Administration Of NPs Research Articles

Nanoparticles for regenerative medicine.

Nanoparticles for regenerative medicine.

Fluorescence Enhancement Effect of TiO2 Nanoparticles and Application for Photodynamic Diagnosis.

Photodynamic diagnosis (PDD) can improve diagnostic accuracy by using PDD agents such as 5-aminolevulinic acid (ALA). However, the weakness and photobleaching of fluorescence of PDD agents may lead to insufficient fluorescence visibility for the detection of cancer during resection operations. We focused on the “fluorescence enhancement effect” resulting from the addition of polyethylene glycol-modified titanium dioxide nanoparticles (TiO2-PEG NPs) to address these problems. The results showed that the combined administration of TiO2-PEG NPs and ALA could enhance and prolong fluorescence in bladder cancer cells, similar to in the mixture alone. It was suggested that the fluorescence enhancement was related to the accumulation of TiO2-PEG NPs in cells via endocytosis, causing the light scattering and enhancement of fluorescence. This fluorescence enhancement effect could be applicable for PDD.

Therapeutic Effect of Yttrium Oxide Nanoparticles for the Treatment of Fulminant Hepatic Failure

Aim: To explore the potential therapeutic effect of yttrium oxide nanoparticles (Y2O3 NPs) on fulminant hepatic failure. Materials & methods: RAW264.7 cells and a lipopolysaccharide/D-galactosamine-induced hepatic failure murine model were used to assess the effects of Y2O3NPs. Results: Y2O3 NPs exhibited anti-inflammatory activity by scavenging cellular reactive oxygen species and dampening reactive oxygen species-mediated NF-κB activation in vitro. A single intraperitoneal administration of Y2O3 NPs (30mg/kg) enhanced hepatic antioxidant status and reduced oxidative stress and inflammatory response in lipopolysaccharide/galactosamine-induced mice. Y2O3 NPs also attenuated hepatic NF-κB activation, cell apoptosis and liver injury. Conclusion: Y2O3 NP administration could be used as a novel therapeutic strategy for treating fulminant hepatic failure and oxidative stress-related diseases.

Protective effects of zinc oxide nanoparticles against doxorubicin induced testicular toxicity and DNA damage in male rats.

The present study aims to investigate the protective effects of zinc oxide nanoparticles (ZnO NPs) on doxorubicin-induced testicular injury. Forty mature male rats were randomly allocated into four equal groups: G1 (control), G2 (3 mg per kg BW of zinc oxide nanoparticles was administered), G3 (6 mg per kg BW of doxorubicin was intraperitoneally injected), and G4 (doxorubicin + ZnO NPs). Some fertility parameters, antioxidant status, genotoxicity assay, and a histopathological examination were used for this investigation. The doxorubicin-treated group showed a significant decrease in the index weight of reproductive organs, epididymal sperm count, motility%, and live sperm% and a significant increase in sperm abnormalities. Moreover, GSH and CAT activities were significantly decreased, and MDA content was significantly increased in the doxorubicin-treated group. Interestingly, co-administration of ZnO NPs significantly reduced the doxorubicin-induced changes in the investigated parameters. In addition, ZnO NPs alone did not show any undesirable effects on the sperm parameters, testis or DNA. However, its administration improves the reproductive parameters and significantly increases the testosterone level. We concluded that the administration of ZnO NPs at 3 mg per kg BW ameliorated the testicular toxicity and genotoxicity caused by doxorubicin through its antioxidant and androgenic activity.

An enhanced charge-driven intranasal delivery of nicardipine attenuates brain injury after intracerebral hemorrhage

Intranasal drug delivery provided an alternative and effective approach for the intervention of an intracerebral hemorrhage (ICH). However, the short retention time at the absorption site and slow drug transport in intranasal gel influence the drug bioavailability and outcome of ICH. Herein, we fabricated a novel intranasal gel with oriented drug migration utilizing a charge-driven strategy to attenuate brain injury after ICH. Nicardipine hydrochloride (NCD) was entrapped in chitosan nanoparticles (CS NPs) and dispersed in an HAMC gel. Subsequently, one side of the gel was coated with a positively charged film. The oriented migration of CS NPs in the HAMC gel was determined, and the drug bioavailability was also enhanced. Furthermore, a blood-induced ICH rat model was established to evaluate the therapeutic effect of CS NPs + HAMC composites. Intranasal administration of the CS NPs + HAMC (+) composite showed a stronger neuroprotective effect in terms of brain edema reduction and neural apoptosis inhibition compared to the CS NPs + HAMC composite. These results suggested that the oriented and rapid drug transport from nose to brain can be achieved using the charge-driven strategy, and this intranasal drug delivery system has the potential to provide a new therapeutic strategy for the treatment of ICH.

Effect of commercial and green synthesized ZnO NPs in murine model of chloroquine-induced pruritus.

Purpose: To investigate the effects of zinc oxide nanoparticles (ZnO NPs) on chloroquine (CQ)-induced itching, and overall behavior of mice after oral administration of ZnO NPs of various sizes and doses.Background: With the wide-spread use of ZnO NPs in pharmaceuticals and cosmetics, concerns about their safety and toxicity are also increasing. Multiple aspects of ZnO NPs regarding cytotoxicity and tolerability are under investigation globally. Still, a clear conclusion about their safety has not been reached. Chloroquine phosphate is an antimalarial with known side effects of itching in humans and animals. In this study, CQ was used to induce itching in mice, and the effects of ZnO NPs on scratching and other neurological behavior of mice were observed.Methods: Female BALB/c mice were divided into eleven groups of six mice each. ZnO NPs of various sizes and doses were administered orally 1 hour before CQ (32 mg/kg body weight) was administered subcutaneously. The effect of ZnO NPs on CQ-induced pruritus was observed for the next 30 minutes. Simultaneously, overall behavioral changes (socialization and locomotion) were also recorded using a video camera.Results: A significant reduction (P˂0.001) in scratching bouts was observed at all three doses of ZnO NPs (particle sizes 100, 30 nm, and green synthesized 30 nm). Locomotion was reduced significantly (P˂0.001) in ZnO NPs-treated groups in comparison to normal saline and CQ group, additionally, a significant increase in socialization (P˂0.05) was observed in ZnO NP-treated groups as compared to CQ group.Conclusion: ZnO NPs, instead of aggravating the dermatological condition, ameliorated the pruritus. All sizes of ZnO NPs used significantly improved socialization among mice and reduced locomotion activity.

SF-1 mediates reproductive toxicity induced by Cerium oxide nanoparticles in male mice

BackgroundCerium oxide nanoparticles (CeO2 NPs) have potential application for use in biomedical and in various consumer products. However, it is largely unclear whether CeO2 NPs have effects on male reproductive function.MethodsIn this study, male mice were examined for toxicity, if any, following chronic oral administration of CeO2 NPs for 32 days. In each animal, epididymides were examined for sperm motility and DNA integrity. Bloods were tested for testosterone levels. Testicular tissues were collected to determine the element Ce content, the daily sperm production (DSP), marker enzymes such as ACP, G6PD, γ-GT and SDH, mRNA expression levels of steroidogenesis genes Star, P450scc, P450c17, 3β-Hsd, and 17β-Hsd, as well as steroidogenic factor-1 (SF-1) gene/protein levels.ResultsThe results showed that CeO2 NPs (20 mg/kg and 40 mg/kg) increased the element Ce content in testis, the testis histopathological patterns and sperm DNA damage whereas decreased the testis weight, DSP and sperm motility. There were also remarkable reduction in testosterone levels and marker enzymes activities, down-regulated mRNA expression levels of several steroidogenesis genes such as Star, P450scc, P450c17, 3β-Hsd, and 17β-Hsd, as well as altered gene and protein expressions of SF-1.ConclusionThese results reveal the male reproductive toxicity of chronic exposure of CeO2 NPs in mice, hinting that the utilization of CeO2 NPs need to be carefully evaluated about their potential reproductive toxicity on the human health.

NLRP3 inflammasome, oxidative stress, and apoptosis induced in the intestine and liver of rats treated with titanium dioxide nanoparticles: in vivo and in vitro study.

PurposeThis study evaluated the effects of titanium dioxide nanoparticles (TiO2 NPs) on liver and intestine of normal rats.MethodsMale rats were divided into four groups as follows: 1) control rats, 2) control rats that orally received 10 mg/kg TiO2 NPs, 3) control rats that orally received 50 mg/kg TiO2 NPs, and 4) control rats that orally received 100 mg/kg TiO2 NPs. After 30 days, the NLRP3 inflammasome pathway (NLRP3, caspase-1, and IL-1β), antioxidant pathway (superoxide dismutase [SOD], glutathione peroxidase [GPx], and catalase [CAT]), inflammatory pathway (inducible nitric oxide synthase [iNOS] and tumor necrosis factor-α [TNF-α]), and the apoptosis pathway (p53, Bax, Bcl-2, and caspase-3) were determined in the intestine and liver of the rats. H&E and Masson’s trichrome (MT) staining as well as TUNEL assay were used to examine the liver and the intestine. Biochemical factors, cytotoxicity, ROS generation, and apoptosis rate were also determined in HepG2 and Caco-2 cells.ResultsTiO2 NPs in a dose-dependent manner increased cytotoxicity, oxidative stress, and apoptosis rate in Caco-2 and HepG2 cells. The administration of TiO2 NPs significantly reduced antioxidant enzyme activity and gene expressions (SOD, CAT, and GPx) as well as glutathione (GSH) levels and total antioxidant capacity (TAC) in a dose-dependent manner. TiO2 NPs also induced the apoptosis pathway and inflammatory pathway gene expressions and caspase-3 activity in the intestine and liver. TUNEL assay was in agreement with gene expressions. TiO2 NPs also led to morphological changes in the liver and intestine.ConclusionTiO2 NPs could have cytotoxic effects on the intestine and liver structure and function by inducing oxidative stress, inflammation, and apoptosis.

Effect of Iron Nanoparticles on the Development of Fish Farm Feeds

Two hundred and seventy monosex males Nile Tilapia (Oreochromis niloticus) with an average body weight of 16.65±0.2 g/fish were used to investigate the effect of dietary replacement of inorganic iron by different levels of Fe-NPs on growth performance, body composition and health status of A. hydrophila challenged Nile tilapia fish. Fish maintained on 30% protein level, Six different experimental diets supplemented with 0.0 (T1), 85.0 mg inorganic Fe/kg (T2) and 85.0, 63.75, 42.5 and 21.25mg Fe-NPs/kg (T3-T5) were fed to triplicates groups of fish. It was found that the final body weight, weight gain, SGR, FCR and PER were significantly improved in the fish fed on the iron-supplemented diets compared to those fed on the iron-deficient diet (T1). Blood pictures and serum biochemical were significantly increased before and after A. hydrophila infection in the iron-supplemented groups compared to the iron-deficient diet group. The dietary administration of iron NPs improved the antioxidant enzymatic activities (CAT and TAC) irrespective of the different iron sources in the basal diet. Moreover, it was observed that the diets containing 63.75 and 42.5 mg/kg of Fe-NPs exhibited the best survival rate compared to the other groups.

Demethoxycurcumin-Loaded Chitosan Nanoparticle Downregulates DNA Repair Pathway to Improve Cisplatin-Induced Apoptosis in Non-Small Cell Lung Cancer.

Demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanoyl chitosan (CHC) nanomatrix has been successfully developed and used as a therapeutic approach to inhibit cisplatin-induced drug resistance by suppressing excision repair cross-complementary 1 (ERCC1) in non-small cell lung carcinoma cells (NSCLC). Previously, DMC significantly inhibited on-target cisplatin resistance protein, ERCC1, via PI3K-Akt-snail pathways in NSCLC. However, low water solubility and bioavailability of DMC causes systemic elimination and prevents its clinical application. To increase its bioavailability and targeting capacity toward cancer cells, a DMC-polyvinylpyrrolidone core phase was prepared, followed by encapsulating in a CHC shell to form a DMC-loaded core-shell hydrogel nanoparticles (DMC-CHC NPs). We aimed to understand whether DMC-CHC NPs efficiently potentiate cisplatin-induced apoptosis through downregulation of ERCC1 in NSCLC. DMC-CHC NPs displayed good cellular uptake efficiency. Dissolved in water, DMC-CHC NPs showed comparable cytotoxic potency with free DMC (dissolved in DMSO). A sulforhodamine B (SRB) assay indicated that DMC-CHC NPs significantly increased cisplatin-induced cytotoxicity by highly efficient intracellular delivery of the encapsulated DMC. A combination of DMC-CHC NPs and cisplatin significantly inhibited on-target cisplatin resistance protein, ERCC1, via the PI3K-Akt pathway. Also, this combination treatment markedly increased the post-target cisplatin resistance pathway including bax, and cytochrome c expressions. Thymidine phosphorylase (TP), a main role of the pyrimidine salvage pathway, was also highly inhibited by the combination treatment. The results suggested that enhancement of the cytotoxicity to cisplatin via administration of DMC-CHC NPs was mediated by down-regulation of the expression of TP, and ERCC1, regulated via the PI3K-Akt pathway.

Evaluation of epigenetic changes of liver tissue induced by oral administration of Titanium dioxide nanoparticles and possible protective role of Nigella Sativa oil, in adult male albino rats

Objective (s): Titanium dioxide nanoparticles (TiO2 NPs) have been recognized as biologically inert material and have been used in a multitude of applications. Nevertheless, the negative impact on the human health is not yet well understood. Aim of the work: The study attempted to evaluate the epigenetic changes of the genome, in the form of DNA methylation in liver tissue samples, resulting from oral administration of TiO2 NPs (mixed rutile and anatase) in adult male albino rats. Furthermore, whether the Nigella sativa oil (NSO) can prevent the toxic effects of TiO2 NPs.Materials and Methods: Thirty-two adult male albino rats were divided into four groups. (I) control, (II) nigella sativa oil, (III) TiO2 NPs and (IV) TiO2 NPs + nigella sativa oil. The impact of TiO2 NPs on the global DNA methylation and the oxidative status were assessed.Results: Among the study groups, TiO2 NPs exposure provoked oxidative stress; increased blood levels of MDA and decreased reduced glutathione (GSH) level. The global DNA methylation levels decreased after exposure to titanium nanoparticles. Significant differences were recorded between the control group and the group receiving TiO2 NPs. Marked improvement was noticed after supplementation of nigella sativa oil in terms of DNA methylation and oxidative stress markers. Conclusion: Oral administration of TiO2 NPs caused global DNA hypo-methylation in liver tissue samples. The epigenetic damage raises the concern about the safety associated with applications of the TiO2 NPs. The maintenance of DNA methylation patterns by Nigella sativa oil has a role in protection against genomic instability.

The Antioxidant Effect of PLGA Nanoparticles Encapsulated with Lutein in Rats Treated with Hypercaloric Diet

Poly lactic-co-glycolic acid (PLGA) is a biodegradable polymer that has been the focus of intense research due to its potential applications in medical research. Its uses in nanotechnology are underlined by its capability of targeting various cells and delivering active compounds to different human tissues. To date, PLGA nanoparticles are employed in areas such as vaccination therapy, diagnostic imaging procedure and various applications in various anticancer therapies. The aim of the present study is to measure and evaluate different correlations between oxidative stress parameters in spleen and liver following administration of nanoparticles encapsulated with lutein in an animal model. Our results show that acute oral administration of PLGA NPs induces a change in the oxidative stress status in both liver and spleen of rats, but does not induce oxidative stress damage to cell structures such as lipids or proteins.

Integration of Phospholipid-Complex Nanocarrier Assembly with Endogenous N-Oleoylethanolamine for Enormously Effective Stroke Therapy

Leading to more and more deaths and disabilities, stroke has become a serious threat to human health. What's more, few effective drugs are available in clinic till now. In this research, we prepared a novel neuroprotective nanoformation (OEA-SPC NPs) via the combination of the nanoparticle drug delivery system with the endogenous N-oleoylethanolamine (OEA). By forming hydrogen bond between OEA and the carrier - soybean phosphatidylcholine (SPC), the form of OEA was turned into amorphus state when loading to the nanoparticles, which greatly improved its bioavailability. Then the following systematic experiments revealed the amazing neuroprotective effect of OEA-SPC NPs in vivo. Compared with the MCAO group, the cerebral infarct volume was reduced by 81.1%, and the edema degree by 78.4% via the oral administration of OEA-SPC NPs. And the neurological deficit scores illustrated that the MCAO rats treated with OEA-SPC NPs exhibited significantly less neurological dysfunction. The Morris water maze test indicated that the spatial learning and memory of cerebral ischemia model rats were almost recovered to the normal level. Besides, the OEA-SPC NPs could inhibit the inflammation of reperfusion to a very slight level. These results suggest that the OEA-SPC NPs have a great chance to be a potential anti-stroke formation for clinic application and actually bring hope to thousands of stroke patients. Funding Statements: This project was supported by the National Natural Science Foundation of China (Nos. 81373407 and 81402921), the Health Science Research Personnel Training Program of Fujian Province (2018-CXB-30), the Fundamental Research Funds for the Central Universities (No. 20720180042), the Natural Science Foundation of Fujian, China (No. 2016D018) and the China Postdoctoral Science Foundation (No. 2017M622080 and 2018M632584). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The experimental protocols were approved by the Animal Care and Use Committee of Medical College of Xiamen University in compliance with the NIH Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23).

Dual purpose hafnium oxide nanoparticles offer imaging Streptococcus mutans dental biofilm and fight it In vivo via a drug free approach

The removal of tenacious dental plaque is of paramount importance; however, early diagnosis can be a challenging task in dental clinics due to the limitations of current approaches, specifically X-ray-based techniques. We have approached this problem by integrating antibacterial properties and X-ray contrast enhancement in a single probe specific to colonies of Streptococcus mutans as the most predominant and carious oral bacteria. We report the synthesis of an inherently therapeutic polymeric silane conjugated hafnium oxide nanoparticles (Hf PS NPs). Using a high-affinity pathogen-selective peptide, the concept of molecularly targeted X-ray imaging of cariogenic pathogen S. mutans was demonstrated. Ex vivo studies using extracted human tooth demonstrated striking X-ray attenuation of NPs vs. tooth. Additionally, Hf PS NPs exhibited significant bactericidal properties against cariogenic pathogen. Electron microscopy revealed that the antibacterial activity occurred via a ‘latch and kill’ mechanism. Mechanistic studies determined that these NPs fragmented bacterial DNA components to exert their antimicrobial effect. Importantly, Hf PS NPs effectively inhibited the growth of a mature biofilm on an ex vivo human tooth model. Finally, the NPs were applied to the rodent model of dental biofilm. Topical administration of the Hf PS NPs for 8 days (1X daily) could effectively attenuate the S. mutans biofilm challenge. This report is the first of its kind to demonstrate that HfO2-based NPs can be used for simultaneous diagnosis and antibacterial treatment without requiring an additional drug.

Effect of titanium dioxide nanoparticles on the cardiovascular system after oral administration

Titanium dioxide nanoparticles (TiO2 NPs) have been widely used in various consumer products, especially food and personal care products. Compared to the well-characterized adverse cardiovascular effect of inhaled ambient ultrafine particles, research on the health response to orally administrated TiO2 NPs is still limited. In our study, we performed an in vivo study in Sprague-Dawley rats to understand the cardiovascular effect of TiO2 NPs after oral intake. After daily gastrointestinal administration of TiO2 NPs at 0, 2, 10, 50 mg/kg for 30 and 90 days, heart rate (HR), blood pressure, blood biochemical parameters and histopathology of cardiac tissues was assessed to quantify cardiovascular damage. Mild and temporary reduction of HR and systolic blood pressure as well as an increase of diastolic blood pressure was observed after daily oral administration of TiO2 NPs for 30 days. Injury of cardiac function was observed after daily oral administration of TiO2 NPs for 90 days as reflected in decreased activities of lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBDH) and creatine kinase (CK). Increased white blood cells count (WBC) and granulocytes (GRN) in blood as well as increased concentrations of tumor necrosis factor α (TNF α) and interleukin 6 (IL-6) in the serum indicated inflammatory response initiated by TiO2 NPs exposure. It was hypothesize that cardiac damage and inflammatory response are the possible mechanisms of the adverse cardiovascular effects induced by orally administrated TiO2 NPs. Data from our study suggested that even at low dose of TiO2 NPs can induce adverse cardiovascular effects after 30 days or 90 days of oral exposure, thus warranting concern for the dietary intake of TiO2 NPs for consumers.

Iron oxide nanoparticles: Synthesis, physical characterization, and intraperitoneal biochemical studies in Rattus norvegicus

In the current work, magnetite (Fe3O4) nanoparticles were prepared by electrochemical method based on surfactant-free synthesis under vacuum. The obtained nanoparticles were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and vibrational sample magnetometer (VSM) techniques. Magnetite nanoparticles (at a dose of 40 mg/kg BW) were administered intraperitoneally to male rats daily up to 14 days. Additionally, a liver histopathology analysis was performed. After 7 days of the intraperitoneal administration of NPs, a significant increase in serum antioxidant enzyme activities was observed whereas other parameters remained unchanged. After two weeks of administration, significant decreases in serum antioxidant enzymes and a significant increase in serum ALT and AST were observed. Throughout the two weeks period, there was no significant difference in serum BUN and creatinine levels between the control group and the treatment group. Obtained results strongly suggest that the magnetite nanoparticles could be safe at proper dose for therapeutic and diagnostic applications.

Curcumin-loaded nanoparticles ameliorate glial activation and improve myelin repair in lyolecithin-induced focal demyelination model of rat corpus callosum

Curcumin has been introduced as effective anti-inflammatory agent in treatment of several inflammatory disorders. Despite the wide range pharmacological activities, clinical application of curcumin is restricted mainly due to the low water solubility of this substance. More recently, we could remarkably improve the aqueous solubility of curcumin by its encapsulation in chitosan-alginate-sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). In this study, the anti-inflammatory and myelin protective effects of curcumin-loaded NPs were evaluated in lysolecithin (LPC)-induced focal demyelination model. Pharmacokinetic of curcumin was assessed using high performance liquid chromatography (HPLC). Local demyelination was induced by injection of LPC into corpus callosum of rats. Animals were pre-treated with intraperitoneal (i.p.) injections of curcumin or curcumin-loaded NPs at dose of 12.5 mg/kg, 10 days prior to LPC injection and the injections were continued for 7 or 14 days post lesion. Hematoxylin and eosin (H&E) staining and immunostaining against activated glial cells including astrocytes and microglia were carried out for assessment of inflammation level in lesion site. Myelin specific staining was performed to evaluate the effect of curcumin-loaded NPs on myelination of LPC receiving animals. HPLC results showed the higher plasma concentration of curcumin after administration of NPs. Histological evaluation demonstrated that, the extent of demyelination areas was reduced in animals under treatment of curcumin-loaded NPs. Furthermore, treatment with curcumin-loaded NPs effectively attenuated glial activation and inflammation in LPC-induced demyelination model compared to curcumin receiving animals. Overall; these findings indicate that treatment with curcumin-loaded NPs preserve myelinated axons through amelioration of glial activation and inflammation in demyelination context.

Fc-modified exenatide-loaded nanoparticles for oral delivery to improve hypoglycemic effects in mice

To improve the oral efficiency of exenatide, we prepared polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) NPs modified with Fc (NPs-Fc) for exenatide oral delivery. Exenatide was encapsulated into the NPs by the w/o/w emulsion-solvent evaporation method. The particle size of the NPs-Fc was approximately 30 nm larger than that of the unmodified NPs with polydispersity indices in a narrow range (PDIs; PDI < 0.3) as detected by DLS, and the highest encapsulation efficiency of exenatide in the NPs was greater than 80%. Fc-conjugated NPs permeated Caco-2 cells faster and to a greater extent compared to unmodified NPs, as verified by CLSM and flow cytometry. Hypoglycemic effect studies demonstrated that oral administration of exenatide-loaded PEG-PLGA NPs modified by an Fc group extended the hypoglycemic effects compared with s.c. injection of the exenatide solution. Fluorescence-labeled NPs were used to investigate the effects of Fc targeting, and the results demonstrated that the NPs-Fc stayed in the gastrointestinal tract for a longer time in comparison with the unmodified NPs, as shown by the whole-body fluorescence images and fluorescence images of the dissected organs detected by in vivo imaging in live mice. Therefore, Fc-targeted nano-delivery systems show great promise for oral peptide/protein drug delivery.

Preclinical Evaluation of Intravesical Cisplatin Nanoparticles for Non–Muscle-Invasive Bladder Cancer

Purpose: Prior clinical trials evaluating cisplatin for non-muscle-invasive bladder cancer (NMIBC) were stopped due to local and systemic toxicity. Currently, there is still a need for improved intravesical therapies, and nanoparticle-based CDDP may be efficacious without the toxicity of free cisplatin observed in the past.Experimental Design: Cisplatin nanoparticles (CDDP NPs) were developed using biocompatible poly(l-aspartic acid sodium salt; PAA), both with and without low and high grafting density of methoxy-polyethylene glycol (PEG). In vitro cytotoxicity studies confirmed activity of CDDP NPs and CDDP solution against a papillary bladder cancer cell line. Local toxicity was assessed by three weekly intravesical administrations of CDDP formulations. CDDP NPs and CDDP solution were evaluated for bladder absorption in murine models 1 and 4 hours after intravesical administration. In vivo efficacy was evaluated in an immunocompetent carcinogen model of NMIBC.Results: CDDP NPs showed decreased local toxicity, as assessed by bladder weight, compared with CDDP solution. Furthermore, >2 μg/mL of platinum was observed in mouse serum after intravesical administration of CDDP solution, whereas serum platinum was below the limit of quantification after intravesical administration of CDDP NPs. CDDP NPs provided significantly increased (P < 0.05) drug levels in murine bladders compared with CDDP solution for at least 4 hours after intravesical administration. In vivo, CDDP NPs reduced cancer cell proliferation compared with untreated controls, and was the only treatment group without evidence of invasive carcinoma.Conclusions: Cisplatin-loaded PAA NPs have the potential to improve intravesical treatment of NMIBC while reducing local and systemic side effects. Clin Cancer Res; 23(21); 6592-601. ©2017 AACR.

Development of a Drug Delivery System Based on Chitosan Nanoparticles for Oral Administration of Interferon-α.

Despite the good clinical efficacy of interferon-alpha (IFNα) to treat some types of cancer and viral infections, this biological drug is underused given its severe adverse effects and high dosing parenteral regimens. Aiming to achieve a breakthrough in therapy with IFNα, this work reports for the first time on the design and full characterization of a novel nanomedicine of IFNα-2b-loaded chitosan nanoparticles (IFN-CT NPs) for oral delivery. IFN-CT NPs produced by ionotropic gelation, encapsulating approximately 100% of the drug, showed a size of 36 ± 8 nm, zeta potential of +30 mV (dynamic light scattering), and spherical morphology (transmission electron microscopy). The antiviral activity of IFN-CT NPs in vitro was comparable to that of commercial IFNα. Remarkably, both treatments stimulated the expression of IFN response genes to a similar extent in both noninfected and infected cells with Human Lymphotropic-T Virus type 1. Finally, oral administration of IFN-CT NPs (0.3 MIU) to CF1 mice showed detectable levels of IFNα in plasma after 1 h, whereas no IFNα was detected with a commercial formulation. These results are encouraging and open a new avenue for the administration of this biological drug in a minimally invasive, safer, and more patient-compliant way.