Iron oxide nanoparticle-mediated radiation delivery for glioblastoma treatment

Radiotherapy is a mainstay adjunctive therapy for glioblastoma (GBM). Despite the outcome improvement achieved with radiation, GBM prognosis remains dismal. Here we introduce a tumor-targeted iron oxide nanoparticle (NP) that intensifies the energy transfer of conventional photon radiotherapy on a selective cellular basis. Several NPs were formulated with systematic architectural variation to study and optimize reactive oxygen species (ROS) production. Selected from this screening stage, a biocompatible tumor-targeted NP was tested in vitro using two models of GBM, and then in vivo, using an orthotopic human primary GBM xenograft mouse model. Animals that received intravenous NP before irradiation demonstrated a 3-fold reduction in tumor growth and a 2-fold increase in survival. Cellular damage was investigated using in vivo magnetic resonance spectroscopy, which demonstrated increased therapeutic cytotoxicity specific to the tumor mass. Our work presents a viable therapeutic strategy to improve radiation therapy for GBM.     

Phospholipid–polymer hybrid nanoparticle-mediated transfollicular delivery of quercetin: prospective implement for the treatment of androgenic alopecia

Abstract

Objectives: The aim of the study was to deliver effective doses of quercetin (Que) to the lower region of hair follicles (HFs) using the transfollicular route through dipalmotylphosphatidylcholine (DPPC)-reinforced poly lactide-co- glycolide nanoparticles (DPPC-PLGA hybrid NPs) for the treatment of alopecia.

Method: PLGA and DPPC-PLGA hybrid NPs were prepared by double-emulsification solvent evaporation method. NPs were characterized for size, shape, zeta potential entrapment and drug release. Drug-polymer interactions were determined by infrared spectroscopy (Fourier transform infrared spectroscopy, FTIR) and differential scanning calorimetry (DSC). Follicular uptake of fluorescent marker tagged NPs was assessed on isolated rat skin by fluorescent microscopy. Potential of hybrid NPs to induce hair regrowth was tested on testosterone-induced alopecia in rat models by visual inspection, hair follicular density measurement (no./mm), and histological skin tissue section studies.

Key findings: Hybrid NPs had mean vesicles size 339?±?1.6, zeta potential –32.6?±?0.51, and entrapment efficiency 78?±?5.5. Cumulative drug release after 12?h was found to be 47.27?±?0.79%. FTIR and DSC confirmed that drug was independently dispersed in the amorphous form in the polymer. Data from fluorescence microscopy suggested that NPs were actively taken up by HFs. In-vivo studies on alopecia-induced rat models showed that hybrid NPs improved hair regrowth potential of Que and accumulation of NPs at HFs end region inhibit HFs cells apoptosis.

Conclusion: This study concludes that phospholipid–polymer hybrid NPs could be the promising transfollicular delivery system for Que in the treatment of androgenic alopecia management.     

Nanotechnology based CRISPR/Cas9 system delivery for genome editing: Progress and prospect

Nano Research - The genome editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, has achieved successful therapeutic efficacy via precise modification of the...     

Optimized allylamine deposition for improved pluripotential cell culture

Deposition of allylamine (ALL) by plasma enhanced chemical vapor deposition has been optimized on silicon based models. Simultaneous energy recoil detection analysis and Rutherford backscattering spectra show that 100 W deposition is ideal in terms of polymerized film formation and H content while, lower or higher power induce reduced film retention or excessive cross linking, respectively. Surface composition of the ALL film was further probed by X-ray photoelectron spectroscopy revealing a monocomponent N 1s spectrum compatible with the presence of primary amines. Optimized ALL films were applied to polycaprolactone (PCL) surfaces after Ar plasma activation with implications in the chemistry and wettability of this biocompatible polymer. Human mesenchymal stem cells (hMSCs) were cultured on ALL coated PCL surface and controls. ALL functionalized PCL was found to be especially attractive for the formation of confluent monolayers of hMSCs after 72 h of culture.     

Mesoporous silica nanoparticles as a delivery system of gadolinium for effective human stem cell tracking

The progress of using gadolinium (Gd)-based nanoparticles in cellular tracking lags behind that of superparamagnetic iron oxide (SPIO) nanoparticles in magnetic resonance imaging (MRI). Here, dual functional Gd-fluorescein isothiocyanate mesoporous silica nanoparticles (Gd-Dye@MSN) that possess green fluorescence and paramagnetism are developed in order to evaluate their potential as effective T1-enhancing trackers for human mesenchymal stem cells (hMSCs). hMSCs are labeled efficiently with Gd-Dye@MSN via endocytosis. Labeled hMSCs are unaffected in their viability, proliferation, and differentiation capacities into adipocytes, osteocytes, and chondrocytes, which can still be readily MRI detected. Imaging, with a clinical 1.5-T MRI system and a low incubation dosage of Gd, low detection cell numbers, and short incubation times is demonstrated on both loaded cells and hMSC-injected mouse brains. This study shows that the advantages of biocompatibility, durability, high internalizing efficiency, and pore architecture make MSNs an ideal vector of T1-agent for stem-cell tracking with MRI.     

Novel drug delivery system for captopril

Abstract

It is known that drug substances showing no difference in absorbance along the whole gastro-intestinal (GI) tract are suitable for SR-formulations with an extended release characteristic. However, a decrease in bioavailability from proximal to distal parts of the gut may be suited for a limited retard effect. In this investigation, attempts have been made to design a suitable delivery system for captopril which is poorly bio-available from the alkaline regions of the GI-tract. The principles of ‘Bioadhesion’ as well as ‘Gastric Floating Systems’ are utilized in this study.     

Novel drug delivery system for captopril

It is known that drug substances showing no difference in absorbance along the whole gastro-intestinal (GI) tract are suitable for SR-formulations with an extended release characteristic. However, a decrease in bioavailability from proximal to distal parts of the gut may be suited for a limited retard effect. In this investigation, attempts have been made to design a suitable delivery system for captopril which is poorly bio-available from the alkaline regions of the GI-tract. The principles of 'Bioadhesion' as well as 'Gastric Floating Systems' are utilized in this study.     

Development of self-microemulsifying drug delivery system for oral delivery of poorly water-soluble nutraceuticals

The objective of the study was to develop a self-microemulsifying drug delivery system (SMEDDS), also known as microemulsion preconcentrate, for oral delivery of five poorly water-soluble nutraceuticals or bioactive agents, namely, vitamin A, vitamin K2, coenzyme Q₁₀, quercetin and trans-resveratrol. The SMEDDS contained a 1:1 mixture (w/w) of Capmul MCM NF (a medium chain monoglyceride) and Captex 355 EP/NF (a medium chain triglyceride) as the hydrophobic lipid and Tween 80 (polysorbate 80) as the hydrophilic surfactant. The lipid and surfactant were mixed at 50:50 w/w ratio. All three of the SMEDDS components have GRAS or safe food additive status. The solubility of nutraceuticals was determined in Capmul MCM, Captex 355, Tween 80, and the SMEDDS (microemulsion preconcentrate mixture). The solubility values of vitamin A palmitate, vitamin K2, coenzyme Q₁₀, quercetin, and trans-resveratrol per g of SMEDDS were, respectively, 500, 12, 8, 56, and 87?mg. Appropriate formulations of nutraceuticals were prepared and filled into hard gelatin capsules. They were then subjected to in vitro dispersion testing using 250?mL of 0.01 N HCl in USP dissolution apparatus II. The dispersion test showed that all SMEDDS containing nutraceuticals dispersed spontaneously to form microemulsions after disintegration of capsule shells with globule size in the range of 25 to 200?nm. From all formulations, except that of vitamin K2, >80–90% nutraceuticals dispersed in 5–10?min and there was no precipitation of compounds during the test period of 120?min. Some variation in dispersion of vitamin K2 was observed due to the nature of the material used (vitamin K2 pre-adsorbed onto calcium phosphate). The present report provides a simple and organic cosolvent-free lipid-based SMEDDS for the oral delivery of poorly water-soluble nutraceuticals. Although a 50:50 w/w mixture of lipid to surfactant was used, the lipid content may be increased to 70:30 without compromising the formation of microemulsion.     

High-throughput formulation screening system for self-microemulsifying drug delivery

Purpose: To develop a high-throughput formulation screening (HTFS) system for self-microemulsifying drug delivery system (SMEDDS) formulations. Methods: Formulations were prepared by dispensing surfactants and a model compound (Nilvadipine) dissolved in ethanol and oil with a robotic liquid dispenser. Screenings of emulsion particle size and phase stability were conducted for selecting SMEDDS formulations by a turbidity assay. Results: Formulations were prepared at 40 minute/96-formulation. Both the screenings were conducted at 1 minute/96-formulation. SMEDDS formulations and the most suitable hydrophilic surfactant (HS)/lipophilic surfactant (LS) combination, which formed the largest SMEDDS area on its corresponding phase diagram, were selected by SMEDDS–HTFS system with minimal manpower (one person) and compound consumption (0.2 mg/formulation). Conclusions: SMEDDS–HTFS system enabled rapid and efficient selections of SMEDDS formulations and the most suitable HS/LS combination for SMEDDS.     

Biodegradable progesterone microsphere delivery system for osteoporosis therapy

The purpose of this study was to formulate and characterize a controlled-release biodegradable delivery system of progesterone for the treatment or prevention of osteoporosis. Microspheres of progesterone were formulated using copolymers of poly(glycolic acid-co-dl-lactic acid)(PGLA 50/50 and PGLA 15/85) and poly(L-lactic acid)(L-PLA) of similar molecular weight by the emulsion solvent evaporation technique. The effects of process variables, such as volume fraction, polyvinyl alcohol (PVA) concentration, polymer composition, and stir speed during preparation, on the yield, encapsulation efficiency (EEF), particle size distribution, in vitro release profiles of progesterone, and surface morphology of progesterone microspheres were investigated. Increasing the volume fraction from 9% to 22% increased the EEF without significantly increasing the yield; however, the rate of progesterone release from the microspheres decreased. Increasing the PVA concentration from 1% to 5% had no significant influence on the EEF, but the rate of progesterone release from microspheres increased. Polymer composition had no significant effect on the EEF, but had a significant effect on the particle size distribution, surface morphology, and release rate of progesterone from the microspheres. Stir speed did not have a significant influence on the EEF; however, stir speed influenced particle size distribution and the rate of progesterone release from microspheres of the same sieve-size range. The results suggest that controlled release of progesterone is possible by varying the different process variables, and that PGLA 50/50 provided the slowest release of progesterone. This should provide a means of delivering progesterone for months for the treatment or prevention of osteoporosis in postmenopausal women.     

Formulation and characterisation of a self‐nanoemulsifying drug delivery system of amphotericin B for the treatment of leishmaniasis

This study was aimed to develop a self‐nanoemulsifying drug delivery system (SNEDDS) for amphotericin B (AmB) potential use in leishmaniasis through topical and oral routes. Two formulations, formulation A and formulation B (FA and FB) of AmB loaded SNEDDS were developed by mixing their excipients through vortex and sonication. The SNEDDS formulation FA and FB displayed a mean droplet size of 27.70 ± 0.5 and 30.17 ± 0.7 nm and zeta potential −11.4 ± 3.25 and −13.6 ± 2.75 mV, respectively. The mucus permeation study showed that formulation FA and FB diffused 1.45 and 1.37%, respectively in up to 8 mm of mucus. The cell permeation across Caco‐2 cells monolayer was 10 and 11%, respectively. Viability of Caco‐2 cells was 89% for FA and 86.9% for FB. The anti‐leishmanial activities of FA in terms of IC₅₀ were 0.017 µg/ml against promastigotes and 0.025 µg/ml against amastigotes, while IC₅₀ values of FB were 0.031 and 0.056 µg/ml, respectively. FA and FB killed macrophage harboured Leishmania parasites in a dose‐dependent manner and a concentration of 0.1 µg/ml killed 100% of the parasites. These formulations have the potential to provide a promising tool for AmB use through oral and topical routes in leishmaniasis therapy.Inspec keywords: nanomedicine, drops, microorganisms, electrokinetic effects, cellular biophysics, drug delivery systems, monolayers, drugs, diseasesOther keywords: self‐nanoemulsifying drug delivery system, topical routes, oral routes, SNEDDS formulation, mucus permeation study, cell permeation, leishmaniasis treatment, amphotericin B, zeta potential, Caco‐2 cell monolayer, vortex, sonication, droplet size, Caco‐2 cell viability, antileishmanial activity, promastigotes, amastigotes, Leishmania parasites     

Development of a cyclodextrin-based nasal delivery system for lorazepam

A new drug delivery system containing hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and a mucoadhesive polymer was developed with the aim to overcome the limitations connected with the nasal application of drugs with low water solubility. Lorazepam, free or as cyclodextrin inclusion complex, was loaded into mucoadhesive microparticles by spray drying, using hydroxypropylmethyl cellulose (HPMC), carbomer, and HPMC/carbomer interpolymer complex (IPC) as mucoadhesive components. Differential scanning calorimetry (DSC) indicated the presence of drug crystalline areas in microparticles loaded with free lorazepam, whereas in those loaded with HP-beta-CD inclusion complex, the drug was amorphous. Zeta potential measurement revealed that the polymer was the main component on the surface of the microparticles. The swelling rate and mucoadhesive properties of the microparticles were determined by the polymer type used in formulation. IPC- and carbomer-based microparticles showed superior swelling rate and mucoadhesion compared with the HPMC-based microparticles (p < .05). Drug loading into the polymer matrix decreased the swelling rate as well as the mucoadhesive properties of microparticles (p < .05), whereas the presence of HP-beta-CD in the matrix did not induce any additional reduction of those parameters (p > .05). The in vitro dissolution studies demonstrated that the microparticles containing the lorazepam inclusion complex displayed 1.8-2.5 times faster drug release compared with those containing free lorazepam. The change in the drug release rate could be connected with improved drug solubility inside the polymer matrix due to inclusion complex formation, as well as to the reduction in crystallinity following complexation, as confirmed by DSC studies.     

Optimized production planning model for a multi-plant cultivation system under uncertainty

An inexact multi-constraint programming model under uncertainty was developed by incorporating a production plan algorithm into the crop production optimization framework under the multi-plant collaborative cultivation system. In the production plan, orders from the customers are assigned to a suitable plant under the constraints of plant capabilities and uncertainty parameters to maximize profit and achieve customer satisfaction. The developed model and solution method were applied to a case study of a multi-plant collaborative cultivation system to verify its applicability. As determined in the case analysis involving different orders from customers, the period of plant production planning and the interval between orders can significantly affect system benefits. Through the analysis of uncertain parameters, reliable and practical decisions can be generated using the suggested model of a multi-plant collaborative cultivation system.     

Rapid magnetic cell delivery for large tubular bioengineered constructs

Delivery of cells into tubular tissue constructs with large diameters poses significant spatial and temporal challenges. This study describes preliminary findings for a novel process for rapid and uniform seeding of cells onto the luminal surface of large tubular constructs. Fibroblasts, tagged with superparamagnetic iron oxide nanoparticles (SPION), were directed onto the luminal surface of tubular constructs by a magnetic field generated by a k4-type Halbach cylinder device. The spatial distribution of attached cells, as measured by the mean number of cells, was compared with a conventional, dynamic, rotational cell-delivery technique. Cell loading onto the constructs was measured by microscopy and magnetic resonance imaging. The different seeding techniques employed had a significant effect on the spatial distribution of the cells (p < 0.0001). The number of attached cells at defined positions within the same construct was significantly different for the dynamic rotation technique (p < 0.05). In contrast, no significant differences in the number of cells attached to the luminal surface were found between the defined positions on the construct loaded with the Halbach cylinder. The technique described overcomes limitations associated with existing cell-delivery techniques and is amenable to a variety of tubular organs where rapid loading and uniform distribution of cells for therapeutic applications are required.     

Functionalized nano-magnetic particles for an in vivo delivery system

Nanotechnologies to allow the nondisruptive introduction of carriers in vivo have wide potential for therapeutic delivery system. We have prepared functional nano-magnetic particles (d = 3 nm) by silanization with (3-aminopropyl) triethoxysilane. For the purpose of functionalizing the surface of the nanoparticles with amino groups for subsequent cross-linking with pharmaceuticals and biomolecules. The extremely small particles were successfully introduced into living cells without any further modification to enhance endocytic internalization, such as the use of a cationic help. The cells containing the internalized particles continued to thrive, indicating that the particles have no inhibition effect for mitosis. In addition, the particles could be incorporated into the subcutaneous tissue of mouse's ear from ear skin and were able to be localized upon application of an external magnetic field. The functionalized nano-magnetic particles are expected to be useful as a new delivery tool.     

pH-Sensitive and mucoadhesive microspheres for duodenum-specific drug delivery system

Particulate systems that could deliver drug specifically to duodenum have not yet been reported. The aim of this study was to develop a novel duodenum-specific drug delivery system based on thiolated chitosan and hydroxypropyl methylcellulose acetate maleate (HPMCAM) for the duodenal ulcer application. Berberine hydrochloride was used as model drug. Thiolated chitosan was synthesized and further used for the preparation of mucoadhesive microspheres. HPMCAM, which is insoluble below pH 3.0 was synthesized and used for the coating of thiolated chitosan microspheres (TCM). The resulting thiolated chitosan immobilized on chitosan was 268.21?±?18 μmol/g. In vitro mucoadhesion study showed that the mucoadhesion property of TCM was better than that of chitosan microspheres. Morphological observation showed that the HPMCAM coating would maintain its integrity in simulated gastric fluid (SGF) for 2?h and dissolved quickly in simulated pathological duodenal fluid (SPDF; pH 3.3). In vitro drug release studies showed that only 4.75% of the drug was released in SGF for 2?h, while nearly 90% of the drug was released within 6?h after transferring into SPDF.     

pH-sensitive and mucoadhesive microspheres for duodenum-specific drug delivery system

Particulate systems that could deliver drug specifically to duodenum have not yet been reported. The aim of this study was to develop a novel duodenum-specific drug delivery system based on thiolated chitosan and hydroxypropyl methylcellulose acetate maleate (HPMCAM) for the duodenal ulcer application. Berberine hydrochloride was used as model drug. Thiolated chitosan was synthesized and further used for the preparation of mucoadhesive microspheres. HPMCAM, which is insoluble below pH 3.0 was synthesized and used for the coating of thiolated chitosan microspheres (TCM). The resulting thiolated chitosan immobilized on chitosan was 268.21?±?18 μmol/g. In vitro mucoadhesion study showed that the mucoadhesion property of TCM was better than that of chitosan microspheres. Morphological observation showed that the HPMCAM coating would maintain its integrity in simulated gastric fluid (SGF) for 2?h and dissolved quickly in simulated pathological duodenal fluid (SPDF; pH 3.3). In vitro drug release studies showed that only 4.75% of the drug was released in SGF for 2?h, while nearly 90% of the drug was released within 6?h after transferring into SPDF.     

Chitosan microparticles as oral delivery system for tetanus toxoid

Systemic and local immune response against Chitosan encapsulated tetanus toxoid (CS-TT) microparticles is studied, prepared by ionic cross-linking using Sodium Tripolyphosphate (STPP). Final formulation was evaluated in terms of release of TT in 0.1 N HCl and PBS (pH 7.4), sedimentation profile and stability. CS-TT microparticles, TT in PBS and plain CS microparticles were orally administered to mice and TT (adsorbed) was administered through intramuscular route. Sera were analyzed for anti-TT IgG and intestinal lavage, faeces, intestinal washings for anti-TT IgA levels using an ELISA. Entrapment efficiency of about 100% was obtained. A dose dependent immune response was observed in mice vaccinated with Chitosan-TT microparticles. A strong enhancement of the systemic and local immune response against TT were found when compared with oral feeding of TT in PBS. The study shows the efficacy of chitosan microparticle suspension system, containing a high molecular protein (TT), in inducing the IgA in intestine and IgG in systemic circulation. This demonstrates that chitosan microparticles can prove to be a promising oral vaccine delivery system for mucosal and systemic immunity.