Temperature-Responsive Polysaccharide Microparticles Containing Nanoparticles: Release of Multiple Cationic/Anionic Compounds.
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ABSTRACT: Most drug carriers used in pulmonary administration are microparticles with diameters over 1 µm. Only a few examples involving nanoparticles have been reported because such small particles are readily exhaled. Consequently, the development of microparticles capable of encapsulating nanoparticles and a wide range of compounds for pulmonary drug-delivery applications is an important objective. In this study, we investigated the development of polysaccharide microparticles containing nanoparticles for the temperature-responsive and two-step release of inclusions. The prepared microparticles containing nanoparticles can release two differently charged compounds in a stepwise manner. The particles have two different drug release pathways: one is the release of nanoparticle inclusions from the nanoparticles and the other is the release of microparticle inclusions during microparticle collapse. The nanoparticles can be efficiently delivered deep into the lungs and a wide range of compounds are released in a charge-independent manner, owing to the suitable roughness of the microparticle surface. These polysaccharide microparticles containing nanoparticles are expected to be used as temperature-responsive drug carriers, not only for pulmonary administration but also for various administration routes, including transpulmonary, intramuscular, and transdermal routes, that can release multiple drugs in a controlled manner.
Project description:A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and β-cyclodextrin (β-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be disassembled by oxidation of ferrocene (Fc) to Fc+, leading to an efficient release of the anticancer drug camptothecin (CPT) to induce tumor cell apoptosis without affecting normal cells. The in vivo experiment results also demonstrated that Fc-CPT@HACD possessed higher anticancer efficiency than free CPT, accompanied by negligible side effects.
Project description:A new, simple one-step approach has been developed to synthesize lignin and lignin amine coated Fe?O? nanoparticles. These nanoparticles (lignin magnetic nanoparticles (LMNPs) and lignin amine magnetic nanoparticles (LAMNPs)) are found to possess not only magnetic response but also pH-dependent adsorption behavior. Results show that the combination of lignin with nanoparticles increased the adsorption capacities 2-5 times higher than other traditional single lignin based adsorbents (211.42 mg/g for methylene blue (MB) by LMNPs and 176.49 mg/g for acid scarlet GR (AS-GR) by LAMNPs). Meanwhile, by simply adjusting the pH, the dye-loaded adsorbents can be regenerated to recycle both adsorbents and dyes with a desorption efficiency up to 90%. Mechanistic study shows that dye structure and surface charges of adsorbents play the most important part in adsorption where dyes interact with the adsorbent surface via ?-? stacking and electrostatic attraction interactions. The efficient fabrication method, eco-friendly reactant, quick magnetic separation, high adsorption and desorption efficiency suggest this novel type of nano-adsorbents to be promising materials for efficient dye pollutant removal and recovery.
Project description:Natural polymers are attractive sustainable materials for production of fibers and composite materials. Cotton and flux are traditional plants used to produce textiles with comforting properties while technologies like Viscose, Lyocell and Ioncell-F allowed to extent fiber use into regenerated cellulose from wood. Neither natural nor man-made fibers completely satisfy the needs for cellulose based fabrics boosting development of new approaches to bring more sustainability into the fashion. Technologies like Spinnova are arising based on the spinning of mechanically pretreated cellulose materials with a lower environmental impact though challenged by the fiber quality and strength related to the inconsistency of the mechanical fibers. Nanoscaled cellulose is an excellent solution to improve the consistency of spin fibers, but charges introduced by traditional chemical treatments prevent rebuilding native hydrogen bonding and compromise the mechanical properties especially in wet conditions. We used nanocellulose with low surface charge isolated using reactive eutectic media to spin fibers able to restore the native hydrogen bonding and enable constitutional mechanical strength of cellulose. We performed un-optimized spinning to reveal the intrinsic properties of the fibers and confirmed the preserved strength of wet fibers compliant with the low surface charge enabling further engineering towards cotton-like fabric from wood.
Project description:t-Butyl hydroperoxide-initiated cycloterpolymerization of diallylaminoaspartic acid hydrochloride [(CH2[double bond, length as m-dash]CHCH2)2NH+CH(CO2H)CH2CO2H Cl-] (I), maleic acid (HO2CH[double bond, length as m-dash]CHCO2H) (II) and cross-linker tetraallylhexane-1,6-diamine dihydrochloride [(CH2[double bond, length as m-dash]CHCH2)2NH+(CH2)6NH+ (CH2CH[double bond, length as m-dash]CH2)2 2Cl-] (III) afforded a new pH-responsive resin (IV), loaded with four CO2H and a chelating motif of NH+⋯CO2 - in each repeating unit. The removal of cationic methylene blue (MB) (3000 ppm) at pH 7.25 and Pb(ii) (200 ppm) at pH 6 by IV at 298, 313, and 328 K followed second-order kinetics with E a of 33.4 and 40.7 kJ mol-1, respectively. Both MB and Pb(ii) were removed fast, accounting for 97.7% removal of MB within 15 min at 313 K and 94% of Pb(ii) removal within 1 min. The super-adsorbent resin gave respective q max values of 2609 mg g-1 and 873 mg g-1 for MB and Pb(ii). IV was also found to trap anionic dyes; it removed 91% Eriochrome Black T (EBT) from its 50 ppm solutions at pH 2. The resin was found to be effective in reducing priority metal contaminants (like Cr, Hg, Pb) in industrial wastewater to sub-ppb levels. The synthesis of the recyclable resin can be easily scaled up from inexpensive starting materials. The resin has been found to be better than many recently reported sorbents.
Project description:The potential toxicity of ligand-protected nanoparticles (NPs) on biological targets is crucial for their clinical translation. A number of studies are aimed at investigating the molecular mechanisms shaping the interactions between synthetic NPs and neutral plasma membranes. The role played by the NP surface charge is still widely debated. We compare, via liposome leakage assays, the perturbation induced by the penetration of sub-6 nm anionic and cationic Au NPs into model neutral lipid membranes composed of the zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Our charged Au NPs are functionalized by a mixture of the apolar 1-octanethiol and a ω-charged thiol which is either the anionic 11-mercapto-1-undecanesulfonate or the cationic (11-mercaptoundecyl)-N,N,N-trimethylammonium. In both cases, the NP uptake in the bilayer is confirmed by quartz crystal microbalance investigations. Our leakage assays show that both negatively and positively charged Au NPs do not induce significant membrane damage on POPC liposomes when penetrating into the bilayer. By means of molecular dynamics simulations, we show that the energy barrier for membrane penetration is the same for both NPs. These results suggest that the sign of the NP surface charge, per se, does not imply different physicochemical mechanisms of interaction with zwitterionic lipid membranes.
Project description:Poly(N-isopropylacrylamide) (pNIPAm) undergoes a hydrophilicity/hydrophobicity change around its lower critical solution temperature (LCST). Therefore, pNIPAm-based polymer nanoparticles (NPs) shrink above their LCST and swell below their LCST. Although temperature responsiveness is an important characteristic of synthetic polymers in drug and gene delivery, few studies have investigated the temperature-responsive catch and release of low-molecular-weight drugs (LMWDs) as their affinity to the target changes. Since LMWDs have only a few functional groups, preparation of NPs with high affinity for LMWDs is hard compared with that for peptides and proteins. However, LMWDs such as anticancer drugs often have a stronger effect than peptides and proteins. Therefore, the development of NPs that can load and release LMWDs is needed for drug delivery. Here, we engineered pNIPAm-based NPs that capture paclitaxel (PTX), an anticancer LMWD that inhibits microtubules, above their LCST and release it below their LCST. The swelling transition of the NPs depended on their hydrophobic monomer structure. NPs with swelling ratios (=NP size at 25 °C/NP size at 37 °C) exceeding 1.90 released captured PTX when cooled to below their LCST by changing the affinity for PTX. On the other hand, NPs with a swelling ratio of only 1.14 released melittin. Therefore, optimizing the functional monomers of temperature-responsive NPs is essential for the catch and release of the target in a temperature-dependent manner. These results can guide the design of stimuli-responsive polymers that catch and release their target molecules.
Project description:Microparticles (MPs) are cell-cell communication vesicles derived from the cell surface plasma membrane, although they are not known to originate from cardiac ventricular muscle. In ventricular cardiomyocytes, the membrane deformation protein cardiac bridging integrator 1 (cBIN1 or BIN1+13+17) creates transverse-tubule (t-tubule) membrane microfolds, which facilitate ion channel trafficking and modulate local ionic concentrations. The microfold-generated microdomains continuously reorganize, adapting in response to stress to modulate the calcium signaling apparatus. We explored the possibility that cBIN1-microfolds are externally released from cardiomyocytes. Using electron microscopy imaging with immunogold labeling, we found in mouse plasma that cBIN1 exists in membrane vesicles about 200 nm in size, which is consistent with the size of MPs. In mice with cardiac-specific heterozygous Bin1 deletion, flow cytometry identified 47% less cBIN1-MPs in plasma, supporting cardiac origin. Cardiac release was also evidenced by the detection of cBIN1-MPs in medium bathing a pure population of isolated adult mouse cardiomyocytes. In human plasma, osmotic shock increased cBIN1 detection by enzyme-linked immunosorbent assay (ELISA), and cBIN1 level decreased in humans with heart failure, a condition with reduced cardiac muscle cBIN1, both of which support cBIN1 release in MPs from human hearts. Exploring putative mechanisms of MP release, we found that the membrane fission complex endosomal sorting complexes required for transport (ESCRT)-III subunit charged multivesicular body protein 4B (CHMP4B) colocalizes and coimmunoprecipitates with cBIN1, an interaction enhanced by actin stabilization. In HeLa cells with cBIN1 overexpression, knockdown of CHMP4B reduced the release of cBIN1-MPs. Using truncation mutants, we identified that the N-terminal BAR (N-BAR) domain in cBIN1 is required for CHMP4B binding and MP release. This study links the BAR protein superfamily to the ESCRT pathway for MP biogenesis in mammalian cardiac ventricular cells, identifying elements of a pathway by which cytoplasmic cBIN1 is released into blood.
Project description:Injectable "smart" microspheres that are sensitive to both temperature and pH have been fabricated and tested for controlled delivery of therapeutic proteins to ischemic skeletal muscle. A library of copolymers composed of N-isopropyl acrylamide (NIPAAm), propyl acrylic acid (PAA), and butyl acrylate (BA) was used to fabricate microspheres using a double emulsion method, and an optimal formulation made from copolymers composed of 57 mol.% NIPAAm, 18 mol.% PAA and 25 mol.% BA copolymers was identified. At 37°C and pH representative of ischemic muscle (i.e. pH 5.2-7.2), these microspheres produced sustained, diffusion-controlled release, and at normal, physiological pH (i.e. pH 7.4), they underwent dissolution and rapid clearance. Delivery of fibroblast growth factor 2 was used to confirm that protein bioactivity was retained following microsphere encapsulation/release based on a dose-dependent increase in NIH3T3 fibroblast proliferation in vitro. Microsphere-loaded or free Cy5.5-labeled albumin was injected into ischemic and control gastrocnemii of mice following unilateral induction of hind limb ischemia to model peripheral arterial disease. In the ischemic limb at days 3.5 and 7, there was higher local retention of the protein delivered via microspheres relative to injected free protein (p<0.05). However, clearance of protein delivered via microspheres was equivalent to free protein at later time points that correspond to ischemic recovery in this model. Finally, histological analysis of the gastrocnemius revealed that the polymeric microspheres did not produce any microscopic signs of toxicity near the injection site. These combined results suggest that the pH- and temperature-responsive microspheres presented herein are a promising technological platform for controlled protein delivery to ischemic tissue.
Project description:Multiply responsive protein nanoparticles are interesting for a variety of applications. Herein, we describe the synthesis of a vault nanoparticle that responds to both temperature and pH. Specifically, poly(N-isopropylacrylamide-co-acrylic acid) with a pyridyl disulfide end group was prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymer had a lower critical solution temperature (LCST) of 31.9 °C at pH 5, 44.0 °C at pH 6 and above 60 °C at pH 7. The polymer was conjugated to human major vault protein (hMVP), and the resulting nanoparticle was analyzed by UV-Vis, dynamic light scattering (DLS) and electron microscopy. The data demonstrated that poly(N-isopropylacrylamide-co-acrylic acid)-vault conjugate did not respond to temperatures below 60 °C at pH 7, while the nanoparticles reversibly aggregated at pH 6. Furthermore, it was shown that the vault nanoparticle structure remained intact for at least three heat and cooling cycles. Thus, these dually responsive nanoparticles may serve as a platform for drug delivery and other applications.