Experimental and computational understanding of pulsatile release mechanism from biodegradable core-shell microparticles.
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ABSTRACT:
SUBMITTER: Sarmadi M
PROVIDER: S-EPMC9278852 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pulsatile delivery of proteins, in which release occurs over a short time after a period of little or no release, is desirable for many applications. This paper investigates the effect of biodegradable polymer shell thickness on pulsatile protein release from biodegradable polymer microcapsules.Using precision particle fabrication (PPF) technology, monodisperse microcapsules were fabricated encapsulating bovine serum albumin (BSA) in a liquid core surrounded by a drug-free poly(lactide-co-glycolide) (PLG) shell of uniform, controlled thickness from 14 to 19 ?m.When using high molecular weight PLG (Mw 88 kDa), microparticles exhibited the desired core-shell structure with high BSA loading and encapsulation efficiency (55-65%). These particles exhibited very slow release of BSA for several weeks followed by rapid release of 80-90% of the encapsulated BSA within 7 days. Importantly, with increasing shell thickness the starting time of the pulsatile release could be controlled from 25 to 35 days.Biodegradable polymer microcapsules with precisely controlled shell thickness provide pulsatile release with enhanced control of release profiles.
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Project description:Development of multifunctional biomaterials that sequester, isolate, and redeliver cell-secreted proteins at a specific timepoint may be required to achieve the level of temporal control needed to more fully regulate tissue regeneration and repair. In response, we fabricated core-shell heparin-poly(ethylene-glycol) (PEG) microparticles (MPs) with a degradable PEG-based shell that can temporally control delivery of protein-laden heparin MPs. Core-shell MPs were fabricated via a re-emulsification technique and the number of heparin MPs per PEG-based shell could be tuned by varying the mass of heparin MPs in the precursor PEG phase. When heparin MPs were loaded with bone morphogenetic protein-2 (BMP-2) and then encapsulated into core-shell MPs, degradable core-shell MPs initiated similar C2C12 cell alkaline phosphatase (ALP) activity as the soluble control, while non-degradable core-shell MPs initiated a significantly lower response (85+19% vs. 9.0+4.8% of the soluble control, respectively). Similarly, when degradable core-shell MPs were formed and then loaded with BMP-2, they induced a ?7-fold higher C2C12 ALP activity than the soluble control. As C2C12 ALP activity was enhanced by BMP-2, these studies indicated that degradable core-shell MPs were able to deliver a bioactive, BMP-2-laden heparin MP core. Overall, these dynamic core-shell MPs have the potential to sequester, isolate, and then redeliver proteins attached to a heparin core to initiate a cell response, which could be of great benefit to tissue regeneration applications requiring tight temporal control over protein presentation. STATEMENT OF SIGNIFICANCE:Tissue repair requires temporally controlled presentation of potent proteins. Recently, biomaterial-mediated binding (sequestration) of cell-secreted proteins has emerged as a strategy to harness the regenerative potential of naturally produced proteins, but this strategy currently only allows immediate amplification and re-delivery of these signals. The multifunctional, dynamic core-shell heparin-PEG microparticles presented here overcome this limitation by sequestering proteins through a PEG-based shell onto a protein-protective heparin core, temporarily isolating bound proteins from the cellular microenvironment, and re-delivering proteins only after degradation of the PEG-based shell. Thus, these core-shell microparticles have potential to be a novel tool to harness and isolate proteins produced in the cellular environment and then control when proteins are re-introduced for the most effective tissue regeneration and repair.
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Project description:Core-shell microparticles containing an aqueous core have demonstrated their value for microencapsulation and drug delivery systems. The most important step in generating these uniquely structured microparticles is the formation of droplets and double emulsion. The droplet generator must meet the performance and reliability requirements, including accurate size control with tunability and monodispersity. Herein, we present a facile technique to generate surfactant-free core-shell droplets with an aqueous core in a microfluidic device. We demonstrate that the geometry of the core-shell droplets can be precisely adjusted by the flow rates of the droplet components. As the shell is polymerized after the formation of the core-shell droplets, the resulting solid microparticles ensure the encapsulation of the aqueous core and prevent undesired release. We then study experimentally and theoretically the behaviour of resultant microparticles under heating and compression. The microparticles demonstrate excellent stability under both thermal and mechanical loads. We show that the rupture force can be quantitatively predicted from the shell thickness relative to the outer shell radius. Experimental results and theoretical predictions confirm that the rupture force scales directly with the shell thickness.
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Project description:In the present paper, facile synthesis of Ag@ZnO core-shell nanocomposites is reported where zinc oxide is coated on biogenic silver nanoparticles synthesized using Andrographis paniculata and Aloe vera leaf extract. Structural features of as synthesized nanocomposites are characterized by UV-visible spectroscopy, XRD, and FTIR. Morphology of the above core-shell nanocomposites is investigated by electron microscopy. As synthesized nanocomposite material has shown antimicrobial activity against Candida krusei, which is an opportunistic pathogen known to cause candidemia. The possible mode of activity of the above material has been studied by in-vitro molecular techniques. Our investigations have shown that surface coating of biogenic silver nanoparticles by zinc oxide has increased its antimicrobial efficiency against Candida krusei, while decreasing its toxicity towards A431 human epidermoid carcinoma cell lines.
| S-EPMC5095647 | biostudies-literature
Project description:For many vaccines, multiple injections are required to confer protective immunity against targeted pathogens. These injections often consist of a primer administration followed by a booster administration of the vaccine a few weeks or months later. A single-injection vaccine formulation that provides for both administrations could greatly improve the convenience and vaccinee's compliance. In this study, we developed parenterally injectable core-shell microspheres with a delayed pulsatile release profile that could serve as the booster in such a vaccine formulation. These microspheres contained bovine serum albumin (BSA) as the model antigen and poly(dl-lactide-co-glycolide) (PLGA) with various dl-lactide:glycolide monomer ratios as the shell material. Highly monodisperse particles with different particle characteristics were obtained using a microfluidic setup. All formulations exhibited a pulsatile in vitro release of BSA after an adjustable lag time. This lag time increased with the increasing lactide content of the polymer and ranged from 3 to 7 weeks. Shell thickness and bovine serum albumin loading had no effect on the release behavior, which could be ascribed to the degradation mechanism of the polymer, with bulk degradation being the main pathway. Co-injection of the core-shell microspheres together with a solution of the antigen that serves as the primer would allow for the desired biphasic release profile. Altogether, these findings show that injectable core-shell microspheres combined with a primer are a promising alternative for the current multiple-injection vaccines.
| S-EPMC8625087 | biostudies-literature
Project description:Activation of the stimulator of interferon gene (STING) pathway within the tumor microenvironment has been shown to generate a strong antitumor response. Although local administration of STING agonists has promise for cancer immunotherapy, the dosing regimen needed to achieve efficacy requires frequent intratumoral injections over months. Frequent dosing for cancer treatment is associated with poor patient adherence, with as high as 48% of patients failing to comply. Multiple intratumoral injections also disrupt the tumor microenvironment and vascular networks and therefore increase the risk of metastasis. Here, we developed microfabricated polylactic-co-glycolic acid (PLGA) particles that remain at the site of injection and release encapsulated STING agonist as a programmable sequence of pulses at predetermined time points that mimic multiple injections over days to weeks. A single intratumoral injection of STING agonist-loaded microparticles triggered potent local and systemic antitumor immune responses, inhibited tumor growth, and prolonged survival as effectively as multiple soluble doses, but with reduced metastasis in several mouse tumor models. STING agonist-loaded microparticles improved the response to immune checkpoint blockade therapy and substantially decreased the tumor recurrence rate from 100 to 25% in mouse models of melanoma when administered during surgical resection. In addition, we demonstrated the therapeutic efficacy of STING microparticles on an orthotopic pancreatic cancer model in mice that does not allow multiple intratumoral injections. These findings could directly benefit current STING agonist therapy by decreasing the number of injections, reducing risk of metastasis, and expanding its applicability to hard-to-reach cancers.
| S-EPMC9019818 | biostudies-literature
Project description:To optimize the anti-tumor efficacy of combination therapy with paclitaxel (PTX) and imatinib (IMN), we used coaxial electrospray to prepare sequential-release core-shell microparticles composed of a PTX-loaded sodium hyaluronate outer layer and an IMN-loaded PLGA core. The morphology, size distribution, drug loading, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, PLGA degradation, cellular growth inhibition, in vivo vaginal retention, anti-tumor efficacy, and local irritation in a murine orthotopic cervicovaginal tumor model after vaginal administration were characterized. The results show that such core-shell microparticles were of spherical appearance, with an average size of 14.65 μm and a significant drug-loading ratio (2.36% for PTX, 19.5% for IMN, w/w), which might benefit cytotoxicity against cervical-cancer-related TC-1 cells. The DSC curves indicate changes in the phase state of PTX and IMN after encapsulation in microparticles. The FTIR spectra show that drug and excipients are compatible with each other. The release profiles show sequential characteristics in that PTX was almost completely released in 1 h and IMN was continuously released for 7 days. These core-shell microparticles showed synergistic inhibition in the growth of TC-1 cells. Such microparticles exhibited prolonged intravaginal residence, a >90% tumor inhibitory rate, and minimal mucosal irritation after intravaginal administration. All results suggest that such microparticles potentially provide a non-invasive local chemotherapeutic delivery system for the treatment of cervical cancer by the sequential release of PTX and IMN.
| S-EPMC8395827 | biostudies-literature
Project description:Poly(glycerol sebacate) (PGS) has increasingly become a desirable biomaterial due to its elastic mechanical properties, biodegradability, and biocompatibility. Here, we report microfibrous core-shell mats of polycaprolactone (PCL)-PGS prepared using wet-wet coaxial electrospinning. The anticoagulant heparin was immobilized onto the surface of these electrospun fiber mats, and they were evaluated for their chemical, mechanical, and biological properties. The core-shell structure of PCL-PGS provided tunable degradation and mechanical properties. The slowly degrading PCL provided structural integrity, and the fast degrading PGS component increased fiber elasticity. Young's modulus of PCL-PGS ranged from 5.6 to 15.7 MPa. The ultimate tensile stress ranged from 2.0 to 2.9 MPa, and these fibers showed elongation from 290 to 900%. The addition of PGS and grafting of heparin improved the attachment and proliferation of human umbilical vein endothelial cells. Core-shell PCL-PGS fibers demonstrate improved performance as three-dimensional fibrous mats for potential tissue-engineering applications.
| S-EPMC6044571 | biostudies-literature
Project description:PURPOSE:This study investigated the effects of the physicochemical properties of antibiotics on the morphology, loading efficiency, size, release kinetics, and antibiotic efficacy of loaded poly(DL-lactic-co-glycolic acid) (PLGA) microparticles (MPs) at different loading percentages. METHODS:Cefazolin, ciprofloxacin, clindamycin, colistin, doxycycline, and vancomycin were loaded at 10 and 20 wt% into PLGA MPs using a water-in-oil-in water double emulsion fabrication protocol. Microparticle morphology, size, loading efficiency, release kinetics, and antibiotic efficacy were assessed. RESULTS:The results from this study demonstrate that the chemical nature of loaded antibiotics, especially charge and molecular weight, influence the incorporation into and release of antibiotics from PLGA MPs. Drugs with molecular weights less than 600 Da displayed biphasic release while those with molecular weights greater than 1,000 Da displayed triphasic release kinetics. Large molecular weight drugs also had a longer delay before release than smaller molecular weight drugs. The negatively charged antibiotic cefazolin had lower loading efficiency than positively charged antibiotics. Microparticle size appeared to be mainly controlled by fabrication parameters, and partition and solubility coefficients did not appear to have an obvious effect on loading efficiency or release. Released antibiotics maintained their efficacy against susceptible strains over the duration of release. Duration of release varied between 17 and 49 days based on the type of antibiotic loaded. CONCLUSIONS:The data from this study indicate that the chemical nature of antibiotics affects properties of antibiotic-loaded PLGA MPs and allows for general prediction of loading and release kinetics.
| S-EPMC4225168 | biostudies-literature
Project description:We describe in this work the synthesis of microparticles with a doxorubicin drug conjugated alginate core and a shell of peptide amphiphile nanofibres functionalized for targeting the folate receptor. The spherical geometry of the particle core allows high drug loading per surface area, whereas the nanoscale fibrous shell formed by self-assembly of peptide amphiphiles offers a high surface to volume ratio that is ideal for targeting. The synthesised microparticles have a 60-fold higher cytotoxicity against MDA-MB-231 breast cancer cells compared to non-targeting particles.
| S-EPMC4308987 | biostudies-literature