Dataset Information

Combinatorial Library of Cyclic Benzylidene Acetal-Containing pH-Responsive Lipidoid Nanoparticles for Intracellular mRNA Delivery.

ABSTRACT: Lipidoid nanoparticles have been demonstrated to be effective for intracellular delivery of small molecule drugs, proteins, and nucleic acids. Stimuli-responsive lipidoid nanoparticles are able to further improve delivery efficacy and reduce carrier-induced toxicity. Our group previously developed reduction and photoresponsive combinatorial libraries of lipidoid nanoparticles for small molecule and biologics delivery. Herein, we describe the synthesis, characterization, and intracellular mRNA delivery application of a new library of pH-responsive lipidoid nanoparticles. The acid-degradable cyclic benzylidene acetal-containing cationic lipidoids (R-O16CBA) were synthesized through a multistep reaction and characterized by NMR and MS. The acid-triggered degradation of lipidoids was studied using NMR, MS, DLS, and TEM. The results revealed that the R-O16CBA lipidoid can be completely degraded at pH 5. The R-O16CBA lipidoid nanoparticles were then fabricated with different formulations of DOPE and cholesterol and tested in vitro for intracellular mRNA delivery.

SUBMITTER: Li Y

PROVIDER: S-EPMC9069324 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Combinatorial Library of Cyclic Benzylidene Acetal-Containing pH-Responsive Lipidoid Nanoparticles for Intracellular mRNA Delivery.

Li Yamin Y Li Raissa R Chakraborty Anirban A Ogurlu Roza R Zhao Xuewei X Chen Jinjin J Xu Qiaobing Q

Bioconjugate chemistry 20200624 7

Lipidoid nanoparticles have been demonstrated to be effective for intracellular delivery of small molecule drugs, proteins, and nucleic acids. Stimuli-responsive lipidoid nanoparticles are able to further improve delivery efficacy and reduce carrier-induced toxicity. Our group previously developed reduction and photoresponsive combinatorial libraries of lipidoid nanoparticles for small molecule and biologics delivery. Herein, we describe the synthesis, characterization, and intracellular mRNA de ...[more]

PMID: 32520527

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Project description:We previously developed a pH-responsive copper-doxorubicin (CuDox) cargo in lysolipid-based temperature-sensitive liposomes (LTSLs). The CuDox complex is released from the particle by elevated temperature; however, full release of doxorubicin from CuDox requires a reduced pH, such as that expected in lysosomes. The primary goal of this study is to evaluate the cellular uptake and intracellular trafficking of the drug-metal complex in comparison with intact liposomes and free drug. We found that the CuDox complex was efficiently internalized by mammary carcinoma cells after release from LTSLs. Intracellular doxorubicin and copper were 6-fold and 5-fold greater, respectively, after a 0.5h incubation with the released CuDox complex, as compared to incubation with intact liposomes containing the complex. Total cellular doxorubicin fluorescence was similar following CuDox and free doxorubicin incubation. Imaging and mass spectrometry assays indicated that the CuDox complex was initially internalized intact but breaks down over time within cells, with intracellular copper decreasing more rapidly than intracellular doxorubicin. Doxorubicin fluorescence was reduced when complexed with copper, and nuclear fluorescence was reduced when cells were incubated with the CuDox complex as compared with free doxorubicin. Therapeutic efficacy, which typically results from intercalation of doxorubicin with DNA, was equivalent for the CuDox complex and free doxorubicin and was superior to that of liposomal doxorubicin formulations. Taken together, the results suggest that quenched CuDox reaches the nucleus and remains efficacious. In order to design protocols for the use of these temperature-sensitive particles in cancer treatment, the timing of hyperthermia relative to drug administration must be examined. When cells were heated to 42°C prior to the addition of free doxorubicin, nuclear drug accumulation increased by 1.8-fold in cancer cells after 5h, and cytotoxicity increased 1.4-fold in both cancer and endothelial cells. Endothelial cytotoxicity was similarly augmented with mild hyperthermia applied prior to treatment with released CuDox. In summary, we find that the drug-metal complex formed in temperature-sensitive particles can be internalized by cancer and endothelial cells resulting in therapeutic efficacy that is similar to free doxorubicin, and this efficacy can be enhanced by elevated temperature.

Dataset Information

Combinatorial Library of Cyclic Benzylidene Acetal-Containing pH-Responsive Lipidoid Nanoparticles for Intracellular mRNA Delivery.

Publications

Combinatorial Library of Cyclic Benzylidene Acetal-Containing pH-Responsive Lipidoid Nanoparticles for Intracellular mRNA Delivery.

Similar Datasets

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