Hydrogel microspheres evading alveolar macrophages for sustained pulmonary protein delivery

Graf, Moritz; Ziegler, Christian E.; Gregoritza, Manuel; Goepferich, Achim

doi:10.1016/j.ijpharm.2019.06.019

Cited by 25 publications

(14 citation statements)

References 55 publications

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“…controlled release formulations is being proposed as potentially beneficial for patients suffering from lung diseases. [11,[13][14][15] Alternative green particle engineering methods using supercritical fluids, especially supercritical carbon dioxide (scCO 2 ), have been proposed to overcome some limitations of the conventional methods which usually require large amounts of organic solvents and thus involve additional extensive purification steps to remove the residual solvent. [16][17][18][19][20][21][22][23] In this work, we investigate the robustness and reliability of scCO 2 technologies to prepare SDF-loaded nano-in-micro drug delivery systems and now report our strategy to directly deliver SDF to the lung, aiming future treatment of arterial hypertension using spray-dried nano-in-microparticles.…”

Section: Poxylated Polyurea Dendrimer Nanoparticles (Pure G4 Oox 48 )mentioning

confidence: 99%

Nano‐in‐Micro Sildenafil Dry Powder Formulations for the Treatment of Pulmonary Arterial Hypertension Disorders: The Synergic Effect of POxylated Polyurea Dendrimers, PLGA, and Cholesterol

Restani

Pires

Baptista

et al. 2020

Part & Part Syst Charact

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POXylated polyurea dendrimer nanoparticles (PURE G4 OOx 48 ) are loaded with sildenafil (SDF) by a supercritical carbon dioxide-assisted (scCO 2 ) impregnation. Further supercritical CO 2 -assisted spray drying (SASD) leads to hybrid nano-in-micro dry powder formulations that are investigated aiming at efficient pulmonary delivery of SDF in pulmonary arterial hypertension treatment. This is the first report of the production of poly(D,L-lactide-coglycolide)-cholesterol (PLGA-Chol) microparticles processed by SASD. The optimized formulation of nano-in-microparticles is composed of PLGA, Chol, and PURE G4 OOx 48 , loaded with SDF solutions in a 77:23 ratio (PLGA-Chol:dendrimer, w/w). The dry powders are fully characterized and found to be highly biodegradable and biocompatible, and the SDF release profile evaluates under different pH values. The median mass average diameter (MMAD) of the nano-in-micro systems varies between 2.57 and 5 µm and the fine particle fraction (FPF) between 36% and 29% for PURE G4 OMeOx 48 [PLGA-Chol] and PURE G4 OEtOx 48 [PLGA-Chol], respectively. The data validate the potential use of these new formulations in inhalation therapy. In vitro studies are also carried out in order to evaluate the effect of the free drug in cell viability and formulations cytotoxicity.

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Section: Poxylated Polyurea Dendrimer Nanoparticles (Pure G4 Oox 48 )mentioning

confidence: 99%

Nano‐in‐Micro Sildenafil Dry Powder Formulations for the Treatment of Pulmonary Arterial Hypertension Disorders: The Synergic Effect of POxylated Polyurea Dendrimers, PLGA, and Cholesterol

Restani

Pires

Baptista

et al. 2020

Part & Part Syst Charact

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“…Prominent examples are ester, amide, carbamate, and carbonate ester groups that degrade at different rates. [ 25–28 ]…”

Section: Introductionmentioning

confidence: 99%

“…Prominent examples are ester, amide, carbamate, and carbonate ester groups that degrade at different rates. [25][26][27][28] The goal of this study was to prepare poly(ethylene glycol) (PEG)-based hydrogels that degrade at different rates. For this purpose, 3,6-epoxy-1,2,3,6-tetrahydrophthalimide (ETPI), phenyl carbamate, carbonate ester, and phenyl carbonate ester were introduced into the norbornene-functionalized eight-armed PEGhydrogel precursor as hydrolytically cleavable groups.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Impact of Hydrolytically Cleavable Groups on the Stability of Poly(ethylene glycol) Based Hydrogels Cross‐Linked via the Inverse Electron Demand Diels–Alder (iEDDA) Reaction

Ziegler

Graf

Nagaoka

et al. 2022

Macromolecular Bioscience

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Eight-armed poly(ethylene glycol) (PEG) hydrogels cross-linked via inverse electron demand Diels-Alder reaction between norbornene and tetrazine groups are promising materials for long-term protein delivery. While a controlled release over 265 days is achieved for 15% w/v hydrogels in the previous study, the material shows high stability over 500 days despite having cleavable ester linkages between the PEG macromonomers and their functionalities. In this study, the hydrolyzable ester linkers in the PEG-norbornene precursor structure are exchanged to reduce the degradation time. To this end, 3,6-epoxy-1,2,3,6-tetrahydrophthalimide, phenyl carbamate, carbonate ester, and phenyl carbonate ester are introduced as degradable functional groups. Oscillatory shear experiments reveal that they are not affected the in situ gelation. All hydrogel types have gel points of less than 20 s even at a low polymer concentration of 5% w/v. Hydrogels with varying polymer concentrations have similar mesh sizes, all of which fell in the range of 4-12 nm. The inclusion of phenyl carbonate ester accelerates degradation considerably, with complete dissolution of 15% w/v hydrogels after 302 days of incubation in phosphate buffer (pH 7.4). Controlled release of 150 kDa fluorescein isothiocyanate-dextran over a period of at least 150 days is achieved with 15% w/v hydrogels.

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“…For example, the copper catalyst involved in the copper-catalyzed azide–alkyne cycloaddition is toxic to healthy tissues even at low concentrations . Furthermore, free-radical polymerization and thiol–ene click chemistry can lead to possible toxic side reactions with proteins or tissues. , …”

Section: Introductionmentioning

confidence: 99%

“…6 Furthermore, freeradical polymerization and thiol−ene click chemistry can lead to possible toxic side reactions with proteins or tissues. 7,8 On the other hand, the high reaction rate is at odds with the requirement that the gelation time is precisely controlled in order to facilitate injection handling and to avoid premature viscosity increase which would result in the clogging of syringe needles. Bi density of alkenyl structures.…”

Section: Introductionmentioning

confidence: 99%

In Situ Forming iEDDA Hydrogels with Tunable Gelation Time Release High-Molecular Weight Proteins in a Controlled Manner over an Extended Time

et al. 2021

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Off-target interactions between reactive hydrogel moieties and drug cargo as well as slow reaction kinetics and the absence of controlled protein release over an extended period of time are major drawbacks of chemically cross-linked hydrogels for biomedical applications. In this study, the inverse electron demand Diels−Alder (iEDDA) reaction between norbornene-and tetrazine-functionalized eight-armed poly(ethylene glycol) (PEG) macromonomers was used to overcome these obstacles. Oscillatory shear experiments revealed that the gel point of a 15% (w/v) eight-armed PEG hydrogel with a molecular weight of 10 kDa was less than 15 s, suggesting the potential for fast in situ gelation. However, the high-speed reaction kinetics result in a risk of premature gel formation that complicates the injection process. Therefore, we investigated the effect of polymer concentration, temperature, and chemical structure on the gelation time. The cross-linking reaction was further characterized regarding bioorthogonality. Only 11% of the model protein lysozyme was found to be PEGylated by the iEDDA reaction, whereas 51% interacted with the classical Diels−Alder reaction. After determination of the mesh size, fluorescein isothiocyanate−dextran was used to examine the release behavior of the hydrogels. When glucose oxidase was embedded into 15% (w/v) hydrogels, a controlled release over more than 250 days was achieved. Overall, the PEG-based hydrogels cross-linked via the fast iEDDA reaction represent a promising material for the long-term administration of biologics.

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Hydrogel microspheres evading alveolar macrophages for sustained pulmonary protein delivery

Cited by 25 publications

References 55 publications

Nano‐in‐Micro Sildenafil Dry Powder Formulations for the Treatment of Pulmonary Arterial Hypertension Disorders: The Synergic Effect of POxylated Polyurea Dendrimers, PLGA, and Cholesterol

Nano‐in‐Micro Sildenafil Dry Powder Formulations for the Treatment of Pulmonary Arterial Hypertension Disorders: The Synergic Effect of POxylated Polyurea Dendrimers, PLGA, and Cholesterol

Investigation of the Impact of Hydrolytically Cleavable Groups on the Stability of Poly(ethylene glycol) Based Hydrogels Cross‐Linked via the Inverse Electron Demand Diels–Alder (iEDDA) Reaction

In Situ Forming iEDDA Hydrogels with Tunable Gelation Time Release High-Molecular Weight Proteins in a Controlled Manner over an Extended Time

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