Dataset Information

Decompression Process of Glycerol Shock Treatment Can Overcome Endo-Lysosomal Barriers for Intracellular Delivery.

ABSTRACT: The glycerol shock treatment has been used to improve the calcium phosphate transfection efficacy for several decades because of its high effectiveness and low toxicity. However, the mechanism of glycerol shock treatment is still obscure. In this study, the endo-lysosomal leakage assay demonstrated that the decompression process of glycerol shock treatment could enhance endo-lysosomal membrane permeabilization, which resulted in facilitating endo-lysosomal escape for effective intracellular delivery. The enhanced decompression treatment derived from glycerol shock treatment could increase the change of osmotic pressure further, which showed higher efficacy for intracellular delivery. Herein, we speculated that the endo-lysosomal swelling originated from the decompression process of glycerol shock treatment could cause endo-lysosomal damage.

SUBMITTER: Wang S

PROVIDER: S-EPMC7774252 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Decompression Process of Glycerol Shock Treatment Can Overcome Endo-Lysosomal Barriers for Intracellular Delivery.

Wang Shupeng S Jin Shaohua S Li Guangzhi G Sun Rui R Shu Qinghai Q Wu Song S

ACS omega 20201216 51

The glycerol shock treatment has been used to improve the calcium phosphate transfection efficacy for several decades because of its high effectiveness and low toxicity. However, the mechanism of glycerol shock treatment is still obscure. In this study, the endo-lysosomal leakage assay demonstrated that the decompression process of glycerol shock treatment could enhance endo-lysosomal membrane permeabilization, which resulted in facilitating endo-lysosomal escape for effective intracellular deli ...[more]

PMID: 33403275

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Project description:A series of endosomolytic mixed micelles was synthesized from two diblock polymers, poly[ethylene glycol-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (PEG-b-pDPB) and poly[dimethylaminoethyl methacrylate-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (pD-b-pDPB), and used to determine the impact of both surface PEG density and PEG molecular weight on overcoming both intracellular and systemic siRNA delivery barriers. As expected, the percent PEG composition and PEG molecular weight in the corona had an inverse relationship with mixed micelle zeta potential and rate of cellular internalization. Although mixed micelles were internalized more slowly, they generally produced similar gene silencing bioactivity (∼ 80% or greater) in MDA-MB-231 breast cancer cells as the micelles containing no PEG (100 D/no PEG). The mechanistic explanation for the potent bioactivity of the promising 50 mol% PEG-b-DPB/50 mol% pD-b-pDPB (50 D) mixed micelle formulation, despite its relatively low rate of cellular internalization, was further investigated as a function of PEG molecular weight (5 k, 10 k, or 20 k PEG). Results indicated that, although larger molecular weight PEG decreased cellular internalization, it improved cytoplasmic bioavailability due to increased intracellular unpackaging (quantitatively measured via FRET) and endosomal release. When delivered intravenously in vivo, 50 D mixed micelles with a larger molecular weight PEG in the corona also demonstrated significantly improved blood circulation half-life (17.8 min for 20 k PEG micelles vs. 4.6 min for 5 kDa PEG micelles) and a 4-fold decrease in lung accumulation. These studies provide new mechanistic insights into the functional effects of mixed micelle-based approaches to nanocarrier surface PEGylation. Furthermore, the ideal mixed micelle formulation identified (50 D/20 k PEG) demonstrated desirable intracellular and systemic pharmacokinetics and thus has strong potential for in vivo therapeutic use.

Project description:BackgroundIn emergencies, language barriers may have dangerous consequences for the patients. There have been some technical approaches to overcome language barriers in medical care but not yet in the prehospital emergency care setting. The use of digital technologies in health care is expanding rapidly. Involving end users at all stages of the development process may help to ensure such technologies are usable and can be implemented.ObjectiveWe aimed to develop a digital communication tool that addresses paramedic needs in the specific circumstances of prehospital emergency care and helps paramedics to overcome language barriers when providing care to foreign-language patients.MethodsWe actively engaged paramedics and software designers in an action-oriented, participatory, iterative development process, which included field observations, workshops, background conversations, questionnaires on rescue missions, studying the literature, and preliminary testing in the field.ResultsWith input from paramedics, we created an app with 600 fixed phrases supporting 18 languages. The app includes medical history-taking questions, phrases asking for consent, and phrases providing specific additional information. Children as patients, as well as their carers and other third parties, can be addressed with appropriate wording. All phrases can be played back audibly or displayed as text. The comprehensive content is grouped into categories and adapted to diverse scenarios, which makes the tool rapidly usable. The app includes a function to document patient responses and the conversation history. For evaluation in a clinical study, the app is run on a smartphone with extra speakers to be of use in noisy environments. The use of prototypes proved valuable to verify that the content, structure, and functions discussed in theory were of value and genuinely needed in practice and that the various device control elements were intuitive.ConclusionsThe nature of the paramedic work environment places specific demands on the communication options used and need for such devices. The active involvement of paramedics in the development process allowed us to understand and subsequently consider their experience-based knowledge. Software designers could understand the paramedics' work environment and consider respective needs in the menu navigation and design principles of the app. We argue that the development of any medical software product should actively involve both end users and developers in all phases of the development process. Providing the users with the opportunity to influence technology development ensures that the result is closer to their needs, which can be seen as crucial for successful implementation and sustainable use.Trial registrationGerman Clinical Trials Register DRKS00016719; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016719.International registered report identifier (irrid)RR2-10.1186/s12913-020-05098-5.

Dataset Information

Decompression Process of Glycerol Shock Treatment Can Overcome Endo-Lysosomal Barriers for Intracellular Delivery.

Publications

Decompression Process of Glycerol Shock Treatment Can Overcome Endo-Lysosomal Barriers for Intracellular Delivery.

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