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Thermodynamic, Spatial and Methodological Considerations for the Manufacturing of Therapeutic Polymer Nanoparticles.

ABSTRACT: PURPOSE:Evaluate fundamental parameters that dictate the effectiveness of drug loading. METHODS:A model water-soluble drug lacking ionizable groups, pirfenidone (PFD), was encapsulated through nanoprecipitation in poly(ethylene glycol)-poly(lactic acid) (PEG-PLA)-poly(lactic-co-glycolic acid) (PLGA) NPs. Firstly, the thermodynamic parameters predicting drug-polymer miscibility were determined to assess the system's suitability. Then, the encapsulation was evaluated experimentally by two different techniques, bulk and microfluidic (MF) nanoprecipitation. Additionally, the number of molecules that fit in a particle core were calculated and the loading determined experimentally for different core sizes. Lastly, the effect of co-encapsulation of ?-lipoic acid (LA), a drug with complementary therapeutic effects and enhanced lipophilicity, was evaluated. RESULTS:The thermodynamic miscibility parameters predicted a good suitability of the selected system. MF manufacturing enhanced the encapsulation efficiency by 60-90% and achieved a 2-fold higher NP cellular uptake. Considering spatial constrictions for drug encapsulation and increasing the size of the PLGA core the number of PFD molecules per NP was raised from under 500 to up to 2000. More so, the co-encapsulation of LA increased the number of drug molecules per particle by 96%, with no interference with the release profile. CONCLUSIONS:Thermodynamic, spatial and methodological parameters should be considered to optimize drug encapsulation.

SUBMITTER: Maslanka Figueroa S

PROVIDER: S-EPMC7040083 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Thermodynamic, Spatial and Methodological Considerations for the Manufacturing of Therapeutic Polymer Nanoparticles.

Maslanka Figueroa Sara S Fleischmann Daniel D Beck Sebastian S Goepferich Achim A

Pharmaceutical research 20200224 3

<h4>Purpose</h4>Evaluate fundamental parameters that dictate the effectiveness of drug loading.<h4>Methods</h4>A model water-soluble drug lacking ionizable groups, pirfenidone (PFD), was encapsulated through nanoprecipitation in poly(ethylene glycol)-poly(lactic acid) (PEG-PLA)-poly(lactic-co-glycolic acid) (PLGA) NPs. Firstly, the thermodynamic parameters predicting drug-polymer miscibility were determined to assess the system's suitability. Then, the encapsulation was evaluated experimentally ...[more]

PMID: 32095934

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Project description:BackgroundMicrodialysis is a technique that can be utilized to sample the interstitial fluid of the central nervous system (CNS), including in primary malignant brain tumors known as gliomas. Gliomas are mainly accessible at the time of surgery, but have rarely been analyzed via interstitial fluid collected via microdialysis. To that end, we obtained an investigational device exemption for high molecular weight catheters (HMW, 100 kDa) and a variable flow rate pump to perform microdialysis at flow rates amenable to an intra-operative setting. We herein report on the lessons and insights obtained during our intra-operative HMW microdialysis trial, both in regard to methodological and analytical considerations.MethodsIntra-operative HMW microdialysis was performed during 15 clinically indicated glioma resections in fourteen patients, across three radiographically diverse regions in each patient. Microdialysates were analyzed via targeted and untargeted metabolomics via ultra-performance liquid chromatography tandem mass spectrometry.ResultsUse of albumin and lactate-containing perfusates impacted subsets of metabolites evaluated via global metabolomics. Additionally, focal delivery of lactate via a lactate-containing perfusate, induced local metabolic changes, suggesting the potential for intra-operative pharmacodynamic studies via reverse microdialysis of candidate drugs. Multiple peri-operatively administered drugs, including levetiracetam, cefazolin, caffeine, mannitol and acetaminophen, could be detected from one microdialysate aliquot representing 10 min worth of intra-operative sampling. Moreover, clinical, radiographic, and methodological considerations for performing intra-operative microdialysis are discussed.ConclusionsIntra-operative HMW microdialysis can feasibly be utilized to sample the live human CNS microenvironment, including both metabolites and drugs, within one surgery. Certain variables, such as perfusate type, must be considered during and after analysis. Trial registration NCT04047264.

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Thermodynamic, Spatial and Methodological Considerations for the Manufacturing of Therapeutic Polymer Nanoparticles.

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Thermodynamic, Spatial and Methodological Considerations for the Manufacturing of Therapeutic Polymer Nanoparticles.

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