34 research outputs found

    Controlled Release of Octreotide and Assessment of Peptide Acylation from Poly(D,L-lactide-co-hydroxymethyl glycolide) Compared to PLGA Microspheres

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    # The Author(s) 2011. This article is published with open access at Springerlink.com Purpose To investigate the in vitro release of octreotide acetate, a somatostatin agonist, from microspheres based on a hydrophilic polyester, poly(D,L-lactide-co-hydroxymethyl glycolide) (PLHMGA). Methods Spherical and non-porous octreotide-loaded PLHMGA microspheres (12 to 16 μm) and loading efficiency of 60–70% were prepared by a solvent evaporation. Octreotide release profiles were compared with commercial PLGA formulation (Sandostatin LAR ®); possible peptide modification with lactic, glycolic and hydroxymethyl glycolic acid units was monitored. Results PLHMGA microspheres showed burst release (~20%) followed by sustained release for 20–60 days, depending on the hydrophilicity of the polymer. Percentage of released loaded peptide was high (70–90%);>60 % of released peptide was native octreotide. PLGA microspheres did not show peptide release for the first 10 days, after which it was released in a sustained manner over the next 90 days;>75 % of released peptides were acylated adducts. Conclusions PLHMGA microspheres are promising controlled systems for peptides with excellent control over release kinetics. Moreover, substantially less peptide modification occurred in PLHMGA than in PLGA microspheres. KEY WORDS acylation. aliphatic polyester. controlle

    Effects of Antibiotic Physicochemical Properties on Their Release Kinetics from Biodegradable Polymer Microparticles

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    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

    Relationship between polarities of antibiotic and polymer matrix on nanoparticle formulations based on aliphatic polyesters

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    In the field of nanomedicine, nanoparticles are developed to target antibiotics to sites of bacterial infection thus enabling adequate drug exposure and decrease development of resistant bacteria. In the present study, we investigated the encapsulation of two antibiotics with different polarity into different PEGylated polymeric nanoparticles based on aliphatic polyesters, to obtain a better understanding of critical factors determining encapsulation and release. The nanoparticles were prepared from diblock copolymers comprising of a poly(ethylene glycol) block attached to an aliphatic polyester block of varying polarity: poly(lactic-co-glycolic acid) (mPEG-PLGA), poly(lactic-co-hydroxymethyl glycolic acid) (mPEG-PLHMGA) and poly(lactic-co-benzyloxymethyl glycolic acid) (mPEG-PLBMGA). Hydrophobic bedaquiline and hydrophilic vancomycin were encapsulated via single and double-emulsion solvent evaporation techniques, respectively. Encapsulation, degradation and release studies at physiological simulating conditions were performed. Drug polarity and preparation techniques influenced encapsulation efficiency into polymer nanoparticles, giving almost complete encapsulation of bedaquiline and approx. 30% for vancomycin independent of the polymer type. The nonpolar bedaquiline showed a predominantly diffusion-controlled release independent of polymer composition. However, polar vancomycin was released by a combination of diffusion and polymer degradation, which was significantly affected by polymer composition, the most hydrophilic polymer displaying the fastest release

    Mapping Microclimate pH in Biodegradable Polymeric Microspheres.

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    The microclimate inside microspheres prepared from biodegradable polymers (e.g., poly(lactic-co-glycolic acid) PLGA) often becomes acidic owing to the accumulation of water-soluble polymer degradation products, which can induce the destablization of encapsulated therapeutic agents. The objective of this dissertation was to quantitatively evaluate the microclimate pH (μpH) inside biodegradable polymeric microspheres in order to facilitate the development of microsphere formulations that control μpH and stabilize acid-labile drugs. Chapter 1 presents an overview of the background of these studies with a focus on the most common biodegradable polymer, PLGA. In Chapter 2, the μpH distribution inside protein-encapsulated PLGA microspheres was accurately quantified using a ratiometric method based on confocal laser scanning microscopy (CLSM). The fluorescent response of Lysosensor yellow/blue® dextran used to map acidic µpH in PLGA was influenced by the presence of encapsulated protein. A method for correction of the interference of protein was developed and validated. The µpH kinetics in four different PLGA microsphere formulations during incubation under physiological conditions were determined to be roughly pH 4 to neutral pH depending on the formulation. Based on previous literature findings of enhanced stability of encapsulated proteins and peptides in hydrophilic and biodegradable poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA) microspheres, the μpH distribution and kinetics in the microspheres prepared from PLHMGAs were evaluated in Chapter 3 by CLSM and compared that with their PLGA counterparts. The PLHMGA microspheres developed a far more neutral μpH than PLGA, which was linked to more rapid diffusion of acidic degradation products out of the polymer. In the last chapter, a mathematical model was developed to simulate the μpH kinetics and spatial distribution inside degrading PLGA microspheres by considering the acid production, mass transfer via diffusion and partition of water-soluble acids that contribute to the development of μpH. Fundamental parameters in the PLGA microspheres were determined from experiments to validate the model. The model successfully predicted the kinetics of μpH development, whereas showing a small difference in distribution compared to experimental results. Hence, these mechanistic approaches may provide valuable experimental and theoretical tools to control μpH inside the most commonly used biodegradable polymer for controlled release of acid-labile therapeutics.PhDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/99989/1/yajunl_1.pd

    The use of light in cancer immunotherapy

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    The breakthrough of immunotherapy for cancer has introduced promising new options, but nonetheless only a minority of cancer patients show significant clinical benefit. This situation has inspired two avenues of research to find solutions to this problem: mechanistic studies to decipher the working mechanisms of immunotherapies and to investigate why many patients do not respond, and studies developing combination treatments to achieve clinical benefit in situations where immunotherapy alone is not sufficient. This thesis explores both these avenues by investigating applications of visible light in immunotherapy of cancer in pre-clinical models. We developed optical imaging platforms for visualization of immune cells and immunotherapies, which can shed light on the immunological events after administration of immunotherapy. In addition, we investigated novel therapies based on the combination of tumor ablation by Photodynamic Therapy and different types of immunotherapy. Our findings may prove useful in understanding success and failure of immunotherapy, and provide new combination treatment options when the efficacy of monotherapy is insufficient.LUMC / Geneeskunde Repositoriu

    Biodegradable Poly(D,L-lactic-co-glycolic acid)-Based Micro/Nanoparticles for Sustained Release of Protein Drugs - A Review

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    Biodegradable poly(D, L-lactide-co-glycolide) (PLGA) and PLGA-based polymeric nanoparticles are widely used for sustained release of protein and peptide drugs. These formulations are usually prepared by water/oil/water (W/O/W) and solid/oil/water (S/O/W) double emulsion solvent evaporation method. Other methods of preparation are nanoprecipitation, emulsion solvent diffusion and salting-out. This review attempts to address the effects of PLGA molecular weight, lactide to glycolide ratio, crystallinity, hydrophilicity as well as nanoparticles preparation variables (e.g., homogenizer speed, surfactants nature and concentration) on the size, morphology, drug encapsulation efficiency and release profile of PLGA mico/nanoparticles. The current knowledge of protein instability during preparation, storage and release from PLGA micro/nanoparticles and protein stabilization approaches has also been discussed in this review.Keywords: Poly(D, L-lactic-co-glycolic acid), Nanoparticles, Microparticles, Protein/peptides, Sustained release, Protein instabilit

    Nanotechnology Synergised Immunoengineering for Cancer

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    Novel strategies modulating the immune system yielded enhanced anticancer responses and improved cancer survival. Nevertheless, the success rate of immunotherapy in cancer treatment has been below expectation(s) due to unpredictable efficacy and off-target effects from systemic dosing of immunotherapeutic. As a result, there is an unmet clinical need for improving conventional immunotherapy. Nanotechnology offers several new strategies, multimodality, and multiplex biological targeting advantage to overcome many of these challenges. These efforts enable programming the pharmacodynamics, pharmacokinetics, delivery of immunomodulatory agents/co-delivery of compounds to prime at the tumor sites for improved therapeutic benefits. This review provides an overview of the design and clinical principles of biomaterials driven nanotechnology and their potential use in personalized nanomedicines, vaccines, localized tumor modulation, and delivery strategies for cancer immunotherapy. In this review, we also summarize the latest highlights and recent advances in combinatorial therapies avail in the treatment of cold and complicated tumors. It also presents key steps and parameters implemented for clinical success. Finally, we analyse, discuss, and provide clinical perspectives on the integrated opportunities of nanotechnology and immunology to achieve synergistic and durable responses in cancer treatment
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