Improved nanoformulation and bio-functionalization of linear-dendritic block copolymers with biocompatible ionic liquids

Christine M. Hamadani, Indika Chandrasiri, Mahesh Loku Yaddehige, Gaya S. Dasanayake, Iyanuoluwani Owolabi, Alex Flynt, Mehjabeen Hossain, Lucy Liberman, Timothy P. Lodge, Thomas A. Werfel, Davita L. Watkins, Eden E. L. Tanner

Research output: Contribution to journalArticlepeer-review

Abstract

Linear-dendritic block copolymers (LDBCs) have emerged as promising materials for drug delivery applications, with their hybrid structure exploiting advantageous properties of both linear and dendritic polymers. LDBCs have promising encapsulation efficiencies that can be used to encapsulate both hydrophobic and hydrophilic dyes for bioimaging, cancer therapeutics, and small biomolecules. Additionally, LDBCS can be readily functionalized with varying terminal groups for more efficient targeted delivery. However, depending on structural composition and surface properties, LDBCs also exhibit high dispersities (Đ), poor shelf-life, and potentially high cytotoxicity to non-target interfacing blood cells during intravenous drug delivery. Here, we show that choline carboxylic acid-based ionic liquids (ILs) electrostatically solvate LDBCs by direct dissolution and form stable and biocompatible IL-integrated LDBC nano-assemblies. These nano-assemblies are endowed with red blood cell-hitchhiking capabilities and show altered cellular uptake behavior ex vivo. When modified with choline and trans-2-hexenoic acid, IL-LDBC dispersity dropped by half compared to bare LDBCs, and showed a significant shift of the cationic surface charge towards neutrality. Proton nuclear magnetic resonance spectroscopy evidenced twice the total amount of IL on the LDBCs relative to an established IL-linear PLGA platform. Transmission electron microscopy suggested the formation of a nanoparticle surface coating, which acted as a protective agent against RBC hemolysis, reducing hemolysis from 73% (LDBC) to 25% (IL-LDBC). However, dramatically different uptake behavior of IL-LDBCs vs. IL-PLGA NPs in RAW 264.7 macrophage cells suggests a different conformational IL-NP surface assembly on the linear versus the linear-dendritic nanoparticles. These results suggest that by controlling the physical chemistry of polymer-IL interactions and assembly on the nanoscale, biological function can be tailored toward the development of more effective and more precisely targeted therapies.

Original languageEnglish (US)
Pages (from-to)6021-6036
Number of pages16
JournalNanoscale
Volume14
Issue number16
DOIs
StatePublished - Apr 1 2022

Bibliographical note

Funding Information:
This work was supported by the College of Liberal Arts at the University of Mississippi, and the Sigma Xi Honor Society Student GIAR program. Cryo-TEM was carried out in the Characterization Facility, University of Minnesota using support from the Materials Research Facilities Network from the NSF through the MRSEC (Award Number DMR-2011401); the facility also receives support from the NSF through the NNCI (Award Number ECCS-2025124).

Publisher Copyright:
© 2022 The Royal Society of Chemistry.

How much support was provided by MRSEC?

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PubMed: MeSH publication types

  • Journal Article

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