Amine as a bottom-line functionality on DDS surface for efficient endosomal escape and further subcellular targets

Roy, Sayoni Maitra; Barman, Sourav; Basu, Arnab; Ghatak, Tapas; Pore, Subrata K.; Ghosh, Surya K.; Mukherjee, Rupam; Maity, Amit Ranjan

doi:10.1016/j.jddst.2022.103303

Cited by 4 publications

(3 citation statements)

References 54 publications

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“…Tertiary amines have a strong proton absorption capacity in the inner body (pH, 5–6) and lysosomes (pH, 4–5), leading to rapid osmotic expansion and mRNA release [ 22 ]. The high transfection efficiencies of Cp1-4 , Cp1-5 , Cp1-6 and Cp1-7 may be related to this.…”

Section: Resultsmentioning

confidence: 99%

Ionizable Lipids with Triazole Moiety from Click Reaction for LNP-Based mRNA Delivery

et al. 2023

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Ionizable lipid-containing lipid nanoparticles (LNPs) as a non-viral vector with good safety and potency have been considered as an ideal delivery system for gene therapy. The screening of ionizable lipid libraries with common features but diverse structures holds the promise of finding new candidates for LNPs to deliver different nucleic acid drugs such as messenger RNAs (mRNAs). Chemical strategies for the facile construction of ionizable lipid libraries with diverse structure are in high demand. Here, we report on the ionizable lipids containing the triazole moiety prepared by the copper-catalyzed alkyne–azide click reaction (CuAAC). We demonstrated that these lipids served well as the major component of LNPs, in order to encapsulate mRNA using luciferase mRNA as the model system. Thus, this study shows the potential of click chemistry in the preparation of lipid libraries for LNP assembly and mRNA delivery.

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Section: Resultsmentioning

confidence: 99%

Ionizable Lipids with Triazole Moiety from Click Reaction for LNP-Based mRNA Delivery

et al. 2023

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“…There are three common approaches to overcome this issue. In the first approach, nanoparticle surface chemistry is designed for endosomal escape. − In this case, the nanoparticle surface is functionalized with primary/secondary/tertiary amines, which offers a proton-sponge effect so that the endosome will swell followed by the release of the nanoparticle. − In some cases nanoparticles are designed in such a way that its chemical changes inside the endosomal compartment can lead to endosomal escape . The second approach involves liposome-based direct cell translocation via cell membrane fusion. − In these processes, liposome interacts with the cell membrane and opens a temporary pore for the drug release.…”

Section: Introductionmentioning

confidence: 99%

Direct Membrane Penetration and Cytosolic Delivery of Nanoparticles via Electrostatically Bound Amphiphiles

Ray,

Pal,

Das

et al. 2024

ACS Appl. Mater. Interfaces

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Nanoparticles usually enter cells through energy-dependent endocytosis that involves their cytosolic entry via biomembrane-coated endosomes. In contrast, direct translocation of nanoparticles with straight access to cytosol/subcellular components without any membrane coating is limited to very selective conditions/approaches. Here we show that nanoparticles can switch from energy-dependent endocytosis to energy-independent direct membrane penetration once an amphiphile is electrostatically bound to their surface. Compared to endocytotic uptake, this direct cell translocation is faster and nanoparticles are distributed inside the cytosol without any lysosomal trafficking. We found that this direct cell translocation option is sensitive to the charges of both the nanoparticles and the amphiphile. We propose that an electrostatically bound amphiphile induces temporary opening of the cell membrane, which allows direct cell translocation of nanoparticles. This approach can be adapted for efficient subcellular targeting of nanoparticles and nanoparticle-based drug delivery application, bypassing the endosomal trapping and lysosomal degradation.

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“…Targeted delivery of DDSs occurs via three-tier distribution levels to reach its intended site of action, involving specific tissue, individual cells, and finally, intracellular organelles to exhibit their pharmacological activities following a particular mechanism of action. – Fascinatingly, the nucleus has gained significant interest as the primary organelle for tumor-targeted drug delivery. , The nucleus serves as the control center of eukaryotic cells, which stores and replicates genetic material, modulates transcription and ribosome assembly, and controls protein synthesis. To achieve efficient therapeutic efficacy, the anticancer drugs must successfully permeate the target cell via the cell membrane and reach the nucleus, thereby enhancing the effectiveness and efficacy of drug treatment. – Various anticancer drugs engage with nuclear DNA and related enzymes, inhibiting DNA replication and inducing cell death.…”

Section: Introductionmentioning

confidence: 99%

Acidic pH-Triggered Release of Doxorubicin from Ligand-Decorated Polymeric Micelles Potentiates Efficacy against Cancer Cells

Maitra Roy,

Barman,

Kishore

et al. 2023

ACS Appl. Nano Mater.

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Current chemotherapeutic strategies against various intractable cancers are futile due to inefficient delivery, poor bioavailability, and inadequate accumulation of anticancer drugs in the diseased site with toxicity caused to the healthy neighboring cells. Drug delivery systems aiming to deliver effective therapeutic concentrations to the site of action have emerged as a promising approach to address the above-mentioned issues. Thus, as several receptors have been identified as being overexpressed on cancer cells including folate receptor (FR), where up to 100–300 times higher overexpression is shown in cancer cells compared to healthy cells, approximately 1–10 million receptor copies per cancer cell can be targeted by a folic acid (FA) ligand. Herein, we developed FA-decorated and doxorubicin-conjugated polymeric micelles of 30 nm size. The hydrophilic block comprises poly(ethylene glycol) units, and the hydrophobic block contains doxorubicin conjugated aspartic acid units. Decoration of FA on the micelle surface induces ligand–receptor interaction, resulting in enhanced internalization into the cancer cell and inside the endolysosomal compartment. Under acidic pH, the micelle structure is disrupted and the hydrazone bond is cleaved, which covalently binds the doxorubicin with the hydrophobic backbone of the polymer and release the drug. We observed that the cellular uptake and nuclear colocalization of the targeted micelle are 2–4 fold higher than the control micelle at various incubation times in FR-overexpressed various cancer cell lines (KB, HeLa, and C6). These results indicate significant prospects for anticancer therapy as an effective and translational treatment strategy.

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Amine as a bottom-line functionality on DDS surface for efficient endosomal escape and further subcellular targets

Cited by 4 publications

References 54 publications

Ionizable Lipids with Triazole Moiety from Click Reaction for LNP-Based mRNA Delivery

Ionizable Lipids with Triazole Moiety from Click Reaction for LNP-Based mRNA Delivery

Direct Membrane Penetration and Cytosolic Delivery of Nanoparticles via Electrostatically Bound Amphiphiles

Acidic pH-Triggered Release of Doxorubicin from Ligand-Decorated Polymeric Micelles Potentiates Efficacy against Cancer Cells

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