Targeting reactive astrocytes by pH-responsive ligand-bonded polymeric nanoparticles in spinal cord injury.

In spinal cord injuries, axonal regeneration decreases with the activation of astrocytes followed by glial scar formation. Targeting reactive astrocytes has been recently performed by unsafe viral vectors to inhibit gliosis. In the current study, biocompatible polymeric nanoparticles were selected as an alternative for viruses to target reactive astrocytes for further drug/gene delivery applications. Lipopolysaccharide-bonded chitosan-quantum dots/poly acrylic acid nanoparticles were prepared by ionic gelation method to target reactive astrocytes both in vitro and in spinal cord-injured rats. Owing to their biocompatibility and pH-responsive behavior, chitosan and poly acrylic acid were the main components of nanoparticles. Nanoparticles were then chemically labeled with quantum dots to track the cell uptake and electrostatically interacted with lipopolysaccharide as a targeting ligand. In vitro and in vivo studies were performed in triplicate and all data were expressed as the mean ± the standard error of the mean. Smart nanoparticles with optimum size (61.9 nm) and surface charge (+ 12.5 mV) successfully targeted primary reactive astrocytes extracted from the rat cerebral cortex. In vitro studies represented high cell viability (96%) in the exposure of biocompatible nanoparticles. The pH-responsive behavior of nanoparticles was proved by their internalization into the cell's nuclei due to the swelling and endosomal escape of nanoparticles in acidic pH. In vivo studies demonstrated higher transfection of nanoparticles into reactive astrocytes compared to the neurons. pH-responsive ligand-bonded chitosan-based nanoparticles are good alternatives for viral vectors in targeted delivery applications for the treatment of spinal cord injuries.

Effect of Physico-Chemical Properties of Nanoparticles on Their Intracellular Uptake.

Cellular internalization of inorganic, lipidic and polymeric nanoparticles is of great significance in the quest to develop effective formulations for the treatment of high morbidity rate diseases. Understanding nanoparticle-cell interactions plays a key role in therapeutic interventions, and it continues to be a topic of great interest to both chemists and biologists. The mechanistic evaluation of cellular uptake is quite complex and is continuously being aided by the design of nanocarriers with desired physico-chemical properties. The progress in biomedicine, including enhancing the rate of uptake by the cells, is being made through the development of structure-property relationships in nanoparticles. We summarize here investigations related to transport pathways through active and passive mechanisms, and the role played by physico-chemical properties of nanoparticles, including size, geometry or shape, core-corona structure, surface chemistry, ligand binding and mechanical effects, in influencing intracellular delivery. It is becoming clear that designing nanoparticles with specific surface composition, and engineered physical and mechanical characteristics, can facilitate their internalization more efficiently into the targeted cells, as well as enhance the rate of cellular uptake.

Facile design of autogenous stimuli-responsive chitosan/hyaluronic acid nanoparticles for efficient small molecules to protein delivery.

Easily assembled and biocompatible chitosan/hyaluronic acid nanoparticles with multiple stimuli-responsive ability are ideally suited for efficient delivery of therapeutic agents under specific endogenous triggers. We report a simple and versatile strategy to formulate oxidative stress and pH-responsive chitosan/hyaluronic acid nanocarriers with high encapsulation efficiencies of small drug molecules and nerve growth factor protein. This is achieved through invoking the dual role of a thioketal-based weak organic acid to disperse and functionalize low molecular weight chitosan in one-pot. Thioketal embedded chitosan/hyaluronic acid nanostructures respond to oxidative stress and show controlled release of quercetin, curcumin and NGF. Lowering the pH in the buffer solution led to higher quercetin release from NPs than at physiological pH, and mimicked the nanoparticle behavior in the environment of early to late endosomes. Curcumin and quercetin loaded NPs killed glioblastoma cells with high efficiency, and NGF-loaded nanoparticles retained biological activity of the protein and increased peripheral nerve outgrowth in explanted mouse dorsal root ganglia.

Stimuli-responsive chitosan as an advantageous platform for efficient delivery of bioactive agents.

Despite a diverse range of active pharmaceutical agents currently at our disposal, high morbidity rate diseases continue to pose a major health crisis globally. One of the important parameters in this regard is the controlled cargo delivery at desired sites. Among a variety of synthetic and natural macromolecular systems, chitosan, an abundant biopolymer, offers a platform for tailored architectures that could have high loading capacity of cargo, target and deliver. Stimuli directed accumulation of vehicles and drug release is an area of direct relevance to biomedical applications. In this review, we highlight essential characteristics of modified chitosan that present themselves for efficient response through an internal (glutathione, reactive oxygen species, pH, temperature, enzymes, and chemical/electrical potential gradient), and external stimuli (ultrasound, light, mechanical stimuli, magnetic and electrical fields). With a brief review of the pertinent properties of chitosan that are relevant to biology, the design and critical evaluation of varied chitosan-based platforms is discussed. Future directions in exploiting important features of chitosan in this area can be derived from the presented comparative evaluation of the current literature in drug delivery.

Preparation of biodegradable gelatin/PVA porous scaffolds for skin regeneration.

Porous scaffolds composed of gelatin/poly (vinyl alcohol), (Gel/PVA), were prepared using combination of freeze gelation and freeze drying methods. The effect of polymer concentration, gelatin/PVA ratio, and glutaraldehyde/gelatin ratio (GA/Gel) was investigated on morphology of pores, swelling ratio, biodegradation, and skin cell culture. At optimum preparation conditions the scaffolds had uniform pore size distributions showing high swelling ratio of 23.6. The scaffolds were of biodegradable nature and almost degraded in 28 days. Human dermal fibroblast cells (HDF) were cultured on the scaffolds and MTS assay was conducted to evaluate the influence of PVA on growth and proliferation of the cells.

Antibacterial silver nanoparticles in polyvinyl alcohol/sodium alginate blend produced by gamma irradiation.

Polyvinyl alcohol/sodium alginate/nano silver (PVA/SA/Ag) composite films were made by solution casting method. Gamma irradiation was used to synthesize silver nanoparticles in situ via reduction of silver nitrate without using harmful chemical agents for biomedical applications. UV-vis and XRD results demonstrated that spherical silver nanoparticles were produced even at low irradiation dose of 5 kGy. By increasing irradiation dose, more nanoparticles were synthesized while no PVA hydrogel was formed up to 15 kGy. Also the size of nanoparticles was reduced with increasing gamma dose evidenced by higher release rate of silver nanoparticles in lukewarm water and SEM images. Comparing SEM images with DLS results indicated good performance of PVA/SA as an efficient stabilizer in preventing agglomeration of the silver nanoparticles. Good miscibility of polyvinyl alcohol and sodium alginate observed on the SEM images was supported with FTIR spectroscopy. Upon addition of sodium alginate to polyvinyl alcohol and increasing silver nanoparticles, the melting peak shifted to lower temperature and crystallinity percent was decreased. Addition of sodium alginate led to remarkable increase in rigidity of PVA. The composites exhibited strong antibacterial activity against Staphylococcus aureus and Escherichia coli even at very low level of silver nanoparticles.

Magnetic nanoparticles-loaded PLA/PEG microspheres as drug carriers.

Surface-modified magnetite (Fe3 O4 ) nanoparticles with an average size of 22 nm were prepared. The nanoparticles had a saturation magnetization of 50.7 emu g(-1) . Then magnetite and drug-loaded microspheres of poly (lactic acid)/poly (ethylene glycol) were prepared at various compositions. The microspheres were spherical in shape and had smooth surface. The diameter size of the microspheres ranged between about 0.2 and 4 µm. Doxorubicin hydrochloride for cancer treatment was the drug that loaded into the microspheres. The prepared microspheres were characterized by FTIR, XRD, VSM, SEM and drug-release measurements. It was found that the drug cumulative release percentage was proportional to (time) (n) where 0.61 < n < 0.75 depending on PEG and Fe3 O4 contents. The drug release was controlled through a combination of diffusion and PLA hydrolysis and obeyed a non-fickian mechanism. The drug release was facilitated by presence of poly (ethylene glycol) as PLA plasticizer and was higher under applied external magnetic field. The obtained magnetic microspheres could be used as drug carriers for targeted drug delivery purposes.