44 research outputs found
Morphologic design of nanostructures for enhanced antimicrobial activity
Despite significant progress in synthetic polymer chemistry and in control over tuning the structures and morphologies of nanoparticles, studies on morphologic design of nanomaterials for the purpose of optimizing antimicrobial activity have yielded mixed results. When designing antimicrobial materials, it is important to consider two distinctly different modes and mechanisms of activity-those that involve direct interactions with bacterial cells, and those that promote the entry of nanomaterials into infected host cells to gain access to intracellular pathogens. Antibacterial activity of nanoparticles may involve direct interactions with organisms and/or release of antibacterial cargo, and these activities depend on attractive interactions and contact areas between particles and bacterial or host cell surfaces, local curvature and dynamics of the particles, all of which are functions of nanoparticle shape. Bacteria may exist as spheres, rods, helices, or even in uncommon shapes (e.g., box- and star-shaped) and, furthermore, may transform into other morphologies along their lifespan. For bacteria that invade host cells, multivalent interactions are involved and are dependent upon bacterial size and shape. Therefore, mimicking bacterial shapes has been hypothesized to impact intracellular delivery of antimicrobial nanostructures. Indeed, designing complementarities between the shapes of microorganisms with nanoparticle platforms that are designed for antimicrobial delivery offers interesting new perspectives toward future nanomedicines. Some studies have reported improved antimicrobial activities with spherical shapes compared to non-spherical constructs, whereas other studies have reported higher activity for non-spherical structures (e.g., rod, discoid, cylinder, etc.). The shapes of nano- and microparticles have also been shown to impact their rates and extents of uptake by mammalian cells (macrophages, epithelial cells, and others). However, in most of these studies, nanoparticle morphology was not intentionally designed to mimic specific bacterial shape. Herein, the morphologic designs of nanoparticles that possess antimicrobial activities per se and those designed to deliver antimicrobial agent cargoes are reviewed. Furthermore, hypotheses beyond shape dependence and additional factors that help to explain apparent discrepancies among studies are highlighted
Design and Preclinical Evaluation of Chitosan/Kaolin Nanocomposites with Enhanced Hemostatic Efficiency
In the current study, hemostatic compositions including a combination of chitosan and kaolin have been developed. Chitosan is a marine polysaccharide derived from chitins, a structural component in the shells of crustaceans. Both chitosan and kaolin have the ability to mediate a quick and efficient hemostatic effect following immediate application to injury sites, and thus they have been widely exploited in manufacturing of hemostatic composites. By combining more than one hemostatic agent (i.e., chitosan and kaolin) that act via more than one mechanism, and by utilizing different nanotechnology-based approaches to enhance the surface areas, the capability of the dressing to control bleeding was improved, in terms of amount of blood loss and time to hemostasis. The nanotechnology-based approaches utilized to enhance the effective surface area of the hemostatic agents included the use of Pluronic nanoparticles, and deposition of chitosan micro- and nano-fibers onto the carrier. The developed composites effectively controlled bleeding and significantly improved hemostasis and survival rates in two animal models, rats and rabbits, compared to conventional dressings and QuikClot® Combat Gauze. The composites were well-tolerated as demonstrated by their in vivo biocompatibility and absence of clinical and biochemical changes in the laboratory animals after application of the dressings
Design and Preclinical Evaluation of Chitosan/Kaolin Nanocomposites with Enhanced Hemostatic Efficiency
In the current study, hemostatic compositions including a combination of chitosan and kaolin have been developed. Chitosan is a marine polysaccharide derived from chitins, a structural component in the shells of crustaceans. Both chitosan and kaolin have the ability to mediate a quick and efficient hemostatic effect following immediate application to injury sites, and thus they have been widely exploited in manufacturing of hemostatic composites. By combining more than one hemostatic agent (i.e., chitosan and kaolin) that act via more than one mechanism, and by utilizing different nanotechnology-based approaches to enhance the surface areas, the capability of the dressing to control bleeding was improved, in terms of amount of blood loss and time to hemostasis. The nanotechnology-based approaches utilized to enhance the effective surface area of the hemostatic agents included the use of Pluronic nanoparticles, and deposition of chitosan micro- and nano-fibers onto the carrier. The developed composites effectively controlled bleeding and significantly improved hemostasis and survival rates in two animal models, rats and rabbits, compared to conventional dressings and QuikClot® Combat Gauze. The composites were well-tolerated as demonstrated by their in vivo biocompatibility and absence of clinical and biochemical changes in the laboratory animals after application of the dressings
Sesamol Loaded Albumin Nanoparticles: A Boosted Protective Property in Animal Models of Oxidative Stress
The current study evaluated the ability of sesamol-loaded albumin nanoparticles to impart protection against oxidative stress induced by anthracyclines in comparison to the free drug. Albumin nanoparticles were prepared via the desolvation technique and then freeze-dried with the cryoprotectant, trehalose. Albumin concentration, pH, and type of desolvating agent were assessed as determining factors for successful albumin nanoparticle fabrication. The optimal nanoparticles were spherical in shape, and they had an average particle diameter of 127.24 ± 2.12 nm with a sesamol payload of 96.89 ± 2.4 μg/mg. The drug cellular protection was tested on rat hepatocytes pretreated with 1 µM doxorubicin, which showed a 1.2-fold higher protective activity than the free sesamol. In a pharmacokinetic study, the loading of a drug onto nanoparticles resulted in a longer half-life and mean residence time, as compared to the free drug. Furthermore, in vivo efficacy and biochemical assessment of lipid peroxidation, cardiac biomarkers, and liver enzymes were significantly ameliorated after administration of the sesamol-loaded albumin nanoparticles. The biochemical assessments were also corroborated with the histopathological examination data. Sesamol-loaded albumin nanoparticles, prepared under controlled conditions, may provide an enhanced protective effect against off-target doxorubicin toxicity
Shell crosslinked knedel-like nanoparticles for delivery of cisplatin: effects of crosslinking
Polymeric micelles and shell crosslinked knedel-like (SCK) nano-particles were loaded with up to 48% (w/w) cisplatin. These spherical cisplatin-loaded nanoparticles displayed sustained platinum release over 5 days in PBS, enhanced stability over free cisplatin in aqueous milieu, and significant antitumor activity in vitro against two cancer cell lines
Differential immunotoxicities of poly(ethylene glycol)- vs. poly(carboxybetaine)-coated nanoparticles
Although the careful selection of shell-forming polymers for the construction of nanoparticles is an obvious parameter to consider for shielding of core materials and their payloads, providing for prolonged circulation in vivo by limiting uptake by the immune organs, and thus, allowing accumulation at the target sites, the immunotoxicities that such shielding layers elicit is often overlooked. For instance, we have previously performed rigorous in vitro and in vivo comparisons between two sets of nanoparticles coated with either non-ionic poly(ethylene glycol) (PEG) or zwitterionic poly(carboxybetaine) (PCB), but only now report the immunotoxicity and anti-biofouling properties of both polymers, as homopolymers or nanoparticle-decorating shell, in comparison to the uncoated nanoparticles, and Cremophor-EL, a well-known low molecular weight surfactant used for formulation of several drugs. It was found that both PEG and PCB polymers could induce the expression of cytokines in vitro and in vivo, with PCB being more immunotoxic than PEG, which corroborates the in vivo pharmacokineties and biodistribution profiles of the two sets of nanoparticles. This is the first study to report on the ability of PEG, the most commonly utilized polymer to coat nanomaterials, and PCB, an emerging zwitterionic anti-biofouling polymer, to induce the secretion of cytokines and be of potential immunotoxicity. Furthermore, we report here on the possible use of immunotoxicity assays to partially predict in vivo pharmacokineties and biodistribution of nanomaterials
Multifunctional Hierarchically Assembled Nanostructures as Complex Stage-Wise Dual-Delivery Systems for Coincidental Yet Differential Trafficking of siRNA and Paclitaxel
Development
of multifunctional nanostructures that can be tuned to codeliver multiple
drugs and diagnostic agents to diseased tissues is of great importance.
Hierarchically
assembled theranostic (HAT) nanostructures based on anionic cylindrical
shell cross-linked nanoparticles and cationic shell cross-linked knedel-like
nanoparticles (cSCKs) have recently been developed by our group to
deliver siRNA intracellularly and to undergo radiolabeling. In the
current study, paclitaxel, a hydrophobic anticancer drug, and siRNA
have been successfully loaded into the cylindrical and spherical components
of the hierarchical assemblies, respectively. Cytotoxicity, immunotoxicity,
and intracellular delivery mechanism of the HAT nanostructures and
their individual components have been investigated. Decoration of
nanoparticles with F3-tumor homing peptide was shown to enhance the
selective cellular uptake of the spherical particles, whereas the
HAT nanoassemblies underwent an interesting disassembly process in
contact with either OVCAR-3 or RAW 264.7 cell lines. The HAT nanostructures
were found to “stick” to the cell membrane and “trigger”
the release of spherical cSCKs templated onto their surfaces intracellularly,
while retaining the cylindrical part on the cell surface. Combination
of paclitaxel and cell-death siRNA (siRNA that induces cell death)
into the HAT nanostructures resulted in greater reduction in cell
viability than siRNA complexed with Lipofectamine and the assemblies
loaded with the individual drugs. In addition, a shape-dependent immunotoxicity
was observed for both spherical and cylindrical nanoparticles with
the latter being highly immunotoxic. Supramolecular assembly of the
two nanoparticles into the HAT nanostructures significantly reduced
the immunotoxicity of both cSCKs and cylinders. HAT nanostructures
decorated with targeting moieties, loaded with nucleic acids, hydrophobic
drugs, radiolabels, and fluorophores, with control over their toxicity,
immunotoxicity, and intracellular delivery might have great potential
for biomedical delivery applications
Functionalizable Hydrophilic Polycarbonate, Poly(5-methyl-5-(2-hydroxypropyl)aminocarbonyl-1,3-dioxan-2-one), Designed as a Degradable Alternative for PHPMA and PEG
Drawbacks of poly(ethylene glycol)
(PEG), the most widely used water-soluble polymer in nanomedicines,
have stimulated development of alternative hydrophilic polymers. Among
the substitutes, poly(<i>N</i>-(2-hydroxypropyl)methacrylamide)
(PHPMA) exhibits water solubility, minimal toxicity, and the possibility
to introduce functionalities through pendant hydroxyl groups; however,
nondegradability may cause long-term health and environmental issues.
Alternatively, polycarbonates based on bis-MPA derivatives, which
are well-known to be biocompatible, biodegradable, and of low toxicity <i>in vivo</i>, could be utilized as degradable equivalents to
polymethacrylates. Therefore, we developed a polycarbonate-based PHPMA
analogue, poly(5-methyl-5-(2-hydroxypropyl)aminocarbonyl-1,3-dioxan-2-one)
(PMHPAC), by amidation of carboxylic acid-functional polycarbonates
with 1-amino-2-propanol. The resulting PMHPAC was highly water-soluble,
with low cyto-/immuno-toxicities, and readily functionalizable. These
characteristics make PMHPAC a promising candidate as a degradable
alternative to PEG and PHPMA. Furthermore, a fully degradable PMHPAC
block copolymer was synthesized to demonstrate synthetic versatility
and formation of nanostructures in aqueous solution for potential
biomedical applications