The Extent to Which Lipid Nanoparticles Require Apolipoprotein E and Low-Density Lipoprotein Receptor for Delivery Changes with Ionizable Lipid Structure

Paunovska, Kalina; Sanchez, Alejandro J. Da Silva; Lokugamage, Melissa P.; Loughrey, David; Echeverri, Elisa Schrader; Cristian, Ana; Hatit, Marine Z. C.; Santangelo, Philip J.; Zhao, Kun; Dahlman, James E.

doi:10.1021/acs.nanolett.2c03741

Cited by 27 publications

(13 citation statements)

References 45 publications

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“…This result is corroborated by recent findings that some lipid nanoparticles can be endocytosed by mechanisms that are independent of classical lipoprotein trafficking pathways. [ 48 ]…”

Section: Resultsmentioning

confidence: 99%

Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption

et al. 2023

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Colloidal drug aggregates enable the design of drug‐rich nanoparticles; however, the efficacy of stabilized colloidal drug aggregates is limited by entrapment in the endo‐lysosomal pathway. Although ionizable drugs are used to elicit lysosomal escape, this approach is hindered by toxicity associated with phospholipidosis. It is hypothesized that tuning the pKa of the drug would enable endosomal disruption while avoiding phospholipidosis and minimizing toxicity. To test this idea, 12 analogs of the nonionizable colloidal drug fulvestrant are synthesized with ionizable groups to enable pH‐dependent endosomal disruption while maintaining bioactivity. Lipid‐stabilized fulvestrant analog colloids are endocytosed by cancer cells, and the pKa of these ionizable colloids influenced the mechanism of endosomal and lysosomal disruption. Four fulvestrant analogs—those with pKa values between 5.1 and 5.7—disrupted endo‐lysosomes without measurable phospholipidosis. Thus, by manipulating the pKa of colloid‐forming drugs, a tunable and generalizable strategy for endosomal disruption is established.

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“…This result is corroborated by recent findings that some lipid nanoparticles can be endocytosed by mechanisms that are independent of classical lipoprotein trafficking pathways. [ 48 ]…”

Section: Resultsmentioning

confidence: 99%

Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption

et al. 2023

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“…DNA sequences have been widely used as barcodes for high-through screening in various biological scenarios, such as single-cell sequencing, drug formulation screening, drug target screening, proteomic analysis, and cancer research. − In addition, DNA barcodes have also been used for the high-throughput screening of functionalized lipids for nanomedicines and vaccines, − lipid formulations for bone marrow disease and endothelial gene editing, , and nanoparticle vehicles for enhanced delivery …”

Section: Dna Barcodementioning

confidence: 99%

Digital Barcodes for High-Throughput Screening

Yang,

Chen,

Xiao

et al. 2024

Chem Bio Eng.

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High-throughput screening is an indispensable technology in drug discovery, cancer therapy, and disease diagnosis, and it could greatly reduce time cost, reagent consumption, and labor expense. Here, four high-throughput screening methods with high sensitivity and accessibility are discussed in detail. Fluorescence, DNA, heavy metal, and nonmetal isotope barcodes, which generally label antibodies, proteins, and saccharides to identify cells, are detected by flow cytometry, second-generation DNA sequencing, mass cytometry, and second-ion mass spectrometry, respectively. Encoding binary information in barcodes, labeling individual cells by barcodes, performing the characterization of cells together, and identifying the result belonging to individual cells via barcodes are the main steps for high-throughput screening. Applications of the four digital barcodes in high-throughput screening for both in vitro and in vivo tests are described in detail, and their advantages and disadvantages are also summarized. High-throughput screening has provided a powerful platform widely accessible for multidisciplinary studies and has greatly sped up the progress of drug discovery, disease diagnosis, and cancer therapy.

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“…LNP delivery systems target hepatocytes through ApoE, which interacts to the low-density lipoprotein receptor (LDLR) expressed on hepatocytes. 113…”

Section: Hepatic-targeted Delivery and Therapymentioning

confidence: 99%