance imaging.

The physical and chemical properties of the nanoparticles influence their pharmacokinetics and ability to accumulate in tumors. In this paper we report a facile method to conjugate folic acid molecule to iron oxide nanoparticles to increase the specific uptake of these nanoparticles by the tumor, which will be useful in targeted imaging of the tumor. The iron oxide nanoparticles were synthesized by alkaline co precipitation method and were surface modified with dextranto make them stable. The folic acid is conjugated to the dextran modified iron oxide nanoparticles by reductive amination process after the oxidation of the dextran with periodate. The synthesized folic acid conjugated nanoparticles were characterized for size, phase, morphology and magnetization by using various physicochemical characterization techniques such as transmission electron microscopy, X-ray diffraction, fourier transform infrared spectroscopy, vibrating sample magnetometry, dynamic light scattering and zetasizer etc. The quantification of the generated carbonyl groups and folic acid conjugated to the surface of the magnetic nanoparticles was done by colorimetric estimations using UV-Visible spectroscopy. The in vitro MR studies were carried out over a range of concentrations and showed significant shortening of the transverse relaxation rate, showing the ability of the nanoconjugate to act as an efficient probe for MR imaging. The biodistribution studies and the scintigraphy done by radiolabeling the nanoconjugate with 99mTc show the enhanced uptake at the tumor site showing its enhanced specificity.

Comparative receptor based brain delivery of tramadol-loaded poly(lactic-co-glycolic acid) nanoparticles.

Receptor mediated endocytosis or transcytosis has been reported for drug delivery across Blood-brain barrier (BBB) and hence, the aim of the present investigations was to prepare and compare brain targeting efficiency of tramadol-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface modified with transferrin (Tf) and lactoferrin (Lf). Nanoparticles of tramadol were prepared using nanoprecipitation technique and surface conjugated with Tf and Lf using epoxy linker. Prepared nanoparticles were characterized for their size, surface charge, drug entrapment, transmission electron microscopy and in vitro drug release. The surface density of Tf and Lf was estimated by protein estimation. The drug distribution in blood, brain and other tissues was studied in mice after intravenous administration. Tf and Lf anchored nanoparticles exhibit enhanced uptake with 2.38 and 3.85 folds higher targeting respectively in the brain when compared with unconjugated nanoparticles. The brain targeting observed for Lf anchored PLGA nanoparticles (Lf-TMD-PLGA-NP) was 1.62 folds that of Tf anchored PLGA nanoparticles (Tf-TMD-PLGA-NP). Hence, the study revealed Tf and specially Lf as promising ligand for enhanced brain deposition of tramadol.

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.

Opsonization, biodistribution, cellular uptake and apoptosis study of PEGylated PBCA nanoparticle as potential drug delivery carrier.

PURPOSE: For 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. METHODS: PEGylated 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. RESULTS: These 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. CONCLUSIONS: The PEGylated PBCA formulation can work as a novel tool for drug delivery which can prevent RES uptake and prolong circulation half life.

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.

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.

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.