Polylactic Acid-polyethylene Glycol Research Articles

Structure–property relationship and controlled drug release from multiphasic electrospun carvacrol-embedded polylactic acid/polyethylene glycol and polylactic acid/polyethylene oxide nanofiber mats

Electrospinning technologies gained considerable interest over the last decade. In this study, it is proposed a systematic study of polylactic acid/polyethylene glycol (PLA/PEG) and polylactic acid/polyethylene oxide (PLA/PEO) electrospun blends at different concentrations. The effect of blend composition and PEG molecular weight on the morphological and mechanical properties of the mats was evaluated. Furthermore, the kinetic release of carvacrol as model drug in phosphate buffer saline at 37℃ was studied and the data were then fitted using an exponential model. The scanning electron microscopy revealed that the morphology of the mats was strongly dependent on the relative ratio PLA:PEG, PLA:PEO and in the presence of carvacrol. Furthermore, the mechanical properties of the mats as well as their carvacrol release rate were successfully tuned by changing the relative ratio of the blend components.

Improved osteogenic differentiation of umbilical cord blood MSCs using custom made perfusion bioreactor

Background3D cell culture is an appropriate method to develop engineered bone tissue, where different bioreactors have been designed to mitigate the challenges in 3D culture. Currently, we tailored a perfusion reactor to witness human mesenchymal stem cells (MSCs) proliferation and differentiation over polylactic acid-polyethylene glycol (PLA/PEG) composite scaffolds. MethodsThe composite scaffolds with different weight ratios of PLA and PEG were prepared using solvent casting-particulate leaching technique. Human umbilcal card blood MSCs were cultured under dynamic and static conditions to elucidate the role of dynamic fluid flow in osteogenesis of MSCs. ResultsThe human MSCs distribution over the scaffolds was confirmed with fluorescent microscopy. Alkaline phosphatase (ALP), calcium mineralization, and collagen formation were found to be higher in PLA90 scaffolds than PLA100 and PLA75. PLA90 scaffolds with better cell adhesion/proliferartion were considered for bioreactor studies and they exhibited enhanced ALP, Ca+2 mineralization and collagen formation under dynamic perfusion than static culture. We further confirmed our observation by looking at expression levels of osteogenic marker (Runx2 and osteonectin) in differentiated MSCs subjected to perfusion culture compared to static culture. ConclusionThe results of the current investigation once again proves that dynamic perfusion cultures improve the osteogenic differentiation of MSCs over hybrid polymer scaffolds (PLA90) for effective bone regeneration.

A gelatin/PLA-b-PEG film of excellent gas barrier and mechanical properties

A polylactic acid-polyethylene glycol block copolymer (PLA-b-PEG) was used as an additive to prepare gelatin/PLA-b-PEG blend films for the first time. The PEG molecule block enhanced the compatibility of the PLA molecule block with gelatin, which greatly improved the excellent mechanical and gas barrier properties of the gelatin film. The film contained 5 wt% PLA-b-PEG possessed the highest tensile strength and the highest elastic modulus. When the PLA-b-PEG content further increased to 20 wt%, the tensile strength, elastic modulus and elongation at the break of the blend film were all higher than pure gelatin film, suggesting that the gelatin/PLA-b-PEG blend film was pliable and tough. The blend film possessed not only excellent oxygen barrier property, but also a much-improved water barrier property. The degradation rate of the blend film was elongated controllably by regulating the content of the PLA-b-PEG copolymer. The blend film showed great potential in the application of food packaging.

Tissue-Penetrating, Hypoxia-Responsive Echogenic Polymersomes For Drug Delivery To Solid Tumors.

Hypoxia in solid tumors facilitates the progression of the disease, develops resistance to chemo and radiotherapy, and contributes to relapse. Due to the lack of tumor penetration, most of the reported drug carriers are unable to reach the hypoxic niches of the solid tumors. We have developed tissue-penetrating, hypoxia-responsive echogenic polymersomes to deliver anticancer drugs to solid tumors. The polymersomes are composed of a hypoxia-responsive azobenzene conjugated and a tissue penetrating peptide functionalized polylactic acid-polyethylene glycol polymer. The drug-encapsulated, hypoxia-responsive polymersomes substantially decreased the viability of pancreatic cancer cells in spheroidal cultures. Under normoxic conditions, polymersomes were echogenic at diagnostic ultrasound frequencies but lose the echogenicity under hypoxia. In-vivo imaging studies with xenograft mouse model further confirmed the ability of the polymersomes to target, penetrate, and deliver the encapsulated contents in hypoxic pancreatic tumor tissues.

Zinc pthalocyanine-loaded chitosan/mPEG-PLA nanoparticles-mediated photodynamic therapy for the treatment of cutaneous squamous cell carcinoma.

Zinc pthalocyanine (ZnPc) is a second-generation photodynamic therapy (PDT) sensitizer with sufficient PDT activity for squamous cell carcinoma (SCC). ZnPc is hydrophobic and insoluble in water, which creates hurdles in systemic administration and hence restricts its use in clinic. Here we have loaded ZnPc on chitosan/methoxy polyethylene glycol-polylactic acid (CPP) nanoparticles to form Z-CPP to enhance PDT efficacy. In vitro and in vivo studies were performed to see dark toxicity of the compounds ZnPc, CPP and Z-CPP. Then PDT was done and its growth inhibitory effect on SCC cells was evaluated. In addition, reactive oxygen species (ROS) formation and apoptosis of cancer cells following PDT were studied. The results showed that the tested compounds exhibit no dark toxicity and the effect of PDT was significantly better with Z-CPP when compared to free ZnPc (P < .05). Photoactivation of Z-CPP led to a dose-dependent growth inhibition of cancer cells of >50% at 1 μM to >80% at 10 μM concentration. Also Z-CPP-treated cells had highest number of apoptotic cells and produced more ROS compared to free ZnPc-treated cells (P < .05). Hence, this study suggests that Z-CPP is a suitable pharmaceutical compound to increase PDT efficacy.

PO-428 Therapeutic potential of nanoparticle encapsulated Wnt and YAP inhibitors using patient derived xenograft models for the treatment of triple negative breast cancer

Introduction Triple negative breast cancer (TNBC) accounts for 15%–20% of all breast cancers but disproportionately accounts for the majority of breast cancer related deaths. Within TNBC, cancer stem cells (CSCs) exist in interconvertible mesenchymal or epithelial sup-populations that cannot be simultaneously targeted by non-specific chemotherapy highlighting the necessity of a therapeutic approach which targets both subpopulations. However, these CSC populations differ dramatically, making therapeutic approaches illusive. Material and methods Initially, we identified that Wnt and YAP signalling suppressed both mesenchymal and epithelial CSCs in vitro and in vivo using TNBC cell lines, patients’ tumour samples, and a database of 2509 patients with invasive breast cancer. Subsequently, we encapsulated Wnt and YAP inhibitors (PRI-724 and simvastatin respectively) in polyethylene glycol–polylactic acid nanoparticles (NPs) to increase intra-tumoral specificity and accumulation. Mice were implanted with patient derived xenografts (PDX) and were treated with NP-encapsulated PRI-724 and simvastatin. Additionally, NP accumulation within the tumour verses other organs was tracked using NP-conjugated fluorophores followed by flow cytometry and in vivo imaging system analysis (IVIS). To determine CSC and tumorigenesis, secondary transplantation was performed after NP treatment. Results and discussions NP-encapsulated PRI-724 and simvastatin effectively suppressed Wnt and YAP gene expression in vitro. NP-encapsulated inhibitors were tolerable in vivo and accumulated in the TNBC PDX tumours. In contrast to paclitaxel (a commonly employed chemotherapeutic agent), NP-encapsulated PRI-724 and simvastatin markedly reduced the epithelial (ALDH+) and mesenchymal (CD44+/CD24-) CSC subpopulations. Additionally, co-administration of NP-encapsulated inhibitors with paclitaxel potently retarded the growth of TNBC PDX tumours but significantly maintained diminished epithelial (ALDH+) and mesenchymal (CD44+/CD24-) CSC populations. Conclusion We developed a novel, tangible approach for the treatment of TNBC using NP-encapsulated Wnt and YAP inhibitors which accumulated in TNBC PDX tumours and potently retarded tumour growth, and inhibited CSC enrichment and tumorigenicity.

In vivo efficacy and pharmacokinetics of bi-aryl oxazolidinone RBx 11760 loaded polylactic acid–polyethylene glycol nanoparticles in mouse hematogenous bronchopneumonia and rat groin abscess caused by Staphylococcus aureus

RBx 11760 is a bi-aryl oxazolidinone antibacterial agent active against Staphylococcus aureus but has poor solubility. Here we have encapsulated RBx 11760 in PLA–PEG NPs with an aim to improve physicochemical, pharmacokinetics and in vivo efficacy. The average size and zeta potential of RBx 11760 loaded NPs were found to be 106.4 nm and −22.2 mV, respectively. The absolute size of nanoparticles by HRTEM was found to be approximately 80 nm. In vitro antibacterial agar well diffusion assay showed clear zone of inhibition of bacterial growth. In pharmacokinetic study, nanoparticle showed 4.6-fold and 7-fold increase in AUCinf and half-life, respectively, as compared to free drug. RBx 11760 nanoparticle significantly reduced bacterial counts in lungs and improved the survival rate of immunocompromised mice as compared to free drugs. Thus, RBx 11760 loaded nanoparticles have strong potential to be used as nanomedicine against sensitive and drug resistant Staphylococcus aureus infections.

Intranasal delivery of α-asarone to the brain with lactoferrin-modified mPEG-PLA nanoparticles prepared by premix membrane emulsification.

Alpha-asarone is a bioactive component of Acorus tatarincuii Schott with low bioavailability, which is often used for treatments of various brain diseases in clinical setting. This study was to formulate biodegradable methoxy polyethylene glycol-polylactic acid (mPEG-PLA) nanoparticles (NPs) surface-modified by lactoferrin (Lf), for delivering α-asarone into the brain following intranasal administration. Alpha-asarone NPs were prepared by premix membrane emulsification. The relative parameters were optimized by a Box-Behnken experimental design. The particle size, zeta potential, and dispersibility index of NPs and Lf-NPs were characterized. Their ex vivo permeation, pharmacokinetics, distribution in the brain and other tissue, brain targeting, and toxicity were investigated. Following intranasal administration, Lf-NPs had a better permeability and no significant poor bioavailability compared to NPs; the area under curve from 0 to 12h of α-asarone in Lf-NPs of the olfactory bulb, hippocampus, olfactory bundles, and thalamus were 2.14-, 4.17-, 3.62-, and 1.96-fold of those in NP group, respectively. Lactoferrin could enhance the efficacy of brain targeting with NPs and reduce its liver accumulation. Toxicity of NPs on nasal mucosal cilia and epithelial cells was also decreased by Lf. To summarize, these results demonstrate that Lf-NPs of α-asarone have potential as a carrier for nose-to-brain delivery of α-asarone for brain diseases.

Antimicrobial effect of PEG-PLA on food-spoilage microorganisms.

Polyethylene glycol (PEG) and polyethylene glycol-polylactic acid (PEG-PLA) have an organic structure and no negative effect on human health. The present study compares the antimicrobial effectiveness of PEG and PEG-PLA on microbial growth. The following pathogens and fungi were examined: seven bacteria strains and 10 fungi (four yeasts and six molds). PEG, a non-modified polymer, exhibited no inhibition effect on all test microorganisms. However, the antimicrobial effect increased with the concentration of PEG-PLA. Bacteria showed more sensitivity to PEG-PLA compared with the other microorganisms used in this study. Enterobacter ATCC 19434 was found to be the most resistant bacteria. Molds and yeasts were more resistant than bacteria against PEG-PLA. MIC and MFC could not be determined on the tested fungi owing to the level of concentrations used, with the exception of the yeast Candida albicans and the molds Penicillium expansum and Aspergillus parasiticus.

Synthesis of Mesoporous Silica-Coated Magnetic Nanocomposites Using Polyethylene Glycol—Polylactic Acid as a New Template

Synthesis of Mesoporous Silica-Coated Magnetic Nanocomposites Using Polyethylene Glycol—Polylactic Acid as a New Template

Multifunctional nanospheres for co-delivery of methotrexate and mild hyperthermia to colon cancer cells

A multifunctional nanomedicine platform was designed and evaluated for efficient colon cancer therapy by a combinatorial therapeutic approach based on a chemotherapeutic drug and mild hyperthermia. Advantage was taken from the dual role of methotrexate (MTX), as folate receptor-targeting, overexpressed in tumor cells, and as anticancer drug. Incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) allows to heat cancer cells externally through an alternating magnetic field. The developed nanocarrier was based on polyethylene glycol–polylactic acid (PEG-PLA) nanospheres to improve biocompatibility, enhancing their targeting by prolonging blood circulation time. By an emulsion-evaporation method the nanospheres were produced and then characterized for size distribution, zeta-potential, in vitro drug release profile and cellular studies. The co-delivery of MTX and SPIONs on PEG-PLA nanospheres resulted in nanocarriers with a size of 160nm in diameter, a polydispersity index below 0.2 and a zeta potential of ca. −18mV. Multifunctional nanospheres were monodisperse and stable up to 3months. MTX was released preferentially under mild hyperthermia conditions. The multifunctional nanospheres were able to increase the cytotoxicity of MTX towards Caco-2 and SW-480 colon cancer cells, in comparison to free drug. Also, the nanospheres allowed the incorporated MTX to induce greater cell cycle arrest and apoptotic effects than the free MTX. This study provides evidences that MTX-SPIONs-PEG-PLA nanospheres are a promising solution to address colorectal cancer over-expressing folate receptors, by a combinatory approach.

Self-assembly of virus capsids decorated with block copolymers: a simulation study

Self-assembly of biocompatible nanoparticles is part of a promising field in drug delivery and biomaterials. Virus capsids are an example of nanoparticles capable of being tethered with functional groups for specific targeting. There have been experimental efforts on grafting polymers to virus capsids to synthesize tailored nanostructures. To provide insight at the nanoscale, we perform a highly coarse-grained molecular dynamics study, simulating the self-aggregation of cowpea mosaic virus (CPMV) capsids decorated with polyethylene glycol (PEG) and PEG polylactic acid (PLA) block polymers. We examined the effects of grafting architecture and volume fraction on equilibrated clusters. Characterization of the aggregation dynamics are summarized by the radius of gyration of the clusters, coordination number distributions, and average cluster size. When the system and methods are parameterized with respect to atomistic models or empirical results, the results can serve as the basis in broadly mapping the theoretical design space for controlled self-assembly of polymer-decorated virus capsids.

The Use of Sequential VEGF- and BMP2-Releasing Biodegradable Scaffolds in Rabbit Mandibular Defects

Promising developments have materialized in reconstructive surgical procedures with the applications of tissue engineering. In our study, we used tissue scaffolds fabricated from polylactic acid-polyethylene glycol (PLLA-PEG) copolymers to ensure different release rates of selective growth factors recombinant human bone morphogenetic protein 2 [rhBMP-2] and vascular endothelial growth factor (rhVEGF165) in the repair of mandibular bone defects. In our experimental study, 54 New Zealand rabbits were used. The rabbits were separated into 4 groups: group I (control group), PLLA-PEG scaffold only; group II, PLLA-PEG scaffold plus rhBMP-2 application; group III, PLLA-PEG scaffold plus VEGF165 application; and group IV, PLLA-PEG scaffold plus rhBMP-2 and VEGF165 applications. The rabbits were killed at 4 and 8weeks postoperatively, and histopathologic and immunohistochemical assessments were performed. The greatest bone volume was observed in rhBMP-2-containing groups, the greatest vessel volume was observed in VEGF165-containing groups; however, the scaffold containing rhBMP-2 and VEGF165 provided the best outcomes in conjunction with increased remodeling of the new bone. The use of polymer tissue scaffolds that release rhVEGF165 and rhBMP-2 in coordination and mimic the natural healing process in the regeneration of especially complex tissues, such as bone, is a promising treatment alternative in the field of reconstructive surgery.

Formulation and dosage of therapeutic nanosuspension for active targeting of docetaxel (WO 2014210485A1)

ABSTRACTNon-specificity and drug resistance are two major limitations of all chemotherapeutic agents. Ligand-conjugated nanomedicine is the most versatile approach for targeted cancer therapy. Attaching a targeting ligand to the nanoparticle surface increases drug concentration at the desired sites, decreases the dose needed and lessens side effects. The subject of this patent evaluation describes the preparation of a therapeutic nanosuspension of an anticancer drug, docetaxel (DTX). The nanoparticle matrix comprised a polylactic acid-polyethylene glycol block copolymer (PLA-PEG). The nanoparticles were actively directed towards prostate-specific membrane antigen (PSMA) over-expressing cancer cells using a targeting ligand S,S-2-{3-[1-carboxy-5-amino-pentyl-]ureido}-pantanedioic acid (GL2). The dose-limiting toxicity and maximum tolerated dose were determined for GL2-conjugated and DTX-loaded polymeric nanosuspensions. The efficacy of nanosuspensions was evaluated in people with various cancer types. The investigators claim the method of preparation of therapeutic nanosuspension, optimized composition of the formulation and dosage regimen for the clinical studies to effectively treat gastroesophageal and breast cancers.

A novel in situ hydrophobic ion pairing (HIP) formulation strategy for clinical product selection of a nanoparticle drug delivery system

The present studies were aimed at formulating AZD2811-loaded polylactic acid–polyethylene glycol (PLA–PEG) nanoparticles with adjustable release rates without altering the chemical structures of the polymer or active pharmaceutical ingredient (API). This was accomplished through the use of a hydrophobic ion pairing approach. A series of AZD2811-containing nanoparticles with a variety of hydrophobic counterions including oleic acid, 1-hydroxy-2-naphthoic acid, cholic acid, deoxycholic acid, dioctylsulfosuccinic acid, and pamoic acid is described. The hydrophobicity of AZD2811 was increased through formation of ion pairs with these hydrophobic counterions, producing nanoparticles with exceptionally high drug loading—up to five fold higher encapsulation efficiency and drug loading compared to nanoparticles made without hydrophobic ion pairs. Furthermore, the rate at which the drug was released from the nanoparticles could be controlled by employing counterions with various hydrophobicities and structures, resulting in release half-lives ranging from about 2 to 120h using the same polymer, nanoparticle size, and nanoemulsion process. Process recipe variables affecting drug load and release rate were identified, including pH and molarity of quench buffer.Ion pair formation between AZD2811 and pamoic acid as a model counterion was investigated using solubility enhancement as well as nuclear magnetic resonance spectroscopy to demonstrate solution-state interactions. Further evidence for an ion pairing mechanism of controlled release was provided through the measurement of API and counterion release profiles using high-performance liquid chromatography, which had stoichiometric relationships. Finally, Raman spectra of an AZD2811-pamoate salt compared well with those of the formulated nanoparticles, while single components (AZD2811, pamoic acid) alone did not.A library of AZD2811 batches was created for analytical and preclinical characterization. Dramatically improved preclinical efficacy and tolerability data were generated for the pamoic acid lead formulation, which has been selected for evaluation in a Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT 02579226). This work clearly demonstrates the importance of assessing a wide range of drug release rates during formulation screening as a critical step for new drug product development, and how utilizing hydrophobic ion pairing enabled this promising nanoparticle formulation to proceed into clinical development.

BODIPY‐Based Nanomicelles as Near‐Infrared Fluorescent “Turn‐On” Sensors for Biogenic Thiols

AbstractWe report novel, aqueous, soluble, distyryl boron dipyrromethene (BODIPY)‐containing nanomicelles as biogenic thiol sensors with near‐infrared (NIR) “turn‐on” properties. The average hydrodynamic diameter of these nanomicelles is 30 nm. They show good photostability, are selective towards biogenic thiols, and function within a broad pH window (pH 3–10). Near‐infrared‐emitting distyryl‐BODIPY was chemically linked to fluorescence quencher group of 2,4‐dinitrobenzenesulfonyl (DNBS) and was then water solubilized and formed into nanomicelles via polylactic acid‐polyethylene glycol (PLA‐PEG) encapsulation. When thiols react with the DNBS moiety, we observe subsequent recovery of distyryl‐BODIPY fluorescence both in vitro and in living cells. This work provides a simple and general method to construct intracellular nanoprobes for biogenic thiols and may pave the way to the development other fluorescence‐dye‐based sensors.

Immune cell impact of three differently coated lipid nanocapsules: pluronic, chitosan and polyethylene glycol.

Lipid nanocapsules (NCs) represent promising tools in clinical practice for diagnosis and therapy applications. However, the NC appropriate functionalization is essential to guarantee high biocompatibility and molecule loading ability. In any medical application, the immune system-impact of differently functionalized NCs still remains to be fully understood. A comprehensive study on the action exerted on human peripheral blood mononuclear cells (PBMCs) and major immune subpopulations by three different NC coatings: pluronic, chitosan and polyethylene glycol-polylactic acid (PEG) is reported. After a deep particle characterization, the uptake was assessed by flow-cytometry and confocal microscopy, focusing then on apoptosis, necrosis and proliferation impact in T cells and monocytes. Cell functionality by cell diameter variations, different activation marker analysis and cytokine assays were performed. We demonstrated that the NCs impact on the immune cell response is strongly correlated to their coating. Pluronic-NCs were able to induce immunomodulation of innate immunity inducing monocyte activations. Immunomodulation was observed in monocytes and T lymphocytes treated with Chitosan-NCs. Conversely, PEG-NCs were completely inert. These findings are of particular value towards a pre-selection of specific NC coatings depending on biomedical purposes for pre-clinical investigations; i.e. the immune-specific action of particular NC coating can be excellent for immunotherapy applications.

Preparation and release behaviour of mPEG-PLA α-asarone nanoparticles designed for nasal administration

Taking α-asarone as model drug, mono methoxy polyethylene glycol-polylactic acid copolymer (mPEG-PLA) as the drug carrier material to prepare drug-loading nanoparticles by premix membrane emulsification for nasal administration. The prepared nanoparticles were spherical with smooth surface and average particle size of 360 nm. Polydispersity index (PDI) was 0. 030, average drug loading of (11.5 ± 0.045) % (n = 3), and the encapsulation efficiency of (86.34 ± 0.11) % (n = 3). X-ray diffraction and differential scanning calorimetry results showed that, α-asarone existed in mPEG-PLA carrier in amorphous or molecular state, different from simple physical mixture. In the in vitro release test in simulated human nasal cavity, α-asarone apis can be released quickly at close to 94% at 102 h, in line with the first-order kinetics (R² = 0.981 9). mPEG-PLA drug-loading nanoparticles release only 54%, with slow release effect, in line with Riger-Peppas model (R² = 0.967 9, n = 0.630 2), for non-fick diffusion, released by the spread of drugs and skeleton dissolution dual control. This provided the foundation for nasal drug delivery in vivo pharmacokinetic study.

Development of polymeric-cationic peptide composite nanoparticles, a nanoparticle-in-nanoparticle system for controlled gene delivery.

We report the formulation of novel composite nanoparticles that combine the high transfection efficiency of cationic peptide-DNA nanoparticles with the biocompatibility and prolonged delivery of polylactic acid–polyethylene glycol (PLA-PEG). The cationic cell-penetrating peptide RALA was used to condense DNA into nanoparticles that were encapsulated within a range of PLA-PEG copolymers. The composite nanoparticles produced exhibited excellent physicochemical properties including size <200 nm and encapsulation efficiency >80%. Images of the composite nanoparticles obtained with a new transmission electron microscopy staining method revealed the peptide-DNA nanoparticles within the PLA-PEG matrix. Varying the copolymers modulated the DNA release rate >6 weeks in vitro. The best formulation was selected and was able to transfect cells while maintaining viability. The effect of transferrin-appended composite nanoparticles was also studied. Thus, we have demonstrated the manufacture of composite nanoparticles for the controlled delivery of DNA.

A Simple and Sensitive Method to Quantify Biodegradable Nanoparticle Biodistribution using Europium Chelates.

The biodistribution of biodegradable nanoparticles can be difficult to quantify. We report a method using time resolved fluorescence (TRF) from a lanthanide chelate to minimize background autofluorescence and maximize the signal to noise ratio to detect biodegradable nanoparticle distribution in mice. Specifically, antenna chelates containing europium were entrapped within nanoparticles composed of polylactic acid-polyethylene glycol diblock copolymers. Tissue accumulation of nanoparticles following intravenous injection was quantified in mice. The TRF of the nanoparticles was found to diminish as a second order function in the presence of serum and tissue compositions interfered with the europium signal. Both phenomena were corrected by linearization of the signal function and calculation of tissue-specific interference, respectively. Overall, the method is simple and robust with a detection limit five times greater than standard fluorescent probes.