Naturally derived nano- and micro-drug delivery vehicles: halloysite, vaterite and nanocellulose

Recent advances in drug delivery and controlled release had a great impact on bioscience, medicine and tissue engineering. Consequently, a variety of advanced drug delivery vehicles either have already reached the market or are approaching the phase of commercial production. Progressive growth of the drug delivery market has led to the necessity to earnestly concern about economically viable, up-scalable and sustainable technologies for a large-scale production of drug delivery carriers. We have identified three attractive natural sources of drug carriers: aluminosilicate clays, minerals of calcium carbonate, and cellulose. Three classes of drug delivery carriers derived from these natural materials are halloysite nanotubes, vaterite crystals and nanocellulose. These carriers can be produced using “green” technologies from some of the most abundant sources on the Earth and have extremely high potential to meet all criteria applied for the manufacture of modern delivery carriers. We provide an up-to-date snapshot of these drug delivery vehicles towards their use for bioapplications, in particular for drug delivery and tissue engineering. The following research topics are addressed: (i) the availability, sources and methodologies used for production of these drug delivery vehicles, (ii) the drug loading and release mechanisms of these delivery vehicles, (iii) in vitro, in vivo, and clinical studies on these vehicles, and (iv) employment of these vehicles for tissue engineering. Finally, the prospects for vehicles’ further development and industrialisation are critically assessed, highlighting most attractive future research directions such as the design of third generation active biomaterials

Binding mechanism of the model charged dye carboxyfluorescein to hyaluronan/polylysine multilayers

Biopolymer-based multilayers become more and more attractive due to the vast span of biological application they can be used for, e.g., implant coatings, cell culture supports, scaffolds. Multilayers have demonstrated superior capability to store enormous amounts of small charged molecules, such as drugs, and release them in a controlled manner; however, the binding mechanism for drug loading into the multilayers is still poorly understood. Here we focus on this mechanism using model hyaluronan/polylysine (HA/PLL) multilayers and a model charged dye, carboxyfluorescein (CF). We found that CF reaches a concentration of 13 mM in the multilayers that by far exceeds its solubility in water. The high loading is not related to the aggregation of CF in the multilayers. In the multilayers, CF molecules bind to free amino groups of PLL; however, intermolecular CF–CF interactions also play a role and (i) endow the binding with a cooperative nature and (ii) result in polyadsorption of CF molecules, as proven by fitting of the adsorption isotherm using the BET model. Analysis of CF mobility in the multilayers by fluorescence recovery after photobleaching has revealed that CF diffusion in the multilayers is likely a result of both jumping of CF molecules from one amino group to another and movement, together with a PLL chain being bound to it. We believe that this study may help in the design of tailor-made multilayers that act as advanced drug delivery platfor

Vaterite-nanosilver hybrids with antibacterial properties and pH-triggered release

Silver nanoparticles (AgNPs) have been used for over a century in various applications due to their distinctive properties. Nonetheless, the poor stability of AgNPs and adverse effects on living organisms have driven the search for materials able to protect and better control their release. Vaterite CaCO3 crystals have been studied in the last two decades as carriers for different drugs due to their biocompatibility, easy synthesis and pH-sensitive properties. Herein, AgNPs were loaded into vaterite to protect, store, and control their release, resulting in CaCO3/AgNPs hybrids. To tune the release of the AgNPs, the recrystallization of the hybrids into thermodynamically more stable calcite was studied and modulated with carboxymethyledextran (DexCM) and poly(4-styrenesulfonic acid) sodium salt (PSS), with the last one being able to stabilise the hybrids and prevent a premature release of the AgNPs at low contents (2%, w/w). The release of AgNPs from the hybrids was studied at pH 5 to 9, showing a pH-dependent release suppression for PSS-stabilised hybrids. Various mathematical models were applied to clarify the release mechanism, confirming the role of PSS in stabilising and targeting the release of AgNPs. The antibacterial studies demonstrated that the hybrids protect the AgNPs without affecting their activity, with the released nanoparticles being effective against Escherichia coli, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Overall, this work sheds light on the release mechanisms of AgNPs from the inorganic hybrids helping to foresee the release profiles of other compounds from vaterite

Comparative study of cytotoxicity of ferromagnetic nanoparticles and magnetitecontaining polyelectrolyte microcapsules

The work was supported by Ministry of Education and Science of the Russian Federation as part of the State task for National Research Mordovia State University, project No. 2952 and the Government of the Russian Federation (grant №14.Z50.31.0004 to support scientific research projects implemented under the supervision of leading scientists

Effect of cholesterol on the dipole potential of lipid membranes

The membrane dipole potential, ψd, is an electrical potential difference with a value typically in the range 150 – 350 mV (positive in the membrane interior) which is located in the lipid headgroup region of the membrane, between the linkage of the hydrocarbon chains to the phospholipid glycerol backbone and the adjacent aqueous solution. At its physiological level in animal plasma membranes (up to 50 mol%), cholesterol makes a significant contribution to ψd of approximately 65 mV; the rest arising from other lipid components of the membrane, in particular phospholipids. Via its effect on ψd, cholesterol may modulate the activity of membrane proteins. This could occur through preferential stabilization of protein conformational states. Based on its effect on ψd, cholesterol would be expected to favour protein conformations associated with a small local hydrophobic membrane thickness. Via its membrane condensing effect, which also produces an increase in ψd, cholesterol could further modulate interactions of polybasic cytoplasmic extensions of membrane proteins, in particular P-type ATPases, with anionic lipid headgroups on the membrane surface, thus leading to enhanced conformational stabilization effects and changes to ion pumping activity.Australian Research Counci

pH- and salt-mediated response of layer-by-layer assembled PSS/PAH microcapsules: fusion and polymer exchange

We have studied the pH-and salt-mediated response of matrix-type polyelectrolyte microcapsules. The capsules were prepared by layer-by-layer (LbL) adsorption on decomposable CaCO3 cores using model polyelectrolytes, namely poly-styrenesulfonic acid (PSS) and poly(allylamine hydrochloride) (PAH). Salt-mediated LbL-made microcapsule fusion has been reported recently with a different polycation (R. Zhang, O. Kreft, A. Skirtach, H. Mohwald and G. Sukhorukov, Soft Matter, 2010, 6, 4742-4747) resulting in merging of the capsule's content and formation of anisotropic "Janus-like'' capsules indicating no polymer exchange between the capsules. Here we have studied PAH/PSS capsule behavior as a function of pH and salt concentration. Salt (NaCl) does not induce any changes in the capsules up to saturation concentration (6.1 M). In contrast, several sequential processes have been identified for capsules in [HCl] > 0.1 M: (i) shrinkage due to polymer network annealing, (ii) transformation from matrix-type to shell-type capsules due to oscillating inflating-deflating cycles caused by CO2 formation, and (iii) collapse. The processes depend on acid concentration and the number of layers. If the capsules contact each other, there is an exchange of polymer molecules followed by fusion. The polymer exchange depends on the outermost layer that determines the overall capsule charge. Exchange is enhanced for capsules of the same outermost layer and can be caused by charge redistribution in the capsules at low pH (the negative charge of PSS is reduced (pK(a) 1) and the positive charge of PAH is in excess). Control over polymer exchange between the capsules is key in order to design capsules as well as to understand and to trigger fusion. We also show that the observed processes are not reversible and can be stopped at any time by replacement of acid with water. Stable gas-filled capsules can be produced by this method upon transformation from matrix to shell-type capsules