Polyester-based Nanoparticles Research Articles

Uniform Polyester-Based Nanoparticles Assembled via Living Crystallization-Driven Self-Assembly as Friction-Reducing Agents in Engine Oil

Uniform Polyester-Based Nanoparticles Assembled via Living Crystallization-Driven Self-Assembly as Friction-Reducing Agents in Engine Oil

Robust Chemical Strategy for Stably Labeling Polyester-Based Nanoparticles with BODIPY Fluorophores.

Aliphatic polyesters are among materials most extensively used for producing biodegradable polymeric nanoparticles currently in development as delivery carriers and imaging agents for a range of biomedical applications. Their clinical translation requires robust particle labeling methodologies that allow reliably monitoring the fate of these formulations in complex biological environments. In the present study, a practical and versatile synthetic strategy providing conjugates of poly(D,L-lactide) representative of this class of polymers with BODIPY fluorophores varying in functional groups and excitation/emission maxima was investigated as a tool for making traceable nanoparticles. Polymer-probe conjugation was accomplished by carbodiimide-induced and 4-(dimethylamino)pyridinium 4-toluenesulfonate-catalyzed esterification of the polymer's terminal hydroxyl group, either directly with a carboxy-functionalized fluorophore or with amine-protected amino acids (Boc-glycine or Boc-6-aminohexanoic acid). In the latter case, the amino acid-derivatized polymeric precursors were reacted with amine-reactive BODIPY dyes after the removal of the protective group. Unlike nanoparticles encapsulating a strongly hydrophobic BODIPY505/515 (logPo/w = 4.3), nanoparticles labeled covalently with its carboxy-functionalized analogue (BODIPY FL) demonstrated stable particle-tracer association under perfect sink conditions. Furthermore, in contrast to the encapsulated dye rapidly partitioning from particles onto cell membranes but not stably retained by cultured cells, the internalization of the covalently attached probe was an irreversible process requiring the presence of serum, consistent with active nanoparticle uptake by endocytosis. In conclusion, the conjugation of particle-forming polymers with BODIPY fluorophores offers an effective and accessible labeling strategy for making traceable polyester-based biodegradable nanoparticles and is expected to facilitate their development and optimization as therapeutic carriers and diagnostic agents.

Recent Advances and Challenges in Gene Delivery Mediated by Polyester-Based Nanoparticles.

Gene therapy is a promising approach for the treatment of several diseases, such as chronic or viral infections, inherited disorders, and cancer. The cellular internalization of exogenous nucleic acids (NA) requires efficient delivery vehicles to overcome their inherent pharmacokinetic drawbacks, e.g. electrostatic repulsions, enzymatic degradation, limited cellular uptake, fast clearance, etc. Nanotechnological advancements have enabled the use of polymer-based nanostructured biomaterials as safe and effective gene delivery systems, in addition to viral vector delivery methods. Among the plethora of polymeric nanoparticles (NPs), this review will provide a comprehensive and in-depth summary of the polyester-based nanovehicles, including poly(lactic-co-glycolic acid) (PLGA) and polylactic acid (PLA) NPs, used to deliver a variety of foreign NA, e.g. short interfering RNA (siRNA), messenger RNA (mRNA), and plasmid DNA (pDNA). The article will review the versatility of polyester-based nanocarriers including their recent application in the delivery of the clustered, regularly‐interspaced, short palindromic repeats/Cas (CRISPR/Cas) genome editing system for treating gene-related diseases. The remaining challenges and future trend of the targeted delivery of this revolutionary genome-editing system will be discussed. Special attention will be given to the pivotal role of nanotechnology in tackling emerging infections such as coronavirus disease 2019 (COVID-19): ground-breaking mRNA vaccines delivered by NPs are currently used worldwide to fight the pandemic, pushing the boundaries of gene therapy.

Preformed Biodegradable Zwitterionic Nanoparticles as Tunable Excipients for the Formulation of Therapeutics Directly at the Point of Care

Polyester-based nanoparticles (NPs) are among the most adopted drug delivery systems developed so far. This is mainly due to their ability to increase the bioavailability of the loaded therapeutics...

Antitubercular nanocarrier monotherapy: Study of In Vivo efficacy and pharmacokinetics for rifampicin

Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles. In a well-established BALB/c mouse model of pulmonary tuberculosis, the nanoparticles provided improved pharmacokinetics and pharmacodynamics. The nanoparticles were well tolerated and much more efficient than an equivalent amount of free rifampicin.

Reshaped as polyester-based nanoparticles, gallic acid inhibits platelet aggregation, reactive oxygen species production and multi-resistant Gram-positive bacteria with an efficiency never obtained.

Natural polyphenols such as Gallic Acid (GA) form an important class of bioactive chemical entities that, having innumerable biological properties, could represent a safer alternative to common drugs against several disorders, including platelet aggregation, radical oxygen species (ROS) hyperproduction, oxidative stress (OS) and bacterial infections. Unfortunately, their clinical uses are limited by pharmacokinetics drawbacks and high sensitivity to environmental factors. In order to overcome these problems and to exploit the GA curative potentials, it has been linked to a biodegradable nanospherical dendrimer matrix, capable of protecting it, thus obtaining a GA-enriched nanosized dendrimer (GAD) endowed with a strong antioxidant capacity. GAD activity as an inhibitor of platelet aggregation and ROS accumulation and its antibacterial efficiency are evaluated here and compared to those of free GA, obtaining outcomes never achieved. Regarding platelet aggregation induced by thrombin and collagen, the GAD proved to be stronger by 7.1 and 7.3 times, respectively. Furthermore, the GAD showed a ROS inhibitory activity higher than that of GA by 8.1 (thrombin) and 6.9 (collagen) times. Concerning the antibacterial activities, evaluated on eleven multi-resistant Gram-positive strains of clinical relevance, the GAD is far more potent than GA, by exerting a growth inhibitory activity at MIC (μM) concentrations lower by factors in the range 12–50.

On-line microfluidic immobilized-enzyme reactors: A new tool for characterizing synthetic polymers

Biodegradable polymeric materials may eventually replace biostable materials for medical applications, including therapeutic devices, scaffolds for tissue engineering, and drug-delivery vehicles. To further develop such materials, a more fundamental understanding is necessary to correlate parameters including chemical-composition distribution within a macromolecular structure with the final properties of the material, including particle-size. A wide variety of analytical techniques have been applied for the characterization of polymer materials, including hyphenated techniques such as comprehensive two-dimensional liquid chromatography (LC × LC). In this context, we have investigated enzymatic degradation of polyester-based nanoparticles, both in-solution and by the use of an immobilized-enzyme reactor (IMER). We have demonstrated for the first time the implementation of such an IMER in a size-exclusion chromatography system for on-line degradation and subsequent analysis of the polymer degradation products. The effect of residence times ranging from 12 s to 4 min on polymer degradation was assessed. IMER-assisted degradation is much faster compared to in-solution degradation, which requires several hours to days, and opens the possibility to use such reactors in LC × LC modulation interfaces.

Peptide-functionalized and high drug loaded novel nanoparticles as dual-targeting drug delivery system for modulated and controlled release of paclitaxel to brain glioma

A dual-targeting drug delivery system for paclitaxel (PTX) was developed by functionalizing novel polyester-based nanoparticles (NPs) with peptides possessing special affinity for low-density lipoprotein receptor (LDLR), overcoming the limitations of the current chemotherapeutics, to transport drug from blood to brain, and then target glioma cells. Employing novel biodegradable block co-polymers (P and 2P), PTX loaded and peptide-functionalized nanoparticles were prepared by a modified nano-co-precipitation method, carried out in one step only without emulsifier, allowing to obtain spherical nanometric (<200 nm), monodisperse (PDI ∼ 0.1), Poly (Ethylene Glycol) (PEG)-coated and high PTX loaded NPs with a slow and controlled release rate for a prolonged period of time. Peptide functionalization, confirmed by fluorimetric assay and HPLC amino acids analysis, enhanced the cellular uptake of functionalized-PTX-NPs by human primary glioblastoma cell line (U-87 MG) and Bovine Brain Endothelial Cells (BBMVECs), compared with non-functionalized-PTX-NPs. To confirm dual-targeting effect, transendothelial transport experiments in an in vitro BBB model and in vitro anti-tumoral activity against U-87 MG revealed that peptide-functionalized-PTX-NPs significantly increased the transport ratio of PTX across the BBB along with an improved anti-proliferative efficiency. Pharmacokinetics and biodistribution studies in rats, carried out by in vivo experiments with 125I radiolabelled dual-targeting PTX-NPs, confirmed the stealthy behavior of NPs and indicated slightly lower levels of penetration into brain tissue in comparison with peptides known to be able to cross the BBB. These promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.

Zwitterionic Polyester-Based Nanoparticles with Tunable Size, Polymer Molecular Weight, and Degradation Time.

Biodegradable polymer nanoparticles are an important class of materials used in several applications for their unique characteristics. In particular, the ones stabilized by zwitterionic materials are gaining increased interest in medicine as alternative to the more common ones based on poly(ethylene glycol) thanks to their superior stability and ability to avoid both the accelerated blood clearance and allergic reactions. In this work, a novel class of zwitterionic based NPs has been produced, and a method to independently control the nanoparticle size, degradation time, and polymer molecular weight has been developed and demonstrated. This has been possible by the synthesis and the fine-tuning of zwitterionic amphiphilic block copolymers obtained via the combination of ring-opening polymerization and reversible addition-fragmentation chain transfer polymerization. The final results showed that when two block copolymers contain the same number of caprolactone units, the one with longer oligoester lateral chains degrades faster. This phenomenon is in sharp contrast with the one seen so far for the common linear polyester systems where longer chains result in longer degradation times, and it can be used to better tailor the degradation behavior of the nanoparticles.

Polyester-Based Nanoparticles for the Encapsulation of Monoclonal Antibodies.

Aliphatic polyesters have been widely explored for biomedical applications (e.g., drug delivery systems, biomedical devices, and tissue engineering). Recently, polyesters have been used in nanoparticle formulations for the controlled release of monoclonal antibodies (mAbs) for the enhanced efficacy of antibody-based therapy. Polyester-based nanoparticles for mAb delivery provide decreased antibody dosage, increased antibody stability and protection and longer therapeutic action, ultimately translating to an increased therapeutic index. Additionally, nanoencapsulation holds the potential for the selective cellular recognition and internalization of mAbs, in the disease context when intracellular organelles and molecules (e.g., enzymes, transcription factors and oncogenic proteins) are the preferred target. We present here a detailed method to prepare mAb-loaded polyester-based nanoparticles and the various techniques to characterize the resulting nanoparticles and mAb structure. Finally, we highlight different biological approaches to assess the in vitro bioactivity of the antibody upon nanoparticle release.

Polyester-Based Nanoparticles for Delivery of Therapeutic Proteins.

Therapeutic proteins are widely used to treat severe conditions, such as oncologic and metabolic diseases, and also for vaccination. They are recognized for its high biopotency, but their hydrophilicity and high molecular weight make its transport through membranes difficult to achieve. They may also suffer in vivo structural instability caused by a proteolytic cleavage, turning them biological inactive. Polyester-based nanoparticles are useful tools to overcome such problems, and deliver therapeutic proteins in a controlled and localized manner, decreasing the number of administrations needed and enhancing the therapeutic outcome. The biodegradable and biocompatible nature of such carriers makes them feasible to be administered by invasive and noninvasive routes. Since nanoparticles are produced in suspension form, they are usually lyophilized to increase its long-term storage stability. Therefore, the aim of this work is to propose an intuitive protocol for production and lyophilization of polyester-based nanoparticles for therapeutic proteins delivery. The characterization techniques to evaluate the nanoparticle and lyophilisate features, as well as the structural stability of the loaded protein are also described. For these purposes, PLGA nanoparticles and human insulin are used as models.

Development and validation of a rapid reversed-phase HPLC method for the quantification of monoclonal antibody bevacizumab from polyester-based nanoparticles

Bevacizumab is a powerful human monoclonal antibody approved worldwide for treatment of several types of cancer and ocular diseases due to its potential as antiangiogenic drug. Nowadays, in order to improve the monoclonal antibody-based therapy, attempts have been focused in the formulation of these biomacromolecules into nanoparticles. Thus, the aim of this work was to develop and validate a reversed-phase high-performance liquid chromatography with fluorescence detection method for the determination of bevacizumab from nanoparticulate systems, according to the International Conference on Harmonization guidelines. Chromatographic analysis were performed on a RP-C8 column with a mobile phase composed by water-0.1% (v/v) TFA and acetonitrile-0.1% (v/v) TFA in gradient mode at a flow rate of 1mLmin−1. Results showed that the proposed method is specific, linear in the range of 10–100μgmL−1 (r2=0.9997), accurate (recovery rate 100.50±0.85%), precise at the intraday and inter-day (relative standard deviation less than 1.79%) and robust. The detection and quantification limits were calculated by specific linear calibration curve with less concentrated standard (range of 1–20μgmL−1). The LOD was 2.16μgmL−1 and LOQ was 6.55μgmL−1. This method was also successfully used, for the first time, to quantify and compare the content of bevacizumab encapsulated into poly(lactic-co-glycolic acid)-based nanoparticles before and after lyophilization.

Polyester-based nanoparticles for the controlled release of bioactive coumarinic derivatives

Event Abstract Back to Event Polyester-based nanoparticles for the controlled release of bioactive coumarinic derivatives Ines Msolli1, 2, Frederic Chaubet1, Raoui Mounir Maaroufi2 and Christel Barbaud1 1 Galilee institute, LVTS, France 2 ISBM, LGBBV, Tunisia Introduction: Advancement in polymer science and engineering led to new polymers for controlled delivery of therapeutic drugs [1]. Poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) and its hydrophobic derivatives can be considered as a family of promising polymers. PDMMLA is polyester synthesized for temporary therapeutic applications. Bioactive coumarinic derivatives, such as warfarin, present biological activities related to the cardiovascular field [2]. The encapsulation of a coumarinic derivative and its controlled delivery would be a relevant application of PDMMLA. Thus we first tried to encapsulate warfarin as a coumarinic model drug to optimize the controlled release settings. Experimental Part: A series of amphiphilic statistical and block copolyesters with different carboxylic acid/hexylic ester proportion: 70/30, 50/50 and 30/70 (mol/mol) belonging to the poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) family have been synthesized [2],[3]. Polymer nanoparticles were further prepared by a nanoprecipitation solvent-evaporation method, and characterized by Transmission Electronic Microscopy (TEM) for nanoparticles morphology and dynamic light scattering for size and zeta potential studies.Controlled release of warfarin as a coumarinic drug model was followed by reversed-phase HPLC. Results: Statistical polymer with 30% of carboxylic acid and 70% of hexylic ester was choosen to investigate warfarin encapsulation by nanoprecipitation method and controlled release efficiency. TEM analysis evidenced spherical nanoparticles (Figure 2), which present an average size in physiological medium of about 80 nm (with a slight evolution of the size distribution over the study (28 days). The release of warfarin in a phosphate buffer saline at pH 7.4 and 37°C was monitored with reversed-phase HPLC over 28 days. The release followed a zero-order kinetics. Conclusion: We prepared a copolyester PDMMLAH30-co-Hex70 able to steadily release warfarin under simulated physiological conditions over 28 days. First results evidenced this polymer as a promising candidate for the delivery of bioactive coumarinic derivatives.

Novel peptide-decorated paclitaxel-loaded polyester-based nanoparticles as delivery systems for brain tumors therapy

Novel peptide-decorated paclitaxel-loaded polyester-based nanoparticles as delivery systems for brain tumors therapy

Surface-Functionalized Biodegradable Nanoparticles Consisting of Amphiphilic Graft Polymers Prepared by Radical Copolymerization of 2-Methylene-1,3-Dioxepane and Macromonomers.

Biodegradable polyester-based nanoparticles were prepared by the precipitation of amphiphilic graft copolymers, which were prepared by the ring-opening radical copolymerization of 2-methylene-1,3-dioxepane (MDO) and amphiphilic macromonomers. The diameter of the nanoparticles was controlled by the degree of grafting and the molecular weight of the grafting oligomer. PMDO-g-poly(ethylene glycol) nanoparticles were degraded by the alkaline hydrolysis of the polyester backbone. Although the colloidal stability of nanoparticles was retained due to the reorientation of the PEG chains during hydrolysis, the size of the nanoparticles decreased with increasing hydrolysis time. We also prepared PMDO-g-poly(N-isopropylacrylamide) nanoparticles, which show aggregation in response to increasing temperature.

Novel 18F labeling strategy for polyester-based NPs for in vivo PET-CT imaging.

Drug-loaded nanocarriers and nanoparticulate systems used for drug release require a careful in vivo evaluation in terms of physicochemical and pharmacokinetic properties. Nuclear imaging techniques such as positron emission tomography (PET) are ideal and noninvasive tools to investigate the biodistribution and biological fate of the nanostructures, but the incorporation of a positron emitter is required. Here we describe a novel approach for the (18)F-radiolabeling of polyester-based nanoparticles. Our approach relies on the preparation of the radiolabeled active agent 4-[(18)F]fluorobenzyl-2-bromoacetamide ([(18)F]FBBA), which is subsequently coupled to block copolymers under mild conditions. The labeled block copolymers are ultimately incorporated as constituent elements of the NPs by using a modified nano coprecipitation method. This strategy has been applied in the current work to the preparation of peptide-functionalized NPs with potential applications in drug delivery. According to the measurements of particle size and zeta potential, the radiolabeling process did not result in a statistically significant alteration of the physicochemical properties of the NPs. Moreover, radiochemical stability studies showed no detachment of the radioactivity from NPs even at 12 h after preparation. The radiolabeled NPs enabled the in vivo quantification of the biodistribution data in rats using a combination of imaging techniques, namely, PET and computerized tomography (CT). Low accumulation of the nanoparticles in the liver and their elimination mainly via urine was found. The different biodistribution pattern obtained for the "free" radiolabeled polymer suggests chemical and radiochemical integrity of the NPs under investigation. The strategy reported here may be applied to any polymeric NPs containing polymers bearing a nucleophile, and hence our novel strategy may find application for the in vivo and noninvasive investigation of a wide range of NPs.

In vivo delivery of peptides and Toll-like receptor ligands by mannose-functionalized polymeric nanoparticles induces prophylactic and therapeutic anti-tumor immune responses in a melanoma model

We hypothesized that the co-entrapment of melanoma-associated antigens and the Toll-like receptor (TLR) ligands Poly(I:C) and CpG, known to be Th1-immunopotentiators, in mannose-functionalized aliphatic polyester-based nanoparticles (NPs) could be targeted to mannose receptors on antigen-presenting cells and induce anti-tumor immune responses. High entrapment efficiencies of antigens and immunopotentiators in 150nm NPs were obtained. The co-entrapment of the model antigen ovalbumin and the TLR ligands was crucial to induce high IgG2c/IgG1 ratios and high levels of IFN-γ and IL-2. Mannose-functionalization of NPs potentiated the Th1 immune response. The nanoparticulate vaccines decreased the growth rate of murine B16F10 melanoma tumors in therapeutic and prophylatic settings. The combination of mannose-functionalized NPs containing MHC class I- or class II-restricted melanoma antigens and the TLR ligands induced the highest tumor growth delay. Overall, we demonstrate that the multifunctional properties of NPs in terms of targeting and antigen/adjuvant delivery have high cancer immunotherapeutic potential.

5-Fluorouracil–lipid conjugate: Potential candidate for drug delivery through encapsulation in hydrophobic polyester-based nanoparticles

The encapsulation of 5-fluorouracil (5-FU) in hydrophobic polymeric materials is made feasible by a lipid-based prodrug approach. A lipid–5-FU conjugate of 5-FU with palmitic acid was synthesized in two-step process. A synthesized dipalmitoyl derivative (5-FUDIPAL) was characterized using Fourier transform infrared spectroscopy and 1H-nuclear magnetic resonance. The 5-FUDIPAL was encapsulated in polyester-based polymers by the double emulsion–solvent evaporation method. The nanoparticles were characterized by scanning electron microscopy, transmission electron microscopy and dynamic light scattering. The thermal stability was assessed by differential scanning calorimetry data. In vitro release kinetics measurements of the drug from nanoparticles showed the controlled release pattern over a period of time. Cytotoxicity measurements by MTT assay confirmed that dipalmitoyl derivative in nano formulation successfully inhibited the cell growth. Thus the combined physical and biological evaluation of the different polyester-based nanoparticle containing the modified drug showed a facile approach to delivering 5-FU to the tumour site with enhanced efficacy.

Tunable Degradation Behavior of PEGylated Polyester-Based Nanoparticles Obtained Through Emulsion Free Radical Polymerization.

In this work PEGylated polyester-based nanoparticles (NPs) for drug delivery applications were synthetized through emulsion free radical polymerization. These NPs are produced starting from functionalized macromonomers whose average chain length can be tuned in a controlled way. Since the degradation of these NPs occurs through the hydrolysis of side chains, by tuning their length it is possible to obtain NPs with a controllable degradation time, comparable to data obtained with NPs internalized into cells. The long-term colloidal stability of these NPs in isotonic environment has been assessed through dynamic light scattering measurements and their degradation rate in cell medium has been proved to be fast and controllable. The NP behavior in gastric and intestinal solution was also studied.

Endocytic Uptake and Intracellular Trafficking of Bis-MPA-Based Hyperbranched Copolymer Micelles in Breast Cancer Cells

Dendrimers and their less well-defined cousins, hyperbranched polymers, are widely investigated as scaffold materials in tissue engineering, as drug delivery agents, and in diagnostic imaging applications. Despite the large interest of using these unique materials as polymer-based nanoparticles in biomedical applications, a clear understanding of the cellular uptake and transport of these polyester-based nanoparticles is still lacking. The objective of this study is to evaluate the cellular uptake profiles and intracellular trafficking of polymer micelles built from the hyperbranched polyester Boltorn, fitted with poly(ethylene glycol) and fluorescent groups in MDA-MB468 breast cancer cells. Results show that the uptake of these nanoparticles correlated positively to both time and concentration, and that the uptake of the nanoparticles was energy dependent. These polyesterbased nanoparticles appear to translocate across cells via clathrin- and macropinocytosis-mediated endocytosis. Observations of the intracellular trafficking of the nanoparticles indicate that particles could be released from early endosomes after being internalized, and the particles exhibit perinuclear localization. The uptake behavior of the nanoparticles was further evaluated in a range of cell lines. These results allow the generation of the knowledge base required to design polyester-based nanocarriers that can be used efficiently and specifically for drug delivery applications and imaging applications.