Identification and optimization of tunable endosomal escape parameters for enhanced efficacy in peptide-targeted prodrug-loaded nanoparticles
Endosomal escape of nanoparticles (NPs) is a weighty consideration for engineering successful nanomedicines. Although it is well-established that incorporation of histidine (His) in particle design improves endosomal escape for NPs, our understanding of its effects for ligand-targeted nanoparticles (TNPs) remains incomplete. Here, we systematically evaluated the cooperativity between targeting ligands and endosomolytic elements using liposomal TNPs with precise stoichiometric control over functional moieties (>90% loading efficiency). We synthesized endosomolytic lipid conjugates consisting of 1 to 10 consecutive His residues presented at the end of linkers between 2 to 45 repeating units of ethylene glycol (Hisn-EGm). Hisn-EGm had minimal effect on NP size (∼115 nm) and had no significant effect on the receptor specificity of TNPs (>90% inhibition by competing peptide). We evaluated various formulations with 8 different targeting ligands relevant to two disease models. Incorporation of His1-EG8 resulted in up to ∼170- and ∼12.9-fold enhancement in intracellular accumulation relative to non-endosomolytic NP and TNP, respectively. These observations were time-dependent, targeted receptor-dependent, and showed different trends for NPs and TNPs. Further evaluation demonstrated short linkers (EG2-4) significantly enhanced nanoparticle internalization compared to EG8 or longer by up to ∼2.5-fold. Finally, rationally optimized formulation, His1-EG2-TNP, improved in vitro toxicity of a DM1 prodrug to SK-BR-3 cells by ∼4.2-fold, with IC50 ∼8.5 nM compared to ∼36 nM for no-His TNP, and >100 nM for non-targeted/no-His NP. This study uncovers an intricate relationship between endosomal escape and ligand-targeted drug delivery, as well as tunable parameters. Furthermore, our findings highlight the value of rational design and systematic analysis for optimization of multifunctional NPs.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nanoscale - 14(2022), 4 vom: 27. Jan., Seite 1226-1240 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mejia, Franklin [VerfasserIn] |
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| Anmerkungen: |
Date Completed 31.01.2022 Date Revised 31.01.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1039/d1nr05357d |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM335288650 |
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| 520 | |a Endosomal escape of nanoparticles (NPs) is a weighty consideration for engineering successful nanomedicines. Although it is well-established that incorporation of histidine (His) in particle design improves endosomal escape for NPs, our understanding of its effects for ligand-targeted nanoparticles (TNPs) remains incomplete. Here, we systematically evaluated the cooperativity between targeting ligands and endosomolytic elements using liposomal TNPs with precise stoichiometric control over functional moieties (>90% loading efficiency). We synthesized endosomolytic lipid conjugates consisting of 1 to 10 consecutive His residues presented at the end of linkers between 2 to 45 repeating units of ethylene glycol (Hisn-EGm). Hisn-EGm had minimal effect on NP size (∼115 nm) and had no significant effect on the receptor specificity of TNPs (>90% inhibition by competing peptide). We evaluated various formulations with 8 different targeting ligands relevant to two disease models. Incorporation of His1-EG8 resulted in up to ∼170- and ∼12.9-fold enhancement in intracellular accumulation relative to non-endosomolytic NP and TNP, respectively. These observations were time-dependent, targeted receptor-dependent, and showed different trends for NPs and TNPs. Further evaluation demonstrated short linkers (EG2-4) significantly enhanced nanoparticle internalization compared to EG8 or longer by up to ∼2.5-fold. Finally, rationally optimized formulation, His1-EG2-TNP, improved in vitro toxicity of a DM1 prodrug to SK-BR-3 cells by ∼4.2-fold, with IC50 ∼8.5 nM compared to ∼36 nM for no-His TNP, and >100 nM for non-targeted/no-His NP. This study uncovers an intricate relationship between endosomal escape and ligand-targeted drug delivery, as well as tunable parameters. Furthermore, our findings highlight the value of rational design and systematic analysis for optimization of multifunctional NPs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Prodrugs |2 NLM | |
| 700 | 1 | |a Khan, Sabrina |e verfasserin |4 aut | |
| 700 | 1 | |a Omstead, David T |e verfasserin |4 aut | |
| 700 | 1 | |a Minetos, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Bilgicer, Basar |e verfasserin |4 aut | |
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