Polylactide-based paclitaxel-loaded nanoparticles fabricated by dispersion polymerization: characterization, evaluation in cancer cell lines, and preliminary biodistribution studies.
ABSTRACT: The macromonomer method was used to prepare cross-linked, paclitaxel-loaded polylactide (PLA)-polyethylene glycol (stealth) nanoparticles using free-radical dispersion polymerization. The method can facilitate the attachment of other molecules to the nanoparticle surface to make it multifunctional. Proton nuclear magnetic resonance and Fourier transform infrared spectra confirm the synthesis of PLA macromonomer and cross-linking agent. The formation of stealth nanoparticles was confirmed by scanning and transmission electron microscopy. The drug release isotherm of paclitaxel-loaded nanoparticles shows that the encapsulated drug is released over 7 days. In vitro cytotoxicity assay in selected breast and ovarian cancer cell lines reveal that the blank nanoparticle is biocompatible compared with medium-only treated controls. In addition, the paclitaxel-loaded nanoparticles exhibit similar cytotoxicity compared with paclitaxel in solution. Confocal microscopy reveals that the nanoparticles are internalized by MCF-7 breast cancer cells within 1 h. Preliminary biodistribution studies also show nanoparticle accumulation in tumor xenograft model. The nanoparticles are suitable for the controlled delivery of bioactive agents.
Project description:This paper presents a study on the electrical properties of new polylactide-basednanocomposites with the addition of silicon-dioxide-lignin nanoparticles and glycerine as a plasticizer.Four samples were prepared with nanoparticle mass fractions ranging between 0.01 to 0.15(0.01, 0.05, 0.10, and 0.15), and three samples were prepared without nanoparticle filler-unfilledand unprocessed polylactide, unfilled and processed polylactide, and polylactide with Fusabondand glycerine. All samples were manufactured using the melt mixing extrusion techniqueand injection molding. Only the unfilled and unprocessed PLA sample was directly preparedby injection molding. Dielectric properties were studied with broadband spectroscopy in a frequencyrange from 0.1 Hz to 1 MHz in 55 steps designed on a logarithmic scale and a temperature rangefrom 293.15 to 333.15 K with a 5 K step. Optical properties of nanocomposites were measuredwith UV-VIS spectroscopy at wavelengths from 190 to 1100 nm. The experimental data show thatthe addition of silicon-dioxide-lignin and glycerine significantly affected the electrical propertiesof the studied nanocomposites based on polylactide. Permittivity and electrical conductivity showa significant increase with an increasing concentration of nanoparticle filler. The optical properties arealso affected by nanofiller and cause an increase in absorbance as the number of silicon-dioxide-ligninnanoparticles increase.
Project description:Chloramphenicol (CAM) has been encapsulated into hydroxyapatite nanoparticles displaying different morphologies and crystallinities. The process was based on typical precipitation of solutions containing phosphate and calcium ions and the addition of CAM once the hydroxyapatite nuclei were formed. This procedure favored a disposition of the drug into the bulk parts of the nanoparticles and led to a fast release in aqueous media. Clear antibacterial activity was derived, being slightly higher for the amorphous samples due to their higher encapsulation efficiency. Polylactide (PLA) microfibers incorporating CAM encapsulated in hydroxyapatite nanoparticles were prepared by the electrospinning technique and under optimized conditions. Drug release experiments demonstrated that only a small percentage of the loaded CAM could be delivered to an aqueous PBS medium. This amount was enough to render an immediate bacteriostatic effect without causing a cytotoxic effect on osteoblast-like, fibroblasts, and epithelial cells. Therefore, the prepared scaffolds were able to retain CAM-loaded nanoparticles, being a reservoir that should allow a prolonged release depending on the polymer degradation rate. The studied system may have promising applications for the treatment of cancer since CAM has been proposed as a new antitumor drug.
Project description:Peritoneal adhesion is a common postoperative complication that causes many kinds of organ dysfunctions. It can be minimized by the integration of physical isolation and pharmaceutical treatment. However, the gas permeability of traditional medical devices for adhesion prevention is not satisfactory, which increases the risk of infection and inflammation, thus facilitating the formation of peritoneal adhesion. In this study, a device of porous polylactide (PLA) film plus atorvastatin (ATV)-loaded thermogel was developed for peritoneal adhesion prevention. PLA film acted as a physical barrier to prevent the connection of fibrin bridges between the injured tissues and nearby normal organs. Simultaneously, ATV was released to achieve the antifibrin deposition and anti-inflammatory effect. The porous properties of PLA film and thermogel increased the gas permeability and further inhibited the inflammatory responses. The in vivo study demonstrated that the porous PLA film with ATV-loaded thermogel possessed excellent anti-inflammation ability and satisfactory antiadhesion capacity, indicating its great potential for clinical application.
Project description:BACKGROUND: There is an urgent need to develop drug-loaded biocompatible nanoscale packages with improved therapeutic efficacy for effective clinical treatment. To address this need, a novel poly (2-hydroxyethyl methacrylate)-poly (lactide)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine [PHEMA-g-(PLA-DPPE)] copolymer was designed and synthesized to enable these nanoparticles to be pH responsive under pathological conditions. METHODS: The structural properties and thermal stability of the copolymer was measured and confirmed by Fourier transform infrared spectroscopy, nuclear magnetic resonance, and thermogravimetric analysis. In order to evaluate its feasibility as a drug carrier, paclitaxel-loaded PHEMA-g-(PLA-DPPE) nanoparticles were prepared using the emulsion-solvent evaporation method. RESULTS: The PHEMA-g-(PLA-DPPE) nanoparticles could be efficiently loaded with paclitaxel and controlled to release the drug gradually and effectively. In vitro release experiments demonstrated that drug release was faster at pH 5.0 than at pH 7.4. The anticancer activity of the PHEMA-g-(PLA-DPPE) nanoparticles was measured in breast cancer MCF-7 cells in vivo and in vitro. In comparison with the free drug, the paclitaxel-loaded PHEMA-g-(PLA-DPPE) nanoparticles could induce more significant tumor regression. CONCLUSION: This study indicates that PHEMA-g-(PLA-DPPE) nanoparticles are promising carriers for hydrophobic drugs. This system can passively target cancer tissue and release drugs in a controllable manner, as determined by the pH value of the area in which the drug accumulates.
Project description:Clinical translation of cancer nanotherapy has largely failed due to the infeasibility of optimizing the complex interaction of nano/drug/tumor/patient parameters. We develop an interdisciplinary approach modeling diffusive transport of drug-loaded gold nanoparticles in heterogeneously-vascularized tumors.Evaluated lung cancer cytotoxicity to paclitaxel/cisplatin using novel two-layer (hexadecanethiol/phosphatidylcholine) and three-layer (with high-density-lipoprotein) nanoparticles. Computer simulations calibrated to in-vitro data simulated nanotherapy of heterogeneously-vascularized tumors.Evaluation of free-drug cytotoxicity between monolayer/spheroid cultures demonstrates a substantial differential, with increased resistance conferred by diffusive transport. Nanoparticles had significantly higher efficacy than free-drug. Simulations of nanotherapy demonstrate 9.5% (cisplatin) and 41.3% (paclitaxel) tumor radius decrease.Interdisciplinary approach evaluating gold nanoparticle cytotoxicity and diffusive transport may provide insight into cancer nanotherapy.
Project description:Cyclic polylactide (<i>c</i>PLA) is a structural isomer of linear polylactide (PLA) although it possesses unique functionalities in comparison to its linear counterpart. Hitherto, the control of stereochemical purity in conventional <i>c</i>PLA synthesis has not been achieved. In this study, highly stereochemically pure <i>c</i>PLA was synthesized in the absence of a metal catalyst and organic solvent, which required high consumption of the residual monomer. The synthesis was conducted in supercritical carbon dioxide under CO? plasticizing polymerization conditions in the presence of an organocatalyst and thiourea additives. In comparison with the stereocomplexes synthesized through conventional methods, <i>c</i>PLA from l-lactide (<i>c</i>PLLA) and <i>c</i>PLA from d-lactide (<i>c</i>PDLA) were synthesized with higher stereochemical purity and improved thermal stability. Moreover, the method presented herein is environmentally friendly and thus, applicable on an industrial level.
Project description:A direct, efficient, and scalable method to prepare stereocomplexed polylactide (PLA)-based nanoparticles (NPs) is achieved. By an appropriate combination of fabrication parameters, NPs with controlled shape and crystalline morphology are obtained and even pure PLA stereocomplexes (PLASC) are successfully prepared using the spray-drying technology. The formed particles of varying D- and L-LA content have an average size of ?400 nm, where the smallest size is obtained for PLA50, which has an equimolar composition of PLLA and PDLA in solution. Raman spectra of the particles show the typical shifts for PLASC in PLA50, and thermal analysis indicates the presence of pure stereocomplexation, with only one melting peak at 226 °C. Topographic images of the particles exhibit a single phase with different surface roughness in correlation with the thermal analysis. A high yield of spherically shaped particles is obtained. The results clearly provide a proficient method for achieving PLASC NPs that are expected to function as renewable materials in PLA-based nanocomposites and potentially as more stable drug delivery carriers.
Project description:Camptothecin-polylactide conjugates (CMPT-PLA) were synthesized by covalent incorporation of CMPT into PLA of different microstructure, i.e., atactic PLA and atactic-block-isotactically enriched PLA (Pm = 0.79) via urethane bonds. The kinetic release of CPMT from CMPT-PLA conjugates, tested in vitro under different conditions, is possible in both cases and notably, strongly dependent on PLA microstructure. It shows that release properties of drug-PLA conjugates can be tailored by controlled design of the PLA microstructure, and allow in the case of CMPT-PLA conjugates for the development of highly controlled biodegradable CMPT systems-important delivery systems for anti-cancer agents.
Project description:Polylactide/triethyl citrate (PLA/TEC) systems were prepared in two ways by introducing TEC to solidified polymer matrix (SS) and by blending in a molten state (MS) to investigate the effectiveness of the plasticization process after solidification of polylactide. The plasticization processes, independently of way of introducing the TEC into PLA matrix, leads to systems characterized by similar stability, morphology and properties. Some differences in mechanical properties between MS and SS systems result primarily from the difference in the degree of crystallinity/crystal thickness of the PLA matrix itself. Based on the presented results, it was concluded that the plasticization process after solidification of polylactide is an alternative to the conventional method of modification-blending in a molten state. Then, this new approach to plasticization process was utilized for interpretation of thermal properties of PLA and PLA/TEC systems. It turned out that double melting peak observed at DSC thermograms does not result from the melting of a double population of crystals with different lamellar thickness, or the melting of both the ?' and ? crystalline phase (commonly used explanations in literature), but is associated with the improvement of perfection of crystalline structure of PLA during heating process.
Project description:Polylactide is a biodegradable polymer that is widely used for biomedical applications, and it is a replacement for some petroleum based polymers in applications that range from packaging to carpeting. Efforts to characterize and further enhance polylactide based systems using molecular simulations have to this point been hindered by the lack of accurate atomistic models for the polymer. Thus, we present force field parameters specifically suited for molecular modeling of PLA. The model, which we refer to as PLAFF3, is based on a combination of the OPLS and CHARMM force fields, with modifications to bonded and nonbonded parameters. Dihedral angle parameters were adjusted to reproduce DFT data using newly developed CMAP dihedral cross terms, and the model was further adjusted to reproduce experimentally resolved crystal structure conformations, melt density, volume expansivity, and the glass transition temperature of PLA. We recommend the use of PLAFF3 in modeling PLA in its crystalline or amorphous states and have provided the necessary input files required for the publicly available molecular dynamics code GROMACS.