Recent advances in oral delivery of macromolecular drugs and benefits of polymer conjugation

Fuhrmann, Kathrin; Fuhrmann, Gregor

doi:10.1016/j.cocis.2017.07.002

Cited by 28 publications

(12 citation statements)

References 51 publications

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“…Based on these findings we loaded EVs with the enzyme glucuronidase to provide a functional biological readout using the substrate fluorescein β-D-glucuronide that is cleaved by glucuronidase releasing fluorescein. Enzymes are ideal as macromolecular model entities due to their inherent susceptibility to physiological conditions 27 and are thus suitable for assessing whether encapsulation into EVs can protect these sensitive biomolecules under different conditions. Glucuronidase was encapsulated into EVs by saponin pre-treatment as reported previously 22 .…”

Section: Resultsmentioning

confidence: 99%

Extracellular vesicles protect glucuronidase model enzymes during freeze-drying

Frank

Richter

Rossi

et al. 2018

Sci Rep

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Extracellular vesicles (EVs) are natural nanoparticles that play important roles in intercellular communication and are increasingly studied for biosignalling, pathogenesis and therapy. Nevertheless, little is known about optimal conditions for their transfer and storage, and the potential impact on preserving EV-loaded cargoes. We present the first comprehensive stability assessment of different widely available types of EVs during various storage conditions including −80 °C, 4 °C, room temperature, and freeze-drying (lyophilisation). Lyophilisation of EVs would allow easy handling at room temperature and thus significantly enhance their expanded investigation. A model enzyme, β-glucuronidase, was loaded into different types of EVs derived from mesenchymal stem cells, endothelial cells and cancer cells. Using asymmetric flow field-flow fractionation we proved that the model enzyme is indeed stably encapsulated into EVs. When assessing enzyme activity as indicator for EV stability, and in comparison to liposomes, we show that EVs are intrinsically stable during lyophilisation, an effect further enhanced by cryoprotectants. Our findings provide new insight for exploring lyophilisation as a novel storage modality and we create an important basis for standardised and advanced EV applications in biomedical research.

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Section: Resultsmentioning

confidence: 99%

Extracellular vesicles protect glucuronidase model enzymes during freeze-drying

Frank

Richter

Rossi

et al. 2018

Sci Rep

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“…OMVs may be bioengineered to possess small moieties enabling optimised targeting to pathogens while concurrently reducing accumulation in healthy mammalian cells as it was shown for other EVs [59]. These OMVs finally present a water-soluble version of poorly water-soluble cystobactamid which is relevant when developing this promising drug for other application routes, such as oral or lung delivery [60]. Ultimately, our findings provide an important step towards further developing OMVs from myxobacteria as promising antimicrobial drug carriers.…”

Section: Discussionmentioning

confidence: 70%

Biocompatible bacteria-derived vesicles show inherent antimicrobial activity

Schulz

Goes

Garcia

et al. 2018

Journal of Controlled Release

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Up to 25,000 people die each year from resistant infections in Europe alone, with increasing incidence. It is estimated that a continued rise in bacterial resistance by 2050 would lead up to 10 million annual deaths worldwide, exceeding the incidence of cancer deaths. Although the design of new antibiotics is still one way to tackle the problem, pharmaceutical companies investigate far less into new drugs than 30 years ago. Incorporation of antibiotics into nanoparticle drug carriers ("nanoantibiotics") is currently investigated as a promising strategy to make existing antibiotics regain antimicrobial strength and overcome certain types of microbial drug resistance. Many of these synthetic systems enhance the antimicrobial effect of drugs by protecting antibiotics from degradation and reducing their side effects. Nevertheless, they often cannot selectively target pathogenic bacteria and -due to their synthetic origin -may induce side-effects themselves.In this work, we present the characterisation of naturally derived outer membrane vesicles (OMVs) as biocompatible and inherently antibiotic drug carriers. We isolated OMVs from two representative strains of myxobacteria, Cystobacter velatus Cbv34 and Sorangiineae species strain SBSr073, a bacterial order with the ability of lysing other bacterial strains and currently investigated as sources of new secondary metabolites. We investigated the myxobacterias' inherent antibacterial properties after isolation by differential centrifugation and purification by size-exclusion chromatography. OMVs have an average size range of 145-194 nm. We characterised their morphology by electron cryomicroscopy and found that OMVs are biocompatible with epithelial cells and differentiated macrophages. They showed a low endotoxin activity comparable to those of control samples, indicating a low acute inflammatory potential. In addition, OMVs showed inherent stability under different storage conditions, including 4 °C, -20 °C, -80 °C and freeze-drying. OMV uptake in Gram-negative model bacterium Escherichia coli (E. coli) showed similar to better incorporation than liposome controls, indicating the OMVs may interact with model bacteria via membrane fusion.Bacterial uptake correlated with antimicrobial activity of OMVs as measured by growth inhibition of E. coli. OMVs from Cbv34 inhibited growth of E. coli to a comparable extent as the clinically established antibiotic gentamicin. Liquid-chromatography coupled mass spectrometry analyses revealed the presence of cystobactamids in OMVs, inhibitors of bacterial topoisomerase currently studied to treat different Gram-negative and Gram-positive pathogens. This work, may serve as an important basis for further evaluation of OMVs derived from myxobacteria as novel therapeutic delivery systems against bacterial infections.

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“…Oral drug delivery is a major challenge in the field of pharmaceutical research due to pH variations and proteolytic enzymes, which are present in GI track [ 31 ]. Oral strip-films (OSFs) containing drug NCs are novel solid dosage forms that disintegrate within a very short period of time when placed in the mouth without water intake or mastication [ 16 , 30 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Fenofibrate Nanocrystals Embedded in Oral Strip-Films for Bioavailability Enhancement

et al. 2018

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The aim of the present study was to make a fenofibrate (FNB) nanocrystal (NC) by wet media milling, characterizations and formulates into oral strip-films (OSFs). Mechanical properties, redispersion study, and solid-state characterizations results suggested that reduction of drug crystal size at nanoscale and incorporation into OSFs does not affect the solid-state properties of the drug. In vitro dissolution kinetics showed enhanced dissolution rate was easily manipulated by changing the thickness of the OSF. In situ UV-imaging was used to monitor drug dissolution qualitatively and quantitatively in real time. Results confirm that the intrinsic dissolution rates and surface drug concentration measured with this device were in agreement with the USP-IV dissolution profiles. In vivo pharmacokinetics in rabbits showed a significant difference in the pharmacokinetics parameter (1.4 fold increase bioavailability) of FNB NC-loaded OSFs as compared to the marketed formulation “Tricor” and as-received (pristine) drug. This approach of drug nanocrystallization and incorporation into OSFs may have significant applications in cost-effective tools for bioavailability enhancement of FNB.

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Recent advances in oral delivery of macromolecular drugs and benefits of polymer conjugation

Cited by 28 publications

References 51 publications

Extracellular vesicles protect glucuronidase model enzymes during freeze-drying

Extracellular vesicles protect glucuronidase model enzymes during freeze-drying

Biocompatible bacteria-derived vesicles show inherent antimicrobial activity

Fenofibrate Nanocrystals Embedded in Oral Strip-Films for Bioavailability Enhancement

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