Aqueous Core Nanocapsules Research Articles

Dual combination of resveratrol and pterostilbene aqueous core nanocapsules for integrated prostate cancer targeting.

Aim: Development and evaluation of aqueous core nanocapsules (ACNs) of BCS-II-class drug like resveratrol (RSV) and pterostilbene (PTE)for prostate cancer.Materials & methods: Identify synergistic effects of molar ratios of RSV and PTE against PC-3 cell. Selected ratio of drugs was added to ACNs by double-emulsification-method using Box-Behnken design. Further, assessed for physicochemical characterization, release kinetics, compatibility, invitro cytotoxicity, in vivo pharmacokinetic and biodistribution studies.Results: Selected 1:1 ratio of RSV and PTE had greatest synergy potential have smaller particle-size (128.1±3.21nm), zeta-potential (-22.12±0.2mV), 0.53PDI, improved encapsulation (87% for RSV, 72% for PTE), stable, no systemic toxicity, high biodistributed/accumulated in prostate cells.Conclusion: ACNs exhibited high t1/2 (12.42±1.92hs) and 8.20±8.21hs Mean Residence Time and lower clearance, proving the high effectiveness for prostate cancer.

Enhancement of Liver Targetability through Statistical Optimization and Surface Modification of Biodegradable Nanocapsules Loaded with Lamivudine.

The intention of the current work was to develop and optimize the formulation of biodegradable polymeric nanocapsules for lamivudine (LMV) in order to obtain desired physical characteristics so as to have improved liver targetability. Nanocapsules were prepared in this study as aqueous-core nanocapsules (ACNs) with poly(lactide-co-glycolide) using a modified multiple emulsion technique. LMV was taken as a model drug to investigate the potential of ACNs developed in this work in achieving the liver targetability. Three formulations factors were chosen and 33 factorial design was adopted. The selected formulation factors were optimized statistically so as to have the anticipated characteristics of the ACNs viz. maximum entrapment efficiency, minimum particle size, and less drug release rate constant. The optimized LMV-ACNs were found to have 71.54 ± 1.93% of entrapment efficiency and 288.36 ± 2.53 nm of particle size with zeta potential of -24.7 ± 1.2 mV and 0.095 ± 0.006 h-1 of release rate constant. This optimized formulation was subjected to surface modification by treating with sodium lauryl sulphate (SLS), which increased the zeta potential to a maximum of -41.6 ± 1.3 mV at a 6 mM concentration of SLS. The results of in vivo pharmacokinetics from blood and liver tissues indicated that hepatic bioavailability of LMV was increased from 13.78 ± 3.48 μg/mL ∗ h for LMV solution to 32.94 ± 5.12 μg/mL ∗ h for the optimized LMV-ACNs and to 54.91 ± 6.68 μg/mL ∗ h for the surface-modified LMV-ACNs.

Dual Vinorelbine bitartrate and Resveratrol loaded polymeric aqueous core nanocapsules for synergistic efficacy in breast cancer

Aim The current study focussed on the development and evaluation of aqueous core nanocapsules (ACNs) as an effective carrier to deliver an optimal synergistic combination of a highly water-soluble Vinorelbine bitartrate (VRL) and a poorly water-soluble Resveratrol (RES) for treatment of breast cancer. Methods Various molar ratios of VRL to RES were screened against MCF-7 cell lines to determine the synergistic effects using the Chou-Talalay method. The synergistic ratio of therapeutic agents was then incorporated into aqueous core nanocapsules utilising a double emulsion solvent evaporation technique to yield dual drug-loaded nanocapsules (dd-ACNs). The dd-ACNs were optimised using Box-Behnken design and characterised for physicochemical parameters such as particle size, zeta potential, polydispersity index, total drug content and encapsulation efficiency, surface morphology, drug excipient compatibility by FTIR and DSC, release kinetics, toxicity studies and anticancer efficacy (in-vitro and in-vivo). Results Results demonstrated that the combination exhibited maximum synergy when higher doses of VRL were combined with smaller doses of RES (1:1, 5:1, and 10:1). The dual drug-loaded ACNs were found to be stable and depicted a core-shell structure, narrow size range (150.2 ± 3.2 nm) with enhanced encapsulation (80% for VRL and 99% for RES). Moreover, the dd-ACNs were 5 times more efficacious in-vitro than a combination of free drugs, while reducing systemic toxicity. Also, pre-clinical evaluation of dd-ACNs also depicted a drastic reduction of tumour volume as compared tp pristine VRL and a physical combination of drugs. Conclusion The developed dd-ACNs can be applied as a potential carrier for delivery of a combination of chemotherapeutics at a synergistic ratio at the tumour site.

Identification of aqueous reservoirs in poly(alkylcyanoacrylate) nanoparticles

Poly (n-butylcyanocrylate) nanocapsules were obtained by interfacial polymerization from a water-in-oil microemulsion. The latter was composed of pharmaceutically acceptable excipients such as Labrafac lipophile WL 1349 (oil), Plurol oleique CC497 (surfactant), and Labrasol (co-surfactant) and was able to incorporate 20% aqueous phase. Pure n-butylcyanoacrylate monomer (without any dilution in a halogenated solvent) was added to the microemulsion in order to obtain an oily suspension of biocompatible and biodegradable aqueous core nanocapsules. Finally, in order to provide a direct evidence of the presence of water within the nanocapsules, a mass balance and nuclear magnetic resonance analysis were performed. The results showed that the presence of water and transmission electronic microscopy confirmed a hybrid structure of the final nanosystem, between a genuine nanocapsule and a matrix system: a nanosystem with multicavities filled with water.

Study on influence of polymer and surfactant on in vitro performance of biodegradable aqueous-core nanocapsules of tenofovirdisoproxil fumarate by response surface methodology

The major objective of this study was to investigate the effect of biodegradable polymer type and surfactant concentration on various characteristics viz. particle size, entrapment efficiency and drug release rate constant of aqueous core nanocapsules (ACNs) containing tenofovirdisoproxil fumarate. In this study, the nanocapsules were prepared by modified multiple emulsion technique with biodegradable polymers viz. poly(lactide-co-glycolide) of two different grades (PLGA RG502H and PLGA RG503H) and poly lactic acid (PLA R203H); and the surfactant employed was span 80. The experiments were designed under response surface methodology by employing the Design Expert software. Entrapment efficiency, particle size and drug release rate constant were taken as response variables. The prepared nanocapsules were subjected to characterization studies and the obtained results were statistically analyzed by Analysis of Variance (ANOVA) for response surface 2-Factorial Interaction model. ANOVA studies showed that the influence of both factors on all the response variables were significant at p<0.05. The optimized formulation was found to have the entrapment efficiency of 71.58%, particle size of 252.41 nm and the drug release rate constant of 0.045 h-1; thus, indicating that the ACNs were obtained with finest characteristics. SEM studies showed that the particles were spherical.

Lipid Based Aqueous Core Nanocapsules (ACNs) for Encapsulating Hydrophillic Vinorelbine Bitartrate: Preparation, Optimization, Characterization and In vitro Safety Assessment for Intravenous Administration.

Vinorelbine bitartrate (VRL) is an antimitotic agent approved by FDA for breast cancer and non-small cell lung cancer (NSCLC) in many countries. However, high aqueous solubility and thermo degradable nature of VRL limited the availability of marketed dosage forms. The current work is focused on the development of lipid based aqueous core nanocapsules which can encapsulate the hydrophilic VRL in the aqueous core of nanocapsules protected with a lipidic shell which will further provide a sustained release. The ACNs were prepared by double emulsification technique followed by solvent evaporation. Box Behnken Design was utilized to optimize the formulation and process variables. Thirteen batches were generated utilizing lipid concentration, surfactant concentration and homogenizer speed as dependent variables (at three levels) and particle size and encapsulation efficiency as critical quality attributes. The ACNs were characterized for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, morphology by Transmission Electron Microscopy (TEM) and in vitro release. The ACNs were further evaluated for safety against intravenous administration by haemocompatibility studies. Results demonstrated that lipidic nanocapsules enhanced the entrapment efficiency of VRL up to 78%. Transmission Electron Microscopy revealed spherical shape of ACNs with core-shell structure. The GMS-VRL-ACNs showed that release followed Korsemeyer peppas kinetics suggesting Fickian diffusion. Moreover, the compliance towards haemocompatibility studies depicted the safety of prepared nanocapsules against intravenous administration. ACNs were found to be promising in encapsulating high aqueous soluble anticancer drugs with enhanced entrapment and safety towards intravenous administration.

Morphology-dependent pH-responsive release of hydrophilic payloads using biodegradable nanocarriers.

The development of functional nanocarriers with stimuli-responsive properties has advanced tremendously to serve biomedical applications such as drug delivery and regenerative medicine. However, the development of biodegradable nanocarriers that can be loaded with hydrophilic compounds and ensure its controlled release in response to changes in the surrounding environment still remains very challenging. Herein, we achieved such demands via the preparation of aqueous core nanocapsules using a base-catalyzed interfacial reaction employing a diisocyanate monomer and functional monomers/polymers containing thiol and hydroxyl functionalities at the droplet interface. pH-responsive poly(thiourethane–urethane) nanocarriers with ester linkages were synthesized by incorporating polycaprolactone diol, which is susceptible to hydrolytic degradation via ester linkages, as a functional monomer in the reaction formulation. We could demonstrate that by systematically varying the number of biodegradable segments, the morphology of the nanocarriers can be tuned without imparting the efficient encapsulation of hydrophilic payload (>85% encapsulation efficiency) and its transfer from organic to aqueous phase. The developed nanocarriers allow for a fast release of hydrophilic payload that depends on pH, the number of biodegradable segments and nanocarrier morphology. Succinctly put, this study provides important information to develop pH-responsive nanocarriers with tunable morphology, using interfacial reactions in the inverse miniemulsion process, by controlling the number of degradable segments to adjust the release profile depending on the type of application envisaged.

Nanoencapsulation strategies for the delivery of novel bifunctional antioxidant/σ1 selective ligands

Nowadays sigma-1 receptors are considered as new therapeutic objectives for central nervous system neurodegenerative diseases. Among different molecules, alpha lipoic acid has been identified as a natural potent antioxidant drug, whose therapeutic efficacy is limited by its many drawbacks, such as fast metabolism, poor bioavailability and high physico-chemical instability. Alfa-lipoic acid derivatives have been recently developed demonstrating their neuroprotective activity and effectiveness in different types of oxidative stress. In this work, two derivatives containing an amide or an ester functional group with different lipophilicity, were selected for their important affinity for sigma-1 receptors. Herein, in order to improve the in vitro stability and antioxidant effectiveness of alpha-lipoic acid derivatives, we focused our efforts in the nanoencapsulation strategies. Aqueous-core nanocapsules for the delivery of the hydrophilic compound and nanostructured lipid carrier for the lipophilic derivative, were properly designed and prepared using a direct or inverse eco-friendly organic solvent-free procedure. All nanosystems were characterized in terms of mean size, polydispersity, stability, morphology, encapsulation efficiency and in vitro release profiles. In order to evaluate the nanocarriers biocompatibility and antioxidant effectiveness, in vitro biological studies (cell viability, total antioxidant capacity and total oxidative status) were developed on primary human whole blood cell cultures, on both unloaded and derivatives-loaded nanodevices.

Innovative hybrid vs polymeric nanocapsules: The influence of the cationic lipid coating on the “4S”

Polymeric and hybrid aqueous-core nanocapsules were prepared using a low energy organic-solvent free procedure as innovative nanodevices for the ophthalmic delivery of melatonin. In order to evaluate how different cationic lipids could affect the main properties of the nanodevices, we focused our attention on mean particles size, surface charge, shape and stability (the “4S”). The results of our study confirmed the hypothesis that the coating material differently affects the overall nanoparticles properties, above all in terms of morphology: in particular, the cationic lipid dimethyldioctadecylammonium bromide allows the formation of very stable well-defined nanocapsules with non-spherical shape with sustained and prolonged drug release, thus representing a great advantage in ophthalmic application.

Aqueous core nanocapsules: a new solution for encapsulating doxorubicin hydrochloride

In this study, we propose a new solution for the nanoencapsulation of hydrophilic anticancer drug, doxorubicin hydrochloride (DOX). The drug molecules are solubilized in the core of aqueous nanoreservoirs, so-called aqueous core nanocapsules (ACN) recently developed by our team, and dispersed in aqueous bulk media. Since it is well acknowledged that the nanoencapsulation of DOX has many advantages, like reducing the sides effects (e.g. cardiac toxicity), we propose through the present study a novel formulation solution for this purpose. After focusing on the formulation process for optimizing the drug encapsulation yield, the DOX-release profiles were followed up and analyzed. Different physicochemical and in vitro characterization were performed, and complement activation experiments. ACN were shown efficient to encapsulate DOX reaching yields as high as 80%, followed by a sustained release governed by a diffusion-controlled mechanism. The loaded nanocarriers showed low levels of complement activation, compatible with stealth properties. To summarize, this study brings out a new tool for the nanoencapsulation of hydrophilic anticancers and could open new doors for the administration of this particular class of drugs.

Nanoencapsulation of antiviral nucleotide analogs

Nucleoside analogs, although widely used in antiviral treatments, possess considerable limitations including an often poorly efficient in vivo phosphorylation, limiting their antiviral efficacy and increasing the possibility of resistance emergence. The administration of already-phosphorylated nucleoside analogs, i.e. "nucleotide analogs", is an appealing strategy to overcome these shortcomings, but requires an appropriate drug delivery approach due to the poor stability and limited intracellular penetration of these very hydrophilic molecules. As an illustration of such approach, the nucleotide analog azidothymidine triphosphate (AZT-TP) has been successfully encapsulated into aqueous-core nanocapsules through the combined use of biodegradable poly(iso-butylcyanoacrylate) and "helper" cationic polymers. These "hybrid" nanocapsules exhibited a controlled release of AZT-TP and dramatically enhanced its uptake by macrophages in vitro. This approach will be reviewed here and compared to the other nanocarriers investigated for the encapsulation of antiviral nucleotide analogs, namely liposomes and nanogels.

Encapsulation of mono- and oligo-nucleotides into aqueous-core nanocapsules in presence of various water-soluble polymers

In a previous study, we have shown that cidofovir (CDV) and azidothymidine-triphosphate (AZT-TP) were poorly encapsulated in poly( iso-butylcyanoacrylate) (PIBCA) aqueous-core nanocapsules. This was attributed to the rapid leakage of these small and hydrophilic molecules through the thin polymer wall of the nanocapsules. In the present study, we have selected various water-soluble polymers as increasing Mw adjuvants and investigated their influence on the entrapment of mononucleotides (CDV, AZT-TP) as well as of oligonucleotides (ODN) into these PIBCA aqueous-core nanocapsules. We show here that the presence of cationic polymers (i.e. poly(ethyleneimine) (PEI) or chitosan) in the nanocapsule aqueous compartment allowed successful encapsulation of AZT-TP and ODN.

Encapsulation of antiviral nucleotide analogues azidothymidine-triphosphate and cidofovir in poly( iso-butylcyanoacrylate) nanocapsules

Nucleoside analogues are widely used in the treatment of various viral infections. However, the poor in vivo conversion of the nucleoside analogues like azidothymidine (AZT) into their active triphosphate nucleotide counterpart limits their pharmacological efficacy. This could be overcome by the direct administration of azidothymidine triphosphate (AZT-TP), but it requires an appropriate drug delivery approach. Besides nucleoside analogues, nucleotide analogues like cidofovir (CDV) are also used in the treatment of viral infections. CDV has raised recent interest because of its promising activity against smallpox, but its use is limited by its poor bioavailability and nephrotoxicity. Here again, a proper drug delivery system should address these issues. In this study, we investigated the encapsulation of the nucleotide analogues AZT-TP and CDV into poly( iso-butylcyanoacrylate) aqueous core nanocapsules, known to efficiently entrap oligonucleotides. We show here that the encapsulation of these mono-nucleotides is less efficient than with oligonucleotides and that a rapid release of AZT-TP from the nanocapsules occurred in vitro. This highlights the importance of the molecular weight of the entrapped molecules which, if they are too small, are diffusing through the thin polymer membrane of the nanocapsules. On the other hand, a good protection of the encapsulated AZT-TP was observed.

Efficacy of siRNA Nanocapsules Targeted Against the EWS–Fli1 Oncogene in Ewing Sarcoma

The EWS-Fli1 fusion gene encodes for a chimeric oncogenic transcription factor considered to be the cause of the Ewing sarcoma. The efficiency of small interfering RNAs (siRNAs) targeted toward the EWS-Fli1 transcript (at the junction point type 1) was studied, free or encapsulated into recently developed polyisobutylcyanoacrylate aqueous core nanocapsules. Because this mRNA sequence is only present in cancer cells, it therefore constituted a relevant target. Studies of the intracellular penetration by confocal microscopy in NIH/3T3 EWS-Fli1 cells showed that nanocapsules improved the intracellular penetration of siRNA with mainly a cytoplasmic localization. These biodegradable siRNA-loaded nanocapsules were then tested in vivo on a mice xenografted EWS-Fli1-expressing tumor; they were found to trigger a dose-dependant inhibition of tumor growth after intratumoral injection. A specific inhibition of EWS-Fli1 was observed, too. These findings now open new prospects for the treatment of experimental cancers with junction oncogenes.

Polyisobutylcyanoacrylate nanocapsules containing an aqueous core as a novel colloidal carrier for the delivery of oligonucleotides.

The goal of the present paper was to encapsulate oligonucleotides in a new particulate carrier in order to protect them from enzymatic degradation. Nanocapsules with an aqueous core containing oligonucleotides were prepared by interfacial polymerization of isobutylcyanoacrylate in a W/O emulsion. Ultracentrifugation and re-suspension in water yielded a dispersion of these containing an aqueous core nanocapsules. Zeta potential measurements and quenching of fluorescence of fluorescein-bounded oligonucleotides were used to study the localization of the oligonucleotides. Oligonucleotide degradation studies were carried out in fetal calf serum. Polydisperse nanocapsules of size ranging from 20 to 400 nm were obtained. Oligonucleotide loading did not significantly influence the zeta potential, suggesting they were located within the core of the nanocapsules. Fluorescence quenching assays confirmed this localization. When encapsulated in the nanocapsules and incubated in the presence of serum, the oligonucleotides were efficiently protected from degradation by nucleases, whereas oligonucleotides adsorbed onto nanospheres were protected less efficiently. This paper describes, for the first time, a nanotechnology able to encapsulate oligonucleotides rather than adsorbing them at the surface of a solid support. Such a formulation has great potential for oligonucleotide delivery.