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Stabilized Interleukin-4-Loaded Poly(lactic-co-glycolic) Acid Films Shift Proinflammatory Macrophages toward a Regenerative Phenotype in Vitro.

ABSTRACT: Macrophages are immune cells involved in wound healing and tissue regeneration; however, the sustained presence of proinflammatory macrophages in wound sites impairs healing. In this study, we shifted peritoneal macrophage polarization away from a proinflammatory (M1) phenotype through exposure to stabilized interleukin-4 (IL-4) in poly(lactic-co-glycolic acid) films in combination with topographical guidance from electrospun poly-L-lactic acid fibers. To our knowledge, this was the first study to stabilize IL-4 with bovine serum albumin (BSA) within a biomaterial. When IL-4 was coloaded with BSA for stabilization, we saw increased IL-4 bioactivity compared to no added stabilization, trehalose stabilization, or murine serum albumin stabilization. We observed increased elongation of peritoneal macrophages, increased RNA expression of anti-inflammatory marker arginase-1, increased ratio of interleukin-10/interleukin- 12 p40 RNA, and decreased protein expression of proinflammatory markers (interleukin-12 p40 and RANTES) compared to controls. Taken together, these results suggest the macrophages were less proinflammatory and were a more pro-resolving phenotype. When stabilized with BSA, IL-4-loaded films effectively shift macrophage polarization state and are thus promising scaffolds to reduce inflammation within in vivo injury models.

SUBMITTER: Ziemba AM

PROVIDER: S-EPMC6499395 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Stabilized Interleukin-4-Loaded Poly(lactic-co-glycolic) Acid Films Shift Proinflammatory Macrophages toward a Regenerative Phenotype in Vitro.

Ziemba Alexis M AM D'Amato Anthony R AR MacEwen Taylor M TM Puhl Devan L DL Koppes Abigail N AN Koppes Ryan A RA Lennartz Michelle R MR Gilbert Ryan J RJ

ACS applied bio materials 20190225 4

Macrophages are immune cells involved in wound healing and tissue regeneration; however, the sustained presence of proinflammatory macrophages in wound sites impairs healing. In this study, we shifted peritoneal macrophage polarization away from a proinflammatory (M1) phenotype through exposure to stabilized interleukin-4 (IL-4) in poly(lactic-co-glycolic acid) films in combination with topographical guidance from electrospun poly-L-lactic acid fibers. To our knowledge, this was the first ...[more]

PMID: 31061988

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Project description:In the pursuit of continuous improvement in the area of biomaterial design, blends of mixed-substituent polyphosphazenes and poly (lactic acid-glycolic acid) (PLGA) were prepared, and their morphology of phase distributions for the first time was studied. The degradation mechanism and osteocompatibility of the blends were also evaluated for their use as regenerative materials. Poly [(ethyl phenylalanato)25(glycine ethyl glycinato)75phosphazene](PNEPAGEG) and poly [(glycine ethyl glycinato)75(phenylphenoxy)25phosphazene](PNGEGPhPh) were blended with PLGA at various weight ratios to yield different blends, namely PNEPAGEG-PLGA 25:75, PNEPAGEG-PLGA 50:50, PNGEGPhPh-PLGA 25:75, and PNGEGPhPh-PLGA 50:50. The molecular interactions, domain sizes, and phase distributions of the blends were confirmed by atomic force microscopy (AFM) as the PNEPAGEG-PLGA and PNGEGPhPh-PLGA blends showed different domain sizes and phase distributions. Due to the extensive hydrogen bonding within the two polymer components, PNEPAGEG-PLGA exhibited small-sized domains and well-distributed morphology. While for the PNGEGPhPh-PLGA blends, the presence of phenylphenol (PhPh) caused the formation of PLGA large-sized domains as the PLGA formed a continuous phase and PNGEGPhPh constituted a dispersed phase. In addition to AFM results, scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDS), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and Fourier transform infrared spectroscopy (FTIR) results demonstrated the miscibility of the blends. The PNEPAGEG-PLGA and PNGEGPhPh-PLGA blends presented in situ 3D interconnected porous structures upon degradation in phosphate-buffered saline (PBS) media at 37°C. However, the blends showed different mechanistic pathways to the formations of the pores. The difference in the erosion patterns could be attributed to the nature of molecular attractions that exist in the blends. Furthermore, the novel blends were able to support cell growth as compared to PLGA, and accommodate cell infiltrations, which ultimately augmented surface area for better cell-material interactions.

Project description:IntroductionGlioblastoma (GBM) therapy is highly challenging, as the tumors are very aggressive due to infiltration into the surrounding normal brain tissue. Even a combination of the available therapeutic regimens may not debulk the tumor completely. GBM tumors are also known for recurrence, resulting in survival rates averaging <18 months. In addition, systemic chemotherapy for GBM has been challenged for its minimal desired therapeutic effects and unwanted side effects.PurposeWe hypothesized that paclitaxel (PTX) and superparamagnetic iron oxide (SPIO)-loaded PEGylated poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs; PTX/SPIO-NPs) can serve as an effective nanocarrier system for magnetic targeting purposes, and we aimed to demonstrate the therapeutic efficacy of this system in an orthotopic murine GBM model.Materials and methodsPTX/SPIO-NPs were prepared by emulsion-diffusion-evaporation method and characterized for physicochemical properties. In vitro cellular uptake of PTX/SPIO-NPs was evaluated by fluorescence microscopy and Prussian blue staining. Orthotopic U87MG tumor model was used to evaluate blood-brain barrier disruption using T1 contrast agent, ex vivo biodistribution, in vivo toxicity and in vivo antitumor efficacy of PTX/SPIO-NPs.ResultsPTX/SPIO-NPs were in the size of 250 nm with negative zeta potential. Qualitative cellular uptake studies showed that the internalization of NPs was concentration dependent. Through magnetic resonance imaging, we observed that the blood-brain barrier was disrupted in the GBM area. An ex vivo biodistribution study showed enhanced accumulation of NPs in the brain of GBM-bearing mice with magnetic targeting. Short-term in vivo safety evaluation showed that the NPs did not induce any systemic toxicity compared with Taxol® (PTX). When tested for in vivo efficacy, the magnetic targeting treatment significantly prolonged the median survival time compared with the passive targeting and control treatments.ConclusionOverall, PTX/SPIO-NPs with magnetic targeting could be considered as an effective anticancer targeting strategy for GBM chemotherapy.

Dataset Information

Stabilized Interleukin-4-Loaded Poly(lactic-co-glycolic) Acid Films Shift Proinflammatory Macrophages toward a Regenerative Phenotype in Vitro.

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Stabilized Interleukin-4-Loaded Poly(lactic-<i>co</i>-glycolic) Acid Films Shift Proinflammatory Macrophages toward a Regenerative Phenotype <i>in Vitro</i>.

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