Exchanging and Releasing Information in Synthetic Digital Polymers Using a Strand-Displacement Strategy.

Toehold-mediated strand displacement (TMSD) was tested as a tool to edit information in synthetic digital polymers. Uniform DNA-polymer biohybrid macromolecules were first synthesized by automated phosphoramidite chemistry and characterized by HPLC, mass spectrometry, and polyacrylamide gel electrophoresis (PAGE). These precursors were diblock structures containing a synthetic poly(phosphodiester) (PPDE) segment covalently attached to a single-stranded DNA sequence. Three types of biohybrids were prepared herein: a substrate containing an accessible toehold as well as input and output macromolecules. The substrate and the input macromolecules contained noncoded PPDE homopolymers, whereas the output macromolecule contained a digitally encoded segment. After hybridization of the substrate with the output, incubation in the presence of the input led to efficient TMSD and the release of the digital segment. TMSD can therefore be used to erase or rewrite information in self-assembled biohybrid superstructures. Furthermore, it was found in this work that the conjugation of DNA single strands to synthetic segments of chosen lengths greatly facilitates the characterization and PAGE visualization of the TMSD process.

Biotinylated magnetic molecularly imprinted polymer nanoparticles for cancer cell targeting and controlled drug delivery.

Here, multivalent functions have been successfully integrated on a single core-shell type nanostructure, for remote-controlled and receptor-targeted intracellular delivery of doxorubicin (DOX) to breast cancer cells that overexpress biotin receptors.

Precisely Defined Aptamer-b-Poly(phosphodiester) Conjugates Prepared by Phosphoramidite Polymer Chemistry.

Uniform conjugates combining a DNA aptamer (either anti-MUC1 or ATP aptamer) and a synthetic polymer segment were synthesized by automated phosphoramidite chemistry. This multistep growth polymer chemistry enables the use of both natural (i.e., nucleoside phosphoramidites) and non-natural monomers (e.g., alkyl- and oligo(ethylene glycol)-phosphoramidites). Thus, in the present work, six different aptamer-polymer conjugates were synthesized and characterized by ion-exchange HPLC, circular dichroism spectroscopy, and electrospray mass spectrometry. All these methods evidenced the formation of uniform molecules with precisely controlled chain-length and monomer sequences. Furthermore, aptamer folding was not affected by polymer bioconjugation. The method described herein is straightforward and allows covalent attachment of homopolymers and copolymers to biofunctional DNA aptamers.

Controlled drug delivery for cancer cell treatment via magnetic doxorubicin imprinted silica nanoparticles.

Herein, we report a facile and rapid one-step synthetic strategy for the development of magnetic doxorubicin imprinted silica nanoparticles for drug release experiments in living cells showing a remotely triggered doxorubicin release upon applying an alternating magnetic field, without temperature elevation of the medium (local heating).

Formulation and In-Vitro Characterization of Chitosan-Nanoparticles Loaded with the Iron Chelator Deferoxamine Mesylate (DFO).

The objective of this study was to develop chitosan (CS) nanoparticles (NPs) loaded with deferoxamine mesylate (DFO) for slow release of this iron-chelating drug. Drug nanoencapsulation was performed via ionic gelation of chitosan using sodium tripolyphosphate (TPP) as cross-linker. Nanoparticles with a size ranging between 150 and 400 nm were prepared for neat CS/TPP with a 2/1 molar ratio while their yield was directly dependent on the applied stirring rate during the preparation process. DFO at different content (20, 45 and 75 wt %) was encapsulated into these nanoparticles. We found that drug loading correlates with increasing DFO content while the entrapment efficiency has an opposite behavior due to the high solubility of DFO. Hydrogen-bonding between amino and hydroxyl groups of DFO with reactive groups of CS were detected using FT-IR spectroscopy while X-ray diffraction revealed that DFO was entrapped in amorphous form in the CS nanoparticles. DFO release is directly dependent on the content of loaded drug, while model analysis revealed that the release mechanism of DFO for the CS/TPP nanoparticles is by diffusion. Treatment of murine RAW 264.7 macrophages with nanoencapsulated DFO promoted an increased expression of transferrin receptor 1 (TfR1) mRNA, a typical homeostatic response to iron deficiency. These data provide preliminary evidence for release of pharmacologically active DFO from the chitosan nanoparticles.

Paclitaxel Magnetic Core⁻Shell Nanoparticles Based on Poly(lactic acid) Semitelechelic Novel Block Copolymers for Combined Hyperthermia and Chemotherapy Treatment of Cancer.

Magnetic hybrid inorganic/organic nanocarriers are promising alternatives for targeted cancer treatment. The present study evaluates the preparation of manganese ferrite magnetic nanoparticles (MnFe2O4 MNPs) encapsulated within Paclitaxel (PTX) loaded thioether-containing ω-hydroxyacid-co-poly(d,l-lactic acid) (TEHA-co-PDLLA) polymeric nanoparticles, for the combined hyperthermia and chemotherapy treatment of cancer. Initially, TEHA-co-PDLLA semitelechelic block copolymers were synthesized and characterized by 1H-NMR, FTIR, DSC, and XRD. FTIR analysis showed the formation of an ester bond between the two compounds, while DSC and XRD analysis showed that the prepared copolymers were amorphous. MnFe2O4 MNPs of relatively small crystallite size (12 nm) and moderate saturation magnetization (64 emu·g-1) were solvothermally synthesized in the sole presence of octadecylamine (ODA). PTX was amorphously dispersed within the polymeric matrix using emulsification/solvent evaporation method. Scanning electron microscopy along with energy-dispersive X-ray spectroscopy and transmission electron microscopy showed that the MnFe2O4 nanoparticles were effectively encapsulated within the drug-loaded polymeric nanoparticles. Dynamic light scattering measurements showed that the prepared nanoparticles had an average particle size of less than 160 nm with satisfactory yield and encapsulation efficiency. Diphasic PTX in vitro release over 18 days was observed while PTX dissolution rate was mainly controlled by the TEHA content. Finally, hyperthermia measurements and cytotoxicity studies were performed to evaluate the magnetic response, as well as the anticancer activity and the biocompatibility of the prepared nanocarriers.

Differentiation Capacity of Monocyte-Derived Multipotential Cells on Nanocomposite Poly(e-caprolactone)-Based Thin Films.

Background: Μonocyte-derived multipotential cells (MOMCs) include progenitors capable of differentiation into multiple cell lineages and thus represent an ideal autologous transplantable cell source for regenerative medicine. In this study, we cultured MOMCs, generated from mononuclear cells of peripheral blood, on the surface of nanocomposite thin films. Methods: For this purpose, nanocomposite Poly(e-caprolactone) (PCL)-based thin films containing either 2.5 wt% silica nanotubes (SiO2ntbs) or strontium hydroxyapatite nanorods (SrHAnrds), were prepared using the spin-coating method. The induced differentiation capacity of MOMCs, towards bone and endothelium, was estimated using flow cytometry, real-time polymerase chain reaction, scanning electron microscopy and fluorescence microscopy after cells' genetic modification using the Sleeping Beauty Transposon System aiming their observation onto the scaffolds. Moreover, Wharton's Jelly Mesenchymal Stromal Cells were cultivated as a control cell line, while Human Umbilical Vein Endothelial Cells were used to strengthen and accelerate the differentiation procedure in semi-permeable culture systems. Finally, the cytotoxicity of the studied materials was checked with MTT assay. Results: The highest differentiation capacity of MOMCs was observed on PCL/SiO2ntbs 2.5 wt% nanocomposite film, as they progressively lost their native markers and gained endothelial lineage, in both protein and transcriptional level. In addition, the presence of SrHAnrds in the PCL matrix triggered processes related to osteoblast bone formation. Conclusion: To conclude, the differentiation of MOMCs was selectively guided by incorporating SiO2ntbs or SrHAnrds into a polymeric matrix, for the first time.

Amphiphilic Block Copolymer Microspheres Derived from Castor Oil, Poly(ε-carpolactone), and Poly(ethylene glycol): Preparation, Characterization and Application in Naltrexone Drug Delivery.

In the present study, the newly synthesized castor oil-derived thioether-containing ω-hydroxyacid (TEHA) block copolymers with polycaprolactone (TEHA-b-PCL), with methoxypoly(ethylene glycol) (mPEG), (TEHA-b-mPEG) and with poly(ethylene glycol) (PEG) (TEHA-b-PEG-b-TEHA), were investigated as polymeric carriers for fabrication of naltrexone (NLX)-loaded microspheres by the single emulsion solvent evaporation technique. These microspheres are appropriate for the long-term treatment of opioid/alcohol dependence. Physical properties of the obtained microspheres were characterized in terms of size, morphology, drug loading capacity, and drug release. A scanning electron microscopy study revealed that the desired NLX-loaded uniform microspheres with a mean particle size of 5⁻10 µm were obtained in all cases. The maximum percentage encapsulation efficiency was found to be about 25.9% for the microspheres obtained from the TEHA-b-PEG-b-TEHA copolymer. Differential scanning calorimetry and X-ray diffractometry analysis confirmed the drug entrapment within microspheres in the amorphous state. In vitro dissolution studies revealed that all NLX-loaded formulations had a similar drug release profile: An initial burst release after 24 h, followed by a sustained and slower drug release for up to 50 days. The analysis of the release kinetic data, which were fitted into the Korsmeyer⁻Peppas release model, indicated that diffusion is the main release mechanism of NLX from TEHA-b-PCL and TEHA-b-mPEG microspheres, while microspheres obtained from TEHA-b-PEG-b-TEHA exhibited a drug release closer to an erosion process.

Magnetic Nanoparticles Create Hot Spots in Polymer Matrix for Controlled Drug Release.

Herein, original magnetic drug delivery nanomaterials for cancer therapy are developed and compared, with the purpose to show active control over drug release by using an alternative magnetic field (AMF). The rationale is to combine polymers and superparamagnetic nanoparticles to trigger such drug release under AMF. Two magnetic nanosystems are thus presented: magnetic nanogels made of thermosensitive and biocompatible polymers and core-shell nanoparticles with a magnetic core and a molecularly imprinted polymer as shell. Both encapsulate doxorubicin (DOX) and the DOX controlled release was investigated in vitro and in cells under AMF excitation. It confirms that the local heat profile at the vicinity of the iron oxide core can be used for the DOX controlled release. It also shows that both nanosystems help delivering more DOX inside the cells compared to internalization of free DOX. Finally, the DOX intracellular release could be remotely triggered under AMF, in athermal conditions, thus enhancing DOX cytotoxicity.

Design of a Multifunctional Nanoengineered PLLA Surface by Maximizing the Synergies between Biochemical and Surface Design Bactericidal Effects.

Nanotechnology, the manipulation of matter on atomic, molecular, and supramolecular scales, has become the most appealing strategy for biomedical applications and is of great interest as an approach to preventing microbial risks. In this study, we utilize the antimicrobial performance and the drug-loading ability of novel nanoparticles based on silicon oxide and strontium-substituted hydroxyapatite to develop nanocomposite antimicrobial films based on a poly(l-lactic acid) (PLLA) polymer. We also demonstrate that nanoimprint lithography (NIL), a process adaptable to industrial application, is a feasible fabrication technique to modify the surface of PLLA, to alter its physical properties, and to utilize it for antibacterial applications. Various nanocomposite PLLA films with nanosized (black silicon) and three-dimensional (hierarchical) hybrid domains were fabricated by thermal NIL, and their bactericidal activity against Escherichia coli and Staphylococcus aureus was assessed. Our findings demonstrate that besides hydrophobicity the nanoparticle antibiotic delivery and the surface roughness are essential factors that affect the biofilm formation.

Use of mesoporous cellular foam (MCF) in preparation of polymeric microspheres for long acting injectable release formulations of paliperidone antipsychotic drug.

In this study, high surface area mesoporous silica foam with cellular pore morphology (MCF) was used for injectable delivery of paliperidone, an antipsychotic drug used in patients suffering from bipolar disorder. The aim was to enhance paliperidone solubility and simultaneously to prepare long active intractable microspheres. For this reason paliperidone was first loaded in MCF silica, and the whole system was further encapsulated into PLA and PLGA 75/25w/w copolymer in the form of microspheres. It was found that paliperidone, after its adsorption into MCF, was transformed in its amorphous state, thus leading to enhanced in vitro dissolution profile. Furthermore, incorporation of the drug-loaded MCF to polymeric microparticles (PLA and PLGA) prolonged the release time of paliperidone from 10 to 15days.

PLGA/SBA-15 mesoporous silica composite microparticles loaded with paclitaxel for local chemotherapy.

In this work, high surface area mesoporous silica (SBA-15) was loaded with paclitaxel (taxol, PTX) and was further entrapped into poly(lactic acid-co-glycolic acid) (PLGA) microparticles (MPs). A modified solvent evaporation-emulsion method was used in order to formulate the composite microparticles with sizes of 8-12µm. PTX loaded SBA-15 as well as the PLGA/PTX-SBA-15 composites were characterized in terms of their morphology, crystal structure and thermal properties. Drug content, loading efficiency, particle size and the in-vitro drug release kinetics of the PLGA/PTΧ-SBA-15 microspheres were also investigated. The in vitro release studies were carried out using Simulated Body Fluid (SBF) at 37°C revealing that the prepared formulations present higher dissolution rate than pure PTX and sustained pattern which is ideal for anticancer carriers. Modeling and data analysis of the in vitro drug release was also investigated. It was also shown that all microparticles have low cytotoxicity in HUVE cells. Finally, it was found that drug loaded microparticles are very effective in Human Cervical Adenocarcinoma (HeLa) cells.