A Comprehensive Investigation of the Structural, Thermal, and Biological Properties of Fully Randomized Biomedical Polyesters Synthesized with a Nontoxic Bismuth(III) Catalyst.

Aliphatic polyesters are the most common type of biodegradable synthetic polymer used in many pharmaceutical applications nowadays. This report describes the ring-opening polymerization (ROP) of l-lactide (L-LA), ε-caprolactone (CL) and glycolide (Gly) in the presence of a simple, inexpensive and convenient PEG200-BiOct3 catalytic system. The chemical structures of the obtained copolymers were characterized by 1H- or 13C-NMR. GPC was used to estimate the average molecular weight of the resulting polyesters, whereas TGA and DSC were employed to determine the thermal properties of polymeric products. The effects of temperature, reaction time, and catalyst content on the polymerization process were investigated. Importantly, the obtained polyesters were not cyto- or genotoxic, which is significant in terms of the potential for medical applications (e.g., for drug delivery systems). As a result of transesterification, the copolymers obtained had a random distribution of comonomer units along the polymer chain. The thermal analysis indicated an amorphous nature of poly(l-lactide-co-ε-caprolactone) (PLACL) and a low degree of crystallinity of poly(ε-caprolactone-co-glycolide) (PCLGA, Xc = 15.1%), in accordance with the microstructures with random distributions and short sequences of comonomer units (l = 1.02-2.82). Significant differences in reactivity were observed among comonomers, confirming preferential ring opening of L-LA during the copolymerization process.

Synthesis of hesperetin-loaded PLGA nanoparticles by two different experimental design methods and biological evaluation of optimized nanoparticles.

Hesperetin was effectively encapsulated into poly (d,l-lactic-co-glycolic acid) nanoparticles by using experimental design methods. A seven-factor Plackett-Burman design was used in order to determine the major process parameters. A significant linear equation, which shows the effect of each process parameter on encapsulation efficiency was developed, and then the most effective factors were determined. Further investigation and optimization was carried out by applying the three-factor three-level Box-Behnken design. Significant second-order mathematical models were developed by regression analysis of the experimental data for both responses: encapsulation efficiency and nanoparticle size. The two step experimental design allowed the synthesis of the desired nanoparticle formulations with maximum encapsulation efficiency (80.5 ± 4.9%) and minimum particle size (260.2 ± 16.5 nm) at optimum process conditions: 0.5% polyvinyl alcohol (PVA) concentration, 5.13 water:organic phase ratio, and 3.59 ml min-1 flow rate of the emulsified solution into 0.1% PVA. Furthermore, the biological activity of these optimized nanoparticles were determined with antimicrobial activity and cytotoxicity studies; results were then compared to the free hesperetin. The cytotoxicity result revealed that hesperetin and hesperetin-loaded nanoparticles were biocompatible with normal cell line L929 fibroblast cells up to 184.83 and 190.88 µg ml-1 for 24 h, and up to 133.24 and 134.80 µg ml-1 for 48 h, respectively. In the antimicrobial study, the optimized nanoparticle showed inhibition activity (minimal inhibitory concentration (MIC) values were 125 µg ml-1 for Escherichia coli, and 200 µg ml-1 for Staphylococcus aureus), while the free hesperetin did not demonstrate activity in both strains (MIC value >200 µg ml-1). These in vitro results may provide useful information for the investigation of hesperetin-loaded nanoparticles in diagnostic and therapeutic applications.

Ring-Opening Polymerization of a New Diester Cyclic Dimer of Mandelic and Glycolic Acid: An Efficient Synthesis Method for Derivatives of Amorphous Polyglycolide with High Tg.

In this study, poly(mandelate-co-glycolate) (PMG), a modified polyglycolide (PGL), is prepared by ring-opening polymerization (ROP) of L-3-phenyl-1,4-dioxane-2,5-dione (PDD); the cyclic dimer of biobased mandelic acid and glycolic acid. The resulting polymer shows an increased glass transition temperature (Tg ) due to the incorporation of phenyl groups in the chain. High molecular weight PMG is obtained by bulk ROP at 150 °C, and it exhibits a glassy amorphous state with enhanced thermal properties such as a Tg being 35 °C higher than conventional PGL. PDD is also copolymerized with glycolide (GL) and lactide (LA), resulting in poly(mandelate-co-glycolate/glycolate) ((P(MG/GL)) with GL and poly(mandelate-co-glycolate/lactide) ((P(MG/LA)) with LA. The thermal properties of P(MG/GL) and P(MG/LA) are found to be distinctly different from PMG and conventional PGL and polylactide, and they are tunable with a changing molar ratio of PDD, GL, and LA. Therefore, PDD opens an elegant way to control and tailor the properties of biobased polyesters.

Preparation of PLGA/Rose Bengal colloidal particles by double emulsion and layer-by-layer for breast cancer treatment.

The use of colloidal particles (CPs) in the transport of drugs is developing rapidly thanks to its effectiveness and biosafety, especially in the treatment of various types of cancer. In this study Rose Bengal/PLGA CPs synthesized by double emulsion (W/O/W) and by electrostatic adsorption (layer-by-layer), were characterized and evaluated as potential breast cancer treatment. CPs were evaluated in terms of size, zeta potential, drug release kinetics and cell viability inhibition efficacy with the triple negative breast cancer cell line HCC70. The results showed that both types of CPs can be an excellent alternative to conventional cancer treatment by taking advantage of the enhanced permeation and retention (EPR) effect, manifested by solid tumors; however, the double emulsion CPs showed more suitable delivery times of up to 60% within two days, while layer-by-layer showed fast release of 50% in 90 min. Both types of CPs were capable to decrease cell viability, which encourage us to further testing in in vivo models to prove their efficacy and feasible use in the treatment of triple negative breast cancer.

Benign preparation of aqueous core poly lactic-co-glycolic acid (PLGA) microcapsules.

Poly lactic-co-glycolic acid (PLGA) has attracted considerable attention as a polymer for drug delivery carriers. However, the hydrophobic property of PLGA often leads to the use of harmful organic solvents and poor encapsulation efficiency of hydrophilic materials. To our knowledge, a preparation method of aqueous core PLGA microcapsules without using harmful organic solvents has not been proposed. In this study, we attempted to establish an encapsulation technique of hydrophilic materials in aqueous core biodegradable and biocompatible PLGA microcapsules using vegetable oil as a continuous phase. As a result, the temperature of the oil/water mixture was required to be above the glass transition temperature. In this condition, two different types of morphology were prepared. When the water volume was below the solubility limit, PLGA microcapsules with a smooth shell were formed. In contrast, when the water volume was above the solubility limit, colloidosome-like microcapsules with PLGA nanoparticles assembled at the interface were formed. The obtained microcapsules were then heated at the glass transition temperature. The result is that aqueous core PLGA microcapsules with a smooth shell were prepared using plant oil as a continuous phase. Rhodamine B used as a hydrophilic model encapsulant, was successfully encapsulated in the PLGA microcapsules.

Fabricating PLGA microparticles with high loads of the small molecule antioxidant N-acetylcysteine that rescue oligodendrocyte progenitor cells from oxidative stress.

Reactive oxygen species (ROS), encompassing all oxygen radical or non-radical oxidizing agents, play key roles in disease progression. Controlled delivery of antioxidants is therapeutically relevant in such oxidant-stressed environments. Encapsulating small hydrophilic molecules into hydrophobic polymer microparticles via traditional emulsion methods has long been a challenge due to rapid mass transport of small molecules out of particle pores. We have developed a simple alteration to the existing water-in-oil-in-water (W/O/W) drug encapsulation method that dramatically improves loading efficiency: doping external water phases with drug to mitigate drug diffusion out of the particle during fabrication. PLGA microparticles with diameters ranging from 0.6 to 0.9 micrometers were fabricated, encapsulating high loads of 0.6-0.9 µm diameter PLGA microparticles were fabricated, encapsulating high loads of the antioxidant N-acetylcysteine (NAC), and released active, ROS-scavenging NAC for up to 5 weeks. Encapsulation efficiencies, normalized to the theoretical load of traditional encapsulation without doping, ranged from 96% to 400%, indicating that NAC-loaded external water phases not only prevented drug loss due to diffusion, but also doped the particles with additional drug. Antioxidant-doped particles positively affected the metabolism of oligodendrocyte progenitor cells (OPCs) under H2 O2 -mediated oxidative stress when administered both before (protection) or after (rescue) injury. Antioxidant doped particles improved outcomes of OPCs experiencing multiple doses of H2 O2 by increasing the intracellular glutathione content and preserving cellular viability relative to the injury control. Furthermore, antioxidant-doped particles preserve cell number, number of process extensions, cytoskeletal morphology, and nuclear size of H2 O2 -stressed OPCs relative to the injury control. These NAC-doped particles have the potential to provide temporally-controlled antioxidant therapy in neurodegenerative disorders such as multiple sclerosis (MS) that are characterized by continuous oxidative stress.

The effect of poly (lactic-co-glycolic) acid composition on the mechanical properties of electrospun fibrous mats.

The aim of this study was to investigate the influence of polymer molecular structure on the electrospinnability and mechanical properties of electrospun fibrous mats (EFMs). Polymers with similar molecular weight but different composition ratios (lactic acid (LA) and glycolic acid (GA)) were dissolved in binary mixtures of N,N-dimethylformamide (DMF) and tetrahydrofuran (THF). The intrinsic viscosity and rheological properties of polymer solutions were investigated prior to electrospinning. The morphology and mechanical properties of the resulting EFMs were characterized by scanning electron microscope (SEM) and dynamic mechanical analysis (DMA). Sufficiently high inter-molecular interactions were found to be a prerequisite to ensure the formation of fibers in the electrospinning process, regardless the polymer composition. The higher the amount of GA in the polymer composition, the more ordered and entangled molecules were formed after electrospinning from the solution in THF-DMF, which resulted in higher Young's modulus and tensile strength of the EFMs. In conclusion, this study shows that the mechanical properties of EFMs, which depend on the polymer molecule-solvent affinity, can be predicted by the inter-molecular interactions in the starting polymer solutions and over the drying process of electrospinning.

Co-delivery of paclitaxel and tetrandrine via iRGD peptide conjugated lipid-polymer hybrid nanoparticles overcome multidrug resistance in cancer cells.

One of the promising strategies to overcome tumor multidrug resistance (MDR) is to deliver anticancer drug along with P-glycoprotein (P-gp) inhibitor simultaneously. To enhance the cancer cellular internalization and implement the controlled drug release, herein an iRGD peptide-modified lipid-polymer hybrid nanosystem (LPN) was fabricated to coload paclitaxel (PTX) and tetrandrine (TET) at a precise combination ratio. In this co-delivery system, PTX was covalently conjugated to poly (D,L-lactide-co-glycolide) polymeric core by redox-sensitive disulfide bond, while TET was physically capsulated spontaneously for the aim to suppress P-gp in advance by the earlier released TET in cancer cells. As a result, the PTX+TET/iRGD LPNs with a core-shell structure possessed high drug loading efficiency, stability and redox-sensitive drug release profiles. Owing to the enhanced cellular uptake and P-gp suppression mediated by TET, significantly more PTX accumulated in A2780/PTX cells treated with PTX+TET/iRGD LPNs than either free drugs or non-iRGD modified LPNs. As expected, PTX+TET/iRGD LPNs presented the highest cytotoxicity against A2780/PTX cells and effectively promoted ROS production, enhanced apoptosis and cell cycle arrests particularly. Taken together, the co-delivery system demonstrated great promise as potential treatment for MDR-related tumors based on the synergistic effects of P-gp inhibition, enhanced endocytosis and intracellular sequentially drug release.

Next Generation Precision-Polyesters Enabling Optimization of Ligand-Receptor Stoichiometry for Modular Drug Delivery.

The success of receptor-mediated drug delivery primarily depends on the ability to optimize ligand-receptor stoichiometry. Conventional polyesters such as polylactide (PLA) or its copolymer, polylactide-co-glycolide (PLGA), do not allow such optimization due to their terminal functionality. We herein report the synthesis of 12 variations of the PLA-poly(ethylene glycol) (PEG) based precision-polyester (P2s) platform, permitting 5-12 periodically spaced carboxyl functional groups on the polymer backbone. These carboxyl groups were utilized to achieve variable degrees of gambogic acid (GA) conjugation to facilitate ligand-receptor stoichiometry optimization. These P2s-GA combined with fluorescent P2s upon emulsification form nanosystems (P2Ns) of size <150 nm with GA expressed on the surface. The P2Ns outclass conventional PLGA-GA nanosystems in cellular uptake using caco-2 intestinal model cultures. The P2Ns showed a proportional increase in cellular uptake with an increase in relative surface GA density from 0 to 75%; the slight decline for 100% GA density was indicative of receptor saturation. The intracellular trafficking of P2Ns in live caco-2 cells demonstrated the involvement of endocytic pathways in cellular uptake. The P2Ns manifest transferrin receptor (TfR) colocalization in ex vivo intestinal tissue sections, despite blocking of the receptor with transferrin (Tf) noncompetitively, i.e., independently of receptor occupation by native ligand. The in vivo application of P2Ns was demonstrated using cyclosporine (CsA) as a model peptide. The P2Ns exhibited modular release in vivo, as a function of surface GA density. This approach may contribute to the development of personalized dose regimen.

PLGA nanoparticles for the oral delivery of nuciferine: preparation, physicochemical characterization and in vitro/in vivo studies.

This article reports a promising approach to enhance the oral delivery of nuciferine (NUC), improve its aqueous solubility and bioavailability, and allow its controlled release as well as inhibiting lipid accumulation. NUC-loaded poly lactic-co-glycolic acid nanoparticles (NUC-PLGA-NPs) were prepared according to a solid/oil/water (s/o/w) emulsion technique due to the water-insolubility of NUC. PLGA exhibited excellent loading capacity for NUC with adjustable dosing ratios. The drug loading and encapsulation efficiency of optimized formulation were 8.89 ± 0.71 and 88.54 ± 7.08%, respectively. NUC-PLGA-NPs exhibited a spherical morphology with average size of 150.83 ± 5.72 nm and negative charge of -22.73 ± 1.63 mV, which are suitable for oral administration. A sustained NUC released from NUC-PLGA-NPs with an initial exponential release owing to the surface associated drug followed by a slower release of NUC, which was entrapped in the core. In addition, ∼77 ± 6.67% was released in simulating intestinal juice, while only about 45.95 ± 5.2% in simulating gastric juice. NUC-PLGA-NPs are more efficient against oleic acid (OA)-induced hepatic steatosis in HepG2 cells when compared to naked NUC (n-NUC, *p < 0.05). The oral bioavailability of NUC-PLGA-NPs group was significantly higher (**p < 0.01) and a significantly decreased serum levels of total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), as well as a higher concentration of high-density lipoprotein cholesterol (HDL-C) was observed, compared with that of n-NUC treated group. These findings suggest that NUC-PLGA-NPs hold great promise for sustained and controlled drug delivery with improved bioavailability to alleviating lipogenesis.