The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers.

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 10(6)-fold improvement over comparable liposomes

Optimization of magnetic actuation protocol to enhance mass transfer in solid/liquid microfluidic systems

This paper was presented at the 4th Micro and Nano Flows Conference (MNF2014), which was held at University College, London, UK. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute, ASME Press, LCN London Centre for Nanotechnology, UCL University College London, UCL Engineering, the International NanoScience Community, www.nanopaprika.eu.The dynamic properties of a 250 m magnetic microparticle in a time varying magnetic field have been studied in a PDMS microreactor with a diameter of 13 mm using a dual coupled quadrupolar arrangement of electromagnets. A sinusoidal applied magnetic field has dictated a circular motion of the particles in the microreactor in the frequency range below 0.6 Hz. Different circular motion modes have been observed at higher frequencies of the applied field. The particular symmetric arrangement of the magnets has allowed a non-steady-state motion with variation in velocity between magnetic poles. The motion of magnetic particle has been described in terms of average velocity and mean square deviation from average velocity. The effect of actuation protocol parameters (frequency, magnetic field strength and phase shift) on particle velocity and acceleration has been investigated. The maximum average velocity of 0.016 m/s has been observed under an optimized actuation protocol. The mass transfer rate towards the particle surface is mainly influenced by the average velocity while the effect of acceleration/deceleration of the particle has an order of magnitude less influence

Model-based optimized steering and focusing of local magnetic particle concentrations for targeted drug delivery

Magnetic drug targeting (MDT) is an application in the field of targeted drug delivery in which magnetic (nano)particles act as drug carriers. The particles can be steered toward specific regions in the human body by adapting the currents of external (electro)magnets. Accurate models of particle movement and control algorithms for the electromagnet currents are two of the many requirements to ensure effective drug targeting. In this work, a control approach for the currents is presented, based on an underlying physical model that describes the dynamics of particles in a liquid in terms of their concentration in each point in space. Using this model, the control algorithm determines the currents generating the magnetic fields that maximize the particle concentration in spots of interest over a period of time. Such an approach is computationally only feasible thanks to our innovative combination of model order reduction with the method of direct multiple shooting. Simulation results of an in-vitro targeting setup demonstrated that a particle collection can be successfully guided toward the targeted spot with limited dispersion through a surrounding liquid. As now present and future particle behavior can be taken into account, and non-stationary surrounding liquids can be dealt with, a more precise and flexible targeting is achieved compared to existing MDT methods. This proves that the presented methodology can bring MDT closer to its clinical application. Moreover, the developed model is compatible with state-of-the-art imaging methods, paving the way for theranostic platforms that combine both therapy as well as diagnostics

Exploration of an electro-magneto-responsive polymeric drug delivery system for enhanced nose-to-brain delivery

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand in fulfilment of the requirements for the degree of Doctor of PhilosophyDelivering drugs to the brain for the treatment of brain diseases has been fraught with low bioavailability of drugs due to the Blood-Brain Barrier (BBB). The intranasal (IN) route of delivery has purportedly been given recognition as an alternative route of delivering drugs to the brain with improved bioavailability if the nose-to-brain option is considered. However, drugs administered through the nasal mucosa suffer some challenges such as mucocilliary clearance, enzymatic degradation, inability of a controllable drug release to give a precise dose, resulting in frequent dosing and absorption into the systemic circulation through the blood rich vessels in the mucosa, thus facing the BBB challenge. The aim of this study was to develop a novel Nano-co-Plex (NCP), a magnetic nano-carrier loaded with a therapeutic agent which is further incorporated into a nasal thermosensitive electro-responsive mucogel (TERM) for in situ gelling, for electroactuated release of the incorporated drug-loaded NCP in a controllable “on-off” pulsatile manner, which is achieved with the aid of an external electric stimulation (ES). The released drug-loaded NCP was then targeted to the brain via a direct nose-to-brain drug delivery pathway with the aid of an external magnetic field (MF) for rapid transportation. The ES was brought about by applying a 5V potential difference (PD) using electrodes on the nose and the external MF would then be applied by placing a magnetic headband on the head of the patient. In this research, the drug-loaded NCP was prepared by firstly synthesizing iron oxide nanoparticles (Magnetite) which were then coated with Polyplex; a polymeric complex fabricated employing polyvinyl alcohol (PVA), polyethyleneimine (PEI) and fIuorecein isothiocyanate (FITC). The coated magnetite was thereafter loaded with Carmustine (BCNU), an effective drug commonly used in brain tumor treatment, to formulate the BCNU-NCP. The TERM was prepared by blending a thermosensitive polymer, Pluronic F127 (F127) with mucoadhesive polymers, chitosan (CS) and hydroxypropyl methylcellulose (HPMC). Polyaniline (PANI) was included in the blend as the electo-active moiety of the formulation. Finally, the BCNU-NCP was incorporated into the gel to form a Nanogel- Composite. A Box–Behnken design model was employed for the optimization of the Nanogel Composite. TERM, BCNU-NCP and Nanogel Composite were characterized employing Thermogravimetric analysis (TGA), Superconducting Quantum Interference Device (SQUID) magnetometry, Fourier Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR), X-ray Diffractometry (XRD), Scanning Electron Microscopy (SEM), Cyclic Voltammetry (CV), Transmission Electron Microscopy (TEM), Rheological, Porositometry, Textural and Zetasize analyses. In vitro drug release, ex vivo permeation and in vivo studies were performed. The BCNU-NCP was found to be paramagnetic with a magnetization value of 61emu/g, possessing a mixture of spherical and hexagonal shaped core-shell nanoparticles of size 30-50nm with zeta potential of +32 ±2mV. The NCP displayed a high degree of crystallinity with 32% Polyplex coating. The loading capacity of NCP was 176.86μg BCNU/mg of the carrier and maximum release of 75.8% of the loaded BCNU was achieved after 24 hours. FTIR and NMR confirmed the conjugation of PVA and PEI of the Polyplex at a ratio of 1:4. Cytotoxicity of the BCNU-loaded Nano-co-Plex displayed superiority over the conventional BCNU towards human glioblastoma (HG) A170 cells. Cell studies revealed enhanced uptake and internalization of BCNU-NCP in HG A170 cells in the presence of an external MF. BCNU-NCP was found to be non-toxic to healthy brain cells. A thermally stable gel with desirable rheological and mucoadhesive properties was developed. The results revealed gelation temperature of 27.5±0.5°C with a porous morphology. Nanogel Composite possesses electroactive properties and shows response to ES and releases incorporated BCNU-NCP in an “on-off” pulsatile drug release profile upon application of a 5V PD. The in vitro release studies showed an average release of BCNU-NCP per release cycle to be 10.28%. Ex vivo permeation studies were performed using a freshly excised nasal tissue of the New Zealand white rabbit; the results showed that BCNU-NCP was able to permeate through the nasal tissue at a 6 times greater amount in the presence of a MF than in the absence of MF. BCNU concentration was found to be high in the brain and CSF of rabbit when the Nanogel Composite is intranasally administered compared to the IV injection of the conventional BCNU. Furthermore, application of the MF was found to increase the concentration of BCNU in the brain and CSF of the rabbit. The result of Field Emission Electron Probe Micro Analyzer (FE EPMA) was further used to confirm the presence of NCP in the rabbit brain tissue. Histopathological results indicated mild lesions in the nasal mucosa of the rabbit after IN administration of Nanogel Composite. The results of the in vitro, ex vivo and the in vivo proved that the Nanogel Composite is superior in delivering BCNU into the brain than the conventional drug delivery system for the treatment of brain tumor as it was able to release the therapeutic agent in a controllable manner. The MF applied aided drug to be targeted and rapidly transported to the brain via a direct nose-to-brain pathway thereby circumventing the BBB and increasing bioavailability of drug in the brain. This vehicle may also be used to deliver other similar therapeutic agents into the brain for the treatment of various brain diseases.MB201

A health concern regarding the protein corona, aggregation and disaggregation

Nanoparticle (NP)-protein complexes exhibit the correct identity of NP in biological media. Therefore, protein-NP interactions should be closely explored to understand and to modulate the nature of NPs in medical implementations. This review focuses mainly on the physicochemical parameters such as dimension, surface chemistry, the morphology of NPs and influence of medium pH on the formation of protein corona and conformational changes of adsorbed proteins by different kinds of methods. Also, the impact of protein corona on the colloidal stability of NPs is discussed. Uncontrolled protein attachment on NPs may bring unwanted impacts such as protein denaturation and aggregation. In contrast, controlled protein adsorption by optimal concentration, size, pH and surface modification of NPs may result in potential implementation of NPs as therapeutic agents especially for disaggregation of amyloid fibrils. Also, the effect of NPs-protein corona on reducing the cytotoxicity and clinical implications such as drug delivery, cancer therapy, imaging and diagnosis will be discussed. Validated correlative physicochemical parameters for NP-protein corona formation frequently derived from protein corona fingerprints of NPs which are more valid than the parameters obtained only on the base of NP features. This review may provide useful information regarding the potency as well as the adverse effects of NPs to predict their behavior in the in vivo experiments.Comment: 40 pages, 20 figure

Multifunctional nanocarriers for lung drug delivery

Nanocarriers have been increasingly proposed for lung drug delivery applications. The strategy of combining the intrinsic and more general advantages of the nanostructures with specificities that improve the therapeutic outcomes of particular clinical situations is frequent. These include the surface engineering of the carriers by means of altering the material structure (i.e., chemical modifications), the addition of specific ligands so that predefined targets are reached, or even the tuning of the carrier properties to respond to specific stimuli. The devised strategies are mainly directed at three distinct areas of lung drug delivery, encompassing the delivery of proteins and protein-based materials, either for local or systemic application, the delivery of antibiotics, and the delivery of anticancer drugs-the latter two comprising local delivery approaches. This review addresses the applications of nanocarriers aimed at lung drug delivery of active biological and pharmaceutical ingredients, focusing with particular interest on nanocarriers that exhibit multifunctional properties. A final section addresses the expectations regarding the future use of nanocarriers in the area.UID/Multi/04326/2019; PD/BD/137064/2018info:eu-repo/semantics/publishedVersio

Hybrid Nano-carriers for Potential Drug Delivery

Nanocarriers have provided the versatile platform for the delivery of various therapeutic and diagnostic agents. Liposome, niosomes, polymeric and solid lipid nanoparticles are the most promising nanocarriers that have been entered in the clinical trials and become commercially available. However, each system has been associated with some problems that can be minimized by using the combinatorial approach of hybrid nanocarriers. These hybrid systems combine the benefits of different structural components to synergize the outcome of the therapy. In this chapter, the different types of hybrid nanocarriers have been described with particular emphasis on the brief rationale for the development of these hybrid nanocarriers along with different fabrication approaches with greater emphasize on the lipid polymer hybrid nanoparticles. A brief description factors governing the optimized response characteristics and their potential application of these hybrid nanoparticles are also presented

Recent insights in magnetic hyperthermia: From the “hot-spot” effect for local delivery to combined magneto-photo-thermia using magneto-plasmonic hybrids

International audienceMagnetic hyperthermia which exploits the heat generated by magnetic nanoparticles (MNPs) when exposed to an alternative magnetic field (AMF) is now in clinical trials for the treatment of cancers. However, this thermal therapy requires a high amount of MNPs in the tumor to be efficient. On the contrary the hot spot local effect refers to the use of specific temperature profile at the vicinity of nanoparticles for heating with minor to no long-range effect. This magneto-thermal effect can be exploited as a relevant external stimulus to temporally and spatially trigger drug release.In this review, we focus on recent advances in magnetic hyperthermia. Indirect experimental proofs of the local temperature increase are first discussed leading to a good estimation of the temperature at the surface (from 0.5 to 6 nm) of superparamagnetic NPs. Then we highlight recent studies illustrating the hot-spot effect for drug- release. Finally, we present another recent strategy to enhance the efficacity of thermal treatment by combining photothermal therapy with magnetic hyperthermia mediated by magneto-plasmonic nanoplatforms