Design of experiments in the optimization of nanoparticle-based drug delivery systems

Rampado, Riccardo; Peer, Dan

doi:10.1016/j.jconrel.2023.05.001

Cited by 23 publications

(9 citation statements)

References 80 publications

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“…The observed zeta potential ranged from −18.7 to −39.2 mV, and pH as well as the zein, quercetin, and α-tocopherol concentrations were found to be the most influential factors. This finding is consistent with those of previous studies, which support the validity and reliability of our findings. − The average particle size, PDI, EE, and zeta potential of the optimized Zein/Que/Toc nanoparticles, as well as the normal probability plots, are shown in the Supporting Information (Figures S2 and S3).…”

Section: Resultssupporting

confidence: 92%

Co-encapsulation of Quercetin and α-Tocopherol Bioactives in Zein Nanoparticles: Synergistic Interactions, Stability, and Controlled Release

Tadele,

Mekonnen

2024

ACS Appl. Polym. Mater.

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This study examined the capabilities of zein-based nanoparticles for the co-delivery of quercetin and α-tocopherol. The results demonstrated an optimal encapsulation efficiency of 96% with an average particle size of 50−320 nm, highlighting the proficiency of the method. Over 60 days, the retention release profiles showed gradual reductions, with the Zein/Que/Toc (20:1:1) and Zein/Que/Toc (20:1:25) formulations exhibiting distinct dynamics. In vitro analyses revealed controlled release, with quercetin reaching 79.7% and α-tocopherol reaching 60.4% after 8 h. The Zein/Que/Toc (20:1:5) combination exhibited a notable release of 73.1% over the same span, indicating a synergistic or stabilizing interplay between the co-encapsulated agents, which is beneficial for digestion. ATR-FTIR, rheology, and fluorescence spectroscopy investigations demonstrated key molecular interactions, including hydrogen bonding and hydrophobic forces. The integration of surfactants enhanced the photostability and retention of both bioactive compounds. This study emphasizes the vast potential of zein-based nanoparticles for bioactive co-delivery, with the Zein/ Que/Toc (20:1:5) formulation emerging as a viable candidate. These findings have implications for the pharmaceutical, nutraceutical supplement, drug, and functional food domains.

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Section: Resultssupporting

confidence: 92%

Co-encapsulation of Quercetin and α-Tocopherol Bioactives in Zein Nanoparticles: Synergistic Interactions, Stability, and Controlled Release

Tadele,

Mekonnen

2024

ACS Appl. Polym. Mater.

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“…It is worth noting that the correlation between in vitro cell culture and in vivo outcomes is generally weak, if present at all, for most applications . Therefore, the design and optimization of improved LNPs through statistical approaches like Design of Experiments (DoE) are imperative . Such approaches must encompass not only physicochemical readouts, but also in vitro and in vivo assessments, biodistribution studies, and toxicological evaluations to pave the way for successful next-generation mRNA LNPs. − …”

Section: Discussionmentioning

confidence: 99%

“…36 Therefore, the design and optimization of improved LNPs through statistical approaches like Design of Experiments (DoE) are imperative. 37 Such approaches must encompass not only physicochemical readouts, but also in vitro and in vivo assessments,…”

Section: ■ Conclusionmentioning

confidence: 99%

Investigations into mRNA Lipid Nanoparticles Shelf-Life Stability under Nonfrozen Conditions

Reinhart,

Osterwald,

Ringler

et al. 2023

Mol. Pharmaceutics

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mRNA LNPs can experience a decline in activity over short periods (ranging from weeks to months). As a result, they require frozen storage and transportation conditions to maintain their full functionality when utilized. Currently approved commercially available mRNA LNP vaccines also necessitate frozen storage and supply chain management. Overcoming this significant inconvenience in the future is crucial to reducing unnecessary costs and challenges associated with storage and transport. In this study, our objective was to illuminate the potential time frame for nonfrozen storage and transportation conditions of mRNA LNPs without compromising their activity. To achieve this goal, we conducted a stability assessment and an in vitro cell culture delivery study involving five mRNA LNPs. These LNPs were constructed by using a standard formulation similar to that employed in the three commercially available LNP formulations. Among these formulations, we selected five structurally diverse ionizable lipids�C12−200, CKK-E12, MC3, SM-102, and lipid 23�from the existing literature. We incorporated these lipids into a standard LNP formulation, keeping all other components identical. The LNPs, carrying mRNA payloads, were synthesized by using microfluidic mixing technology. We evaluated the shelf life stability of these LNPs over a span of 9 weeks at temperatures of 2−8, 25, and 40 °C, utilizing an array of analytical techniques. Our findings indicated minimal impact on the hydrodynamic diameter, zeta potential, encapsulation efficiency, and polydispersity of all LNPs across the various temperatures over the studied period. The RiboGreen assay analysis of LNPs showed consistent mRNA contents over several weeks at various nonfrozen storage temperatures, leading to the incorrect assumption of intact and functional LNPs. This misunderstanding was rectified by the significant differences observed in EGFP protein expression in an in vitro cell culture (using HEK293 cells) across the five LNPs. Specifically, only LNP 1 (C12−200) and LNP 4 (SM-102) exhibited high levels of EGFP expression at the start (T0), with over 90% of HEK293 cells transfected and mean fluorescence intensity (MFI) levels exceeding 1. Interestingly, LNP 1 (C12−200) maintained largely unchanged levels of in vitro activity over 11 weeks when stored at both 2−8 and 25 °C. In contrast, LNP 4 (SM-102) retained its functionality when stored at 2−8 °C over 11 weeks but experienced a gradual decline of in vitro activity when stored at room temperature over the same period. Importantly, we observed distinct LNP architectures for the five formulations through cryo-EM imaging. This highlights the necessity for a deeper comprehension of structure−activity relationships within these complex continued...

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“…Critical Process Parameters (CPPs) are essential operational variables within a manufacturing system that influence the quality of the final output. These variables interface with Critical Material Attributes (CMAs), which embody the physical, chemical, or biological properties of the raw materials used in production [ 13 ]. The interaction of CPPs and CMAs informs the Critical Quality Attributes (CQAs), quantifiable properties that delineate the desired product quality thresholds.…”

Section: Introductionmentioning

confidence: 99%

Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns

Roldan,

Li,

Guillon

et al. 2024

Pharmaceutics

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NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in the presence of a Vitamin E TPGS aqueous stabilizer solution. Critical processing parameters and material attributes were optimized to reduce particle size and determine the effect on dissolution rate and burn healing efficacy. The antisolvent/solvent ratio (A/S), dose concentration (DC), and drug/stabilizer ratio (D/S) were the critical sonoprecipitation factors that control particle size. These factors were subjected to a Box–Behnken design and response surface analysis, and model quality was assessed. Maximize desirability and simulation experiment optimization approaches were used to determine nanosuspension parameters with the smallest size and the lowest defect rate within the 10–50 nm specification limits. Optimized and unoptimized nanosuspensions were prepared and characterized. An established depilatory double-disc mouse model was used to evaluate the healing of nitrogen mustard-induced dermal injuries. Optimized nanosuspensions (A/S = 6.2, DC = 2% w/v, D/S = 2.8) achieved a particle size of 31.46 nm with a narrow size range (PDI = 0.110) and a reduced defect rate (42.2 to 6.1%). The optimized nanosuspensions were stable and re-dispersible, and they showed a ~45% increase in cumulative drug release and significant edema reduction in mice. Optimized NDH-4338 nanosuspensions were smaller with more uniform sizes that led to improved physical stability, faster dissolution, and enhanced burn healing efficacy compared to unoptimized nanosuspensions.

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Design of experiments in the optimization of nanoparticle-based drug delivery systems

Cited by 23 publications

References 80 publications

Co-encapsulation of Quercetin and α-Tocopherol Bioactives in Zein Nanoparticles: Synergistic Interactions, Stability, and Controlled Release

Co-encapsulation of Quercetin and α-Tocopherol Bioactives in Zein Nanoparticles: Synergistic Interactions, Stability, and Controlled Release

Investigations into mRNA Lipid Nanoparticles Shelf-Life Stability under Nonfrozen Conditions

Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns

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